The Australian Short Course on Intensive Care Medicine
The Australian Short Course on Intensive Care Medicine 2005 Handbook The Australian Short Course on Intensive Care Medicine 2005 Handbook Editor L.I.G. Worthley Published in 2005 by The Australasian Academy of Critical Care Medicine “Ulimaroa” 630 St Kilda Rd, Melbourne, Victoria 3004 ISSN 1327-4759 2005 The Australasian Academy of Critical Care Medicine Requests to reproduce original material should be addressed to the publisher. Printed by Gillingham Printers Pty Ltd 153 Holbrooks Road Underdale South Australia 5032 CONTENTS Page Chapter 1. Red blood cell production and haemoglobin function 1 Chapter 2. Anaemias and polycythaemias 17 Chapter 3. Haemostasis, platelet function and coagulation 35 Trainee Presentations 65 Index 135 iii iv 2005 SHORT COURSE PROGRAMME April 12th FMC Travel to FMC Interactive April 13th RAH April 14th RAH 0900 April 11th FMC Travel to FMC Lecture Lecture OSCE Presentations Introduction Vivas 1015 Introduction to the critically ill patient L W. Interactive L. W Interactive R.Y Clinical cases OSCE Biochemistry ECG’s Vivas Vivas L.W. Interactive L.W Interactive Clinical Cases Clinical cases OSCE Clinical Vignettes L.W. Biochemistry Vivas Vivas B.V Lunch Clinical Cases Lecture Interactive OSCE Hepatic Failure Interpretation of CXR and CT head C.J Lecture Adrenocortical function in the critically ill B.V Interactive Vivas 0815 1130 1245 1400 Review 1515 A.H. Lecture 1630 Acute respiratory failure syndrome AB Lecture Presentations 1745 L.W Travel To RAH FMC = Flinders Medical Centre Dinner at: Biochemistry, bacteriology C.J. Travel to RAH R.Y. OSCE Vivas Dinner RAH = Royal Adelaide Hospital 19:00 hr, Wednesday 13th April 2005 Old Lion Hotel 161 Melbourne St, Adelaide v REGISTRANTS Code Name Institution *† 1. Dr. B. Cheung Intensive Care Unit, Ipswich Hospital, Queensland *† 2. Dr. J. Lewis Intensive Care Unit, Royal Perth Hospital, WA *† 3. Dr. D. Moxon Intensive Care Unit, Royal Perth Hospital, WA *† 4. Dr. M. Ibrahim Intensive Care Unit, The Austin Hospital, Victoria *† 5. Dr. M. Reade Intensive Care Unit, The Austin Hospital, Victoria *† 6. Dr. T. Corcoran Intensive Care Unit, Royal Perth Hospital, WA *† 7. Dr. S. Simpson Intensive Care Unit, Women’s and Children’s Hospital, SA *† 8. Dr. T. Fraser Intensive Care Unit, The Geelong Hospital, Victoria *† 9. Dr. A. Holley Intensive Care Unit, Royal Brisbane Hospital, Queensland *†10. Dr. M. Heaney Intensive Care Unit, Royal Perth Hospital, WA *†11. Dr. R. Rai Intensive Care Unit, Royal Adelaide Hospital, SA *†12. Dr. M. Sanap Intensive Care Unit, Flinders Medical Centre, SA *†13. Dr. P. Rangappa Intensive Care Unit, Queen Elizabeth Hospital, SA *†14. Dr. W. M. G. Kwan Intensive Care Unit, Queen Elizabeth Hospital, Hong Kong *†15. Dr. H. Ramaswamykanive Intensive Care Unit, Concord Hospital, NSW †16. Dr. H. Tewari Intensive Care Unit, Queen Elizabeth Hospital, SA *‡17. Dr. R. Ramadoss Department of Critical Care Medicine, FMC, SA *‡18. Dr. S. Verghese Department of Critical Care Medicine, FMC, SA *‡19. Dr. D. Gardiner ICU, Princess Alexandria Hospital, Queensland *‡20. Dr. G. Ding Intensive Care Unit, The Canberra Hospital, ACT * 21. Dr. J. Bellapart Intensive Care Unit, Royal Brisbane Hospital, Queensland * 22. Dr. V. Hamilton Intensive Care Unit, Royal Adelaide Hospital, SA * 23. Dr. S. Sane Department of Critical Care Medicine, FMC, SA * 24. Dr. M. Davey Intensive Care Unit, The Canberra Hospital, ACT * 25. Dr. S. Senthuran Intensive Care Unit, Royal Brisbane Hospital, Queensland * 26. Dr. D. Rigg Intensive Care Unit, The Canberra Hospital, ACT * 27. Dr. W-P. Chan Intensive Care Unit, The John Hunter Hospital, NSW * 28. Dr. A. MacCormick Intensive Care Unit, Royal Melbourne Hospital, Victoria * 29. Dr. L. Min Intensive Care Unit, Flinders Medical Centre, SA * 30. Dr. W. Newman Intensive Care Unit, Mackay Base Hospital, Queensland * 31. Dr. P. Dubey Intensive Care Unit, Mater Hospital, Queensland * 32. Dr. A. Enslin Intensive Care Unit, Canberra Hospital, ACT FACULTY FMC RAH GUESTS Dr. L. Worthley (L.W) Dr. R. Young (R.Y) Dr. B. Venkatesh (J.C) Dr. A. Bersten (A.B) Dr. M. White (M.W) Dr. P. Morley (P.M) Dr. A. Holt (A.H) Dr. N. Edwards (N.E) Dr. C. Joyce (C.J) Dr. M. Chapman (M.C) Dr. J. Morgan (J.M) ACH Dr. P. Sharley (P.S) Dr. N. Matthews (N.M) Dr. D. Evans (D.E) Dr. S. Keeley (S.K) Dr. A. Flabouris (A.F) Dr. A. Slater (A.S) Dr. T. Brownridge (D.C) Dr. S. Peake (S.P) *† = registrants for both sessions * = registrants for Interactive sessions at the FMC † = active registrants for Exam oriented sessions at the RAH ‡ = observer registrants for Exam oriented sessions at the RAH vi PREFACE A working knowledge of the basic sciences of anatomy, physiology and pharmacology is the basis for the understanding and management of the critically ill patient. This year the Australian Short Course on Intensive Care Medicine handbook has included a review of the basic sciences of the haemopoietic system with chapters on red blood cell production, haemoglobin function, anaemias and polycythaemias. I have also included a chapter on haemostasis, platelet function and coagulation. As with the previous editions, the course registrants presentations (or those that have been submitted on time) have also been included. This handbook still remains the working document of the Australian Short Course on Intensive Care Medicine and is designed to supplement the course. During the sessions, you may find it useful to mark and note the text to facilitate your recall and review of the course at a later date. Along with the previous editions I trust that you will also find this edition useful. Dr. L.I.G. Worthley Adelaide, April 2005 vii viii Chapter 1 RED BLOOD CELL PRODUCTION and HAEMOGLOBIN FUNCTION RED BLOOD CELL PRODUCTION The red blood cell (RBC) is derived from a bone marrow pluripotent stem cell which has a morphological characteristic of a lymphocyte and is capable of both self-renewal and differentiation to form RBCs, granulocytes, monocytes or platelets. It is a committed erythroid cell when it becomes a proerythroblast. Normally the transition from the proerythroblast to the most mature normoblast involves three or four cell divisions over a 4 day period. During this time, the nucleus becomes smaller and an increasing amount of haemoglobin is produced in the cytoplasm. With the last division, the nucleus is removed from the normoblast forming the reticulocyte, which stays in the bone marrow for 2.5 - 3.0 days. The reticulocyte is then released into the circulation, where it circulates for 24 hr before it loses its mitochondria and ribosomes and assumes the morphological appearance of a mature RBC. Erythropoietin is a glycoprotein with a molecular weight of 30,000 – 36,000, the majority of which is produced by the kidney in response to hypoxia (10 - 15% is produced in the liver).1 It interacts with receptors on the surface of proerythroblasts, inducing them to differentiate into pronormoblasts. The hormone also acts on later red cell precursors, stimulating haemoglobin synthesis. Red cell mass is regulated by renal erythropoietin secretion which is in turn regulated by tissue hypoxia. The RBC is 7.5 µm in diameter and 2 µm thick and each contains about 29 pg of haemoglobin. There is, on average, about 3 x 1013 RBCs and about 900 g of haemoglobin in the circulating blood in an adult man, with about 7.5 g of haemoglobin destroyed and produced daily (one unit of blood contains about 75 g of haemoglobin). The RBC survives in the circulation for an average of 120 days. HAEMOGLOBIN BIOSYNTHESIS Haemoglobin is a protein with an anhydrous molecular weight of 64,458. It is a tetramer composed of two pairs of four possible polypeptide chains designated alpha, beta, gamma and delta, each of which are covalently linked to a haem group. Each chain harbours one haem (consisting of protoporphyrin IX and Fe2+), and each haem molecule may bind reversibly to a molecule of oxygen, with the affinity for oxygen increasing as each haem moiety takes up oxygen. In the RBCs of normal adults, 97% of the haemoglobin is haemoglobin A (or HbA, which consists of two alpha chains of 141 amino acid residues and two beta chains of 146 amino acid residues i.e. alpha2, beta2), the remaining 3% is mainly haemoglobin A2 (HbA2; alpha2, delta2) . Fetal haemoglobin (HbF; alpha2, gamma2) usually accounts for less than 1% of the haemoglobin in the normal adult RBC. Disorders of haemoglobin biosynthesis In disorders of haemoglobin biosynthesis, the production of haemoglobin may be affected in one of three ways: 1 RBC Production and Haemoglobin Function 1. 2. 3. Decreased production of a normal chain (i.e. thalassaemias): these disorders have a recessive inheritance and therefore occur as homozygote (i.e. major) or heterozygote (i.e. minor) forms: a) Alpha thalassaemia is caused by depressed alpha-chain production. b) Beta thalassaemia is caused by depressed beta-chain production, causing an increase in HbF and HbA2 levels. This is the commonest form of thalassaemia. The homozygous form presents as a severe anaemia early in life with hepatosplenomegaly, cardiomyopathy, leg ulcers, gall stones, transfusion haemosiderosis, and expansion of bone marrow to give high cheek bones and enlargement of necks of ribs on the chest X-ray. The heterozygous form may be asymptomatic (i.e. thalassaemia minima) or present with mild anaemia (i.e. thalassaemia minor). Treatment is often with regular blood transfusions or the judicious use of splenectomy and iron chelation therapy;2 although bone marrow transplantation3 and fetal globin synthesis stimulation using azacitidine4 have been used with some success. Production of an abnormal chain (e.g. sickle cell anaemia): this is caused by the substitution of one of the amino acids in the polypeptide chains (e.g. HbS in sickle cell anaemia). In sickle cell anaemia HbS precipitates at low oxygen tensions, causing the cells to sickle and to lead to stasis in small vessels with subsequent microinfarction. Haemolytic crises may be precipitated by infection, exertion or anoxia. The homozygous state is associated with HbS levels of 76 - 100%. The heterozygous state is associated with HbS levels of 22 - 45%, and is asymptomatic although under severe stress some sickling may occur. Persistence of the developmental chain (i.e., fetal haemoglobin) HAEM BIOSYNTHESIS Within the hepatic cell and precursor RBC mitochondria, glycine and succinyl CoA, in the presence of aminolaevulinic acid (ALA) synthase, form alpha-amino-beta-keto-adipic acid. This, in the presence of pyridoxal phosphate, is decarboxylated by the enzyme ALA-synthase (which is under negative feedback by haem) to form delta-ALA. Increased demands for haem are met by increased synthesis of hepatic ALA-synthase. This enzyme may be induced by a large number of drugs that are substrates and inducers of cytochrome P450. During the process of drug metabolism, consumption of haem by cytochrome P450 is greatly increased, which in turn greatly reduces intracellular haem concentration and its effect on ALA synthase, increasing haem synthesis. In the cytosol, the delta-ALA is acted upon by ALA-dehydratase (a zinc-containing enzyme which is inhibited by lead) to form porphobilinogen (PBG). This is acted on by PBGdeaminase to form hydroxymethylbilane which is the precursor of porphyrins. Porphyrins are tetrapyrrole pigments that serve as intermediates in haem biosynthesis (Figure 1.1). Haem is required for haemoglobin, myoglobin and some respiratory enzymes. The synthesis of haem in red cell precursors is closely linked to haemoglobin synthesis. Disorders of haem biosynthesis The porphyrias The porphyrias are a group of disorders characterised by an inherited or acquired enzymatic block in the biosynthesis of the porphyrins (Table 1.1),5 leading to an overproduction of porphyrins and/or their precursors. They are classified as either hepatic or erythropoietic, depending upon whether the defect in porphyrin metabolism is in the liver (without affecting haemoglobin formation) or the bone marrow. Protoporphyria has abnormalities in porphyrin 2 RBC Production and Haemoglobin Function metabolism in both the liver and the bone marrow, therefore it is often classified as an erythrohepatic porphyria. Congenital erythropoietic porphyria has an autosomal recessive inheritance, the remainder are inherited by an autosomal dominance and have a variable clinical expression. Porphyria cutanea tarda is an acquired disorder which is associated with alcoholic cirrhosis, hepatic tumours or exposure to polychlorinated hydrocarbons. Figure 1.1 The biosynthetic pathway of haem ALA ALA PBG Uro P'gen Uro P'gen Synthase dehydratase deaminase cosynthase decarboxylase Glycine (IAP) (EPP) (PCT) + ALA PBG → Hydroxy → Uro P'gen III → Copro P'gen III Succinyl CoA (EPP) methylbilane ↓ Coproporphyrinogen Uroporphyrin I ← Uro P'gen I oxidase (HCP) ↓ Coproporphyrin I ← Copro P'gen I Protoporphyrinogen IX Protoporphyrinogen (VP) oxidase Ferrochelatase Haem ← (EHP) Protoporphyrin IX ALA = delta aminolaevulinic acid, PBG = porphobilinogen. The enzyme defects of the porphyrias are bracketed (IAP = Intermittent acute porphyria, EPP = erythropoietic porphyria, PCT = porphyria cutanea tarda, HCP = Hereditary coproporphyria, VP = variegate porphyria, EHP = erythrohepatic protoporphyria) Clinical features. These usually relate to either skin or neurological abnormalities. The hepatic porphyrias are commonly characterised by the four 'P's' (i.e. abdominal pain, peripheral neuritis, psychosis and purple or ‘port wine’ coloured urine). 1. 2. Skin lesions: congenital erythropoietic porphyria, protoporphyria and porphyria cutanea tarda predominantly have skin lesions with sensitivity of the skin to sunlight with blistering and excessive fragility to mechanical trauma and scarring. If severe, dermal features not unlike scleroderma appear. The skin lesions may also be associated with hirsutism and hyperpigmentation, particularly of the face and hands. Congenital erythropoietic porphyria is also associated with a haemolytic anaemia, splenomegaly and erythrodontia. Neurological lesions: intermittent acute porphyria (IAP), variegate porphyria (VP - which also has the skin lesions) and the rare hereditary coproporphyria (HCP) have neurological lesions which cause intermittent attacks of: a) Nervous system dysfunction with lower motor neurone disorders (e.g. generalised weakness, wrist and foot drop, flaccid quadriparesis, bulbar palsy, absence of deep tendon reflexes), epilepsy, and mental disturbances of confusion, hysteria, depression and psychosis. Neuritic pain in the limbs, back, buttocks and thighs, with areas of paraesthesia and hyperaesthesia may also occur. The neuropathy is often reversible.6 3 RBC Production and Haemoglobin Function Table 1. 1 Characteristics of the Porphyrias Erythropoietic Hepatic Erythro-Hepatic Congenital Intermittent Hereditary Variegate Porphyria Proto erythropoietic Acute copro Porphyria Cutanea porphyria porphyria porphyria porphyria Tarda Enzyme defect PBG deaminase & or Uro P'gen cosynthase Clinical Skin Neuro Incidence +++ 70 cases Onset (yr) 0-2 Biochem Urine PBG & ALA N Uro P +++ Copro P ++ Faeces Copro P + RBC Uro P +++ Copro P ++ Proto P (+) PBG C-P'gen deaminase oxidase P-P'gen oxidase U-P'gen Ferro decarboxylase chelatase +++ 1.5 per 100,000 15-30 +++ 30 cases ++ +++ +++ - +++ - 15-50 40-60 5-15 (+++) ++ N (+++) + ++ (+++) + ++ N +++ + N N (+) N +++ ++ (+) (+) N N N N N N N N N N N N + + +++ PBG = porphobilinogen, ALA = delta aminolaevulinic acid, Uro P = uroporphyrin, Copro P = coproporphyrin, Proto P = protoporphyrin, N = normal, (+) = increased in some patients only, (+++) = increased only during acute attacks b) c) Abdominal pain, constipation, colic and vomiting, which are caused by an autonomic neuropathy. There is no abdominal rigidity and minimal abdominal tenderness, although fever, tachycardia and leucocytosis may be found. Hypertension, postural hypotension and angio-oedema. Although specific enzyme deficiencies are required to produce IAP, HCP and VP, approximately 90% of individuals with a deficiency of one of these enzymes remain biochemically and clinically normal throughout life.7 Development of the disease state depends on factors that increase the activity or concentration of ALA synthase, which catalyses the rate limiting step in hepatic haem biosynthesis. Increased activity of ALA synthase, in combination with the specific enzyme deficiency (porphobilinogen deaminase in IAP, copro-porphyrinogen oxidase in HCP, or protoporphyrinogen oxidase in VP), causes accumulation of the porphyrin precursor ALA and subsequent precursors to haem, and hence induces the acute attack. 4 RBC Production and Haemoglobin Function Investigations. During the acute attack, a rapid classification of the porphyria may be based on the screening of urine for PBG, and faeces and RBCs for excess porphyrins.8 All hepatic porphyrias (apart from porphyria cutanea tarda) are associated with a positive urinary PBG screen. Faeces from patients with porphyria variagata and hereditary coproporphyria, produce a pink luminescent colour under ultraviolet light. The only hepatic porphyria with a negative faecal screen is the acute intermittent type. RBCs from patients with congenital erythropoietic porphyria and protoporphyria produce a pink luminescent colour under ultraviolet light. All relatives of the patient should be screened for the disease, as all porphyrias (apart from congenital erythropoietic porphyria) are transmitted as a mendelian dominant. Treatment. Skin lesions may be treated with skin lotions protecting against ultra violet, skin coverings and avoidance of sunlight. Activated charcoal, to bind porphyrins within the gastrointestinal tract, has been used successfully to reduce the photocutaneous sensitivity in a patient with congenital erythropoietic porphyria.9 The use of beta carotene (30 mg/day)10 is still experimental. However, as many of the clinical features of acute porphyrias are caused by an acute over production of porphyrins, treatment is often aimed at supression of porphyrin production (e.g. supression of delta aminolaevulinic acid synthase). For example, treatment of the acute gastrointestinal or neurological attack due to any of the acute hepatic porphyrias involves: 1. Supportive therapy, correcting fluid and electrolyte abnormalities and folic acid (the latter has been used to activate porphobilinogen deaminase - the enzyme deficient in intermittent acute porphyria - although, clinical benefit with its use has not yet been reported).11 2. Intravenous glucose at 20 g/hr (glucose depresses hepatic ALA-synthase induction thereby decreasing ALA production. The effect is dose-related with increasing amounts of glucose progressively depressing ALA-synthase induction).12 3. Intravenous haematin (to suppress ALA-synthase), 4 mg/kg infused over 10 min every 12 hr for 3 - 6 days.13 Because haematin is unstable and decays with time (with the decay products exhibiting anticoagulant effects of prolongation of APTT, INR and thrombocytopenia),14 it needs to be lyophilised, sealed under a vacuum and stored at 4ºC and, when reconstructed, used immediately, as it has a half-life of only 4 hr.15 Rarely, when tolerance to haematin occurs, coadministration of an inhibitor of haem oxygenase (e.g. tin protoporphyrin or zinc mesoporphyrin) to inhibit haem catabolism, is required.16 4. Use only ‘safe’ drugs for pain relief and sedation or drugs that do not induce cytochrome P450 and thereby induce ALA synthase (Table 1.2).14,17,18,19 Complete lists of potentially safe and unsafe drugs are available at http://www.porphyria-europe.com and http://www.uct.ac.za/ depts/porphyria. One report documented a patient with severe and incapacitating acute intermittent porphyria being cured with an orthotopic liver transplant.20 Altered Haem Methaemoglobinaemia21,22 Methaemoglobin arises when the haem moiety of the haemoglobin molecule is oxidised from the ferrous to the ferric state. The altered haem is unable to bind oxygen and therefore is inactive, becoming fully active only if the iron is reduced from ferric to ferrous. When one or more of the iron molecules in the haemoglobin tetramer is in a ferric state, the other nonaffected haem moieties have an increased affinity for oxygen (i.e. the curve is shifted to the left). 5 RBC Production and Haemoglobin Function Table 1.2 Drugs in acute hepatic porphyria Drugs that may precipitate Drugs that do not precipitate or exacerbate an attack or exacerbate an attack Drugs used in Anaesthetic practice Halothane Bupivacaine Enflurane Succinylcholine Methoxyflurane Nitrous oxide Barbiturates Atropine Hyoscine Morphine Ketamine Pethidine Lignocaine Salicylates Pancuronium Tubocurarine Propanidid Phenoperidine Propofol Fentanyl Cardiovascular agents Spironolactone Digoxin Frusemide Diazoxide Aminophylline Thiazides Hydralazine Propranolol Minoxidil Atenolol Methyl-dopa Adrenaline Sedatives tranquillisers Diazepam Chlorpromazine Nitrazepam Oxazepam Antidepressants Amitriptyline Anticonvulsants Phenytoin Magnesium sulphate Carbamazepine Clonazepam Antidiabetic Chlorpropamide Insulin Tolbutamide Antibiotics Erythromycin Penicillins Sulphonamides Cephalosporins Metronidazole Aminoglycosides Rifampicin Chloramphenicol Steroids Oestrogens Corticosteroids Progesterones Miscellaneous Metoclopramide Heparin Cimetidine Warfarin Alcohol Aspirin 6 RBC Production and Haemoglobin Function Methaemoglobin formation is normally prevented by two protective mechanisms: 1. Reduced glutathione and ascorbic acid. 2. Enzymatic reduction: two enzymatic systems may be utilised, either a. NADH methaemoglobin reductase which transfers an electron from NADH to haem, using cytochrome b5 as an electron carrier, or b. NADPH methaemoglobin reductase which transfers an electron from NADPH (generated via the pentose phosphate shunt) to haem. In vivo, however, there is no electron carrier for this system and it acts only if an electron carrier (e.g. methylene blue) is present. This mechanism reduces methaemoglobin 10 times more rapidly than the normal NADH methaemoglobin reductase mechanism. Causes. Methaemoglobinaemia may be caused by an inherited abnormality or an acquired disorder (Table 1.3). Table 1. 3 Causes of methaemoglobinaemia Acquired Chemical compounds sodium nitrite, amyl nitrite, ethyl nitrite, ammonium nitrite, silver nitrate, bismuth subnitrate, potassium chlorate, aniline dyes, nitrobenzenes, aminobenzines, nitrotoluenes, phenylenediamine, acetanilid, potassium permanganate Therapeutic agents sulphonamides, glyceryl trinitrate, phenacetin, benzocaine, lignocaine, prilocaine, chloroquine, dapsone Inherited Methaemoglobin reductase deficiency Cytochrome b5 deficiency M Haemoglobins Clinical features. In the absence of cardiovascular disease or severe anaemia, patients with methaemoglobinaemia levels < 20% are usually asymptomatic. The symptoms of dyspnoea, tachycardia, headaches and fatigueability, are commonly present at methaemoglobin levels of 30 - 40% (i.e. 45 - 55 g/L of blood). The lethal level of methaemoglobin is 70 - 80%, a state in which the patient is practically black with cyanosis. Clinically, symptoms usually do not arise unless the methaemoglobin level is greater than 10% (i.e., at 13 - 16 g of methaemoglobin/L of blood).21 Cyanosis is the main feature of this condition, with the impairment in function of the patient less than would be anticipated from the intensity of the cyanosis. Patients who have congenital methaemoglobinaemia are often described as being more blue than sick. Clinical cyanosis appears with 15 g of methaemoglobin/L of blood. Investigations. The investigations include: 1. Methaemoglobin level: normal levels of methaemoglobin are usually 0.2 - 0.5% of the total haemoglobin level, and methaemoglobinaemia is defined as being present when more than 1% of the total haemoglobin is methaemoglobin.21 Methaemoglobin is unique among the haemoglobin derivatives because it changes colour with changing pH. In an acidic environment (i.e. pH < 7.3) it is brown, in an alkaline environment (i.e. pH > 7.4) it is dark red. 7 RBC Production and Haemoglobin Function Methaemoglobin levels in excess of 10% produces a brown discolouration when one drop of blood is soaked into filter paper. 2. Blood gas analysis: This is performed to demonstrate a normal PaO2 in the presence of cyanosis. Treatment. If the patient is suffering no functional impairment, then nothing needs to be done, because normal mechanisms will reduce and correct the methaemoglobinaemia within 24 - 48 hr, provided there is no continuing activity of a toxic compound. In severe cases, intravenous methylene blue 1 - 2 mg/kg over 5 min will correct the cyanosis within 1 hr. However the RBC pentose phosphate pathway needs to be effective. Accordingly, if a patient has glucose 6-phosphate dehydrogenase (GPD) deficiency, methylene blue will be ineffective, furthermore it may initiate a haemolytic episode in GPD deficient individuals, further embarrassing their oxygen carrying capacity.23 Ascorbic acid in high doses and riboflavine (60 -120 mg daily) are effective but have delayed onset of action and are of limited value in an emergency.24 Oxygen therapy does not reverse the defect. If rebound methaemoglobinaemia develops following successful treatment with methylene blue (usually from 1 - 20 hr) then the dose 1 - 2 mg/kg may be repeated,25 although the total dose should not exceed 7 mg/kg due to adverse effects of nausea, vomiting and diarrhoea (excess doses e.g. 15 mg/kg may even increase the methaemoglobinaemia).26 Sulphaemoglobinaemia27 Sulphaemoglobin is a green-pigmented molecule with a sulphur atom incorporated irreversibly into the porphyrin ring and a markedly reduced oxygen affinity. Because the remaining unsulphurated haems have a decreased affinity for oxygen, the curve is shifted to the right. For this reason dyspnoea is absent unless the level of sulphaemoglobin is extraordinarily high. As the altered haems in sulphaemoglobin (like methaemoglobin) do not transport oxygen, the effected individuals suffer the effects of an anaemia. Cause. Hydrogen sulphide, sulphonamides, phenacetin and dapsone may produce sulphaemoglobinaemia. Sulphaemoglobin may be mixed with methaemoglobin in sulphonamide toxicity. Clinical features. These patients may be profoundly cyanosed with minimal dyspnoea. This is because cyanosis is detected at a blood sulphaemoglobin level of 5 g/L, and the rightward shift of the dissociation curve causes the normal haemoglobin to be desaturated at high PaO2 levels. Treatment. The abnormality remains with the RBC for its life span. Thus the main therapy is to remove the cause. If severe sulphaemoglobinaemia exists, then an exchange transfusion may be required. HAEMOGLOBIN FUNCTION When fully saturated, 1 g of haemoglobin A (15.51 µmol) combines with 1.39 mL of oxygen at STPD (i.e. 62.06 µmol of oxygen). The iron in the haem molecule stays in a ferrous state, so that the reaction is an oxygenation, not an oxidation. Haemoglobin-oxygen affinity By shifting the relationship of the 4 component polypeptide chains, HbA promotes either, oxygen uptake by moving the two beta chains closer together, or oxygen delivery by moving the beta chains further apart. This effect is caused by a competitive binding of oxygen and 2,3DPG with haemoglobin; 2,3-DPG binds specifically to deoxyhaemoglobin in the ratio of one molecule of 2,3-DPG per haemoglobin tetramer molecule. It binds to the positively charged 8 RBC Production and Haemoglobin Function residues of both beta chains that face the central cavity of the haemoglobin molecule, reducing the haemoglobin affinity for oxygen. The wider gap between the beta chains in the deoxy state allows entry of the 2,3-DPG to stabilise this state and reduce oxygen affinity of haemoglobin. With oxygenation, the 2,3-DPG is displaced from the haemoglobin molecule. As each haem moiety takes up oxygen, the affinity of haemoglobin for 2,3-DPG is reduced and the affinity of the remaining binding sites for oxygen on the same haemoglobin molecule is progressively increased, providing a sigmoid shape to the oxygen-haemoglobin dissociation curve. An increase in RBC 2,3-DPG lowers the affinity of haemoglobin for oxygen directly as well as indirectly by lowering the RBC pH (Bohr effect). In the absence of 2,3 DPG, the curve would shift to the extreme left, i.e. the P50 of haemoglobin would decrease from its normal value of 26.6 to a value similar to that of myoglobin (i.e. 1 mmHg).28 Fetal haemoglobin (HbF) has two alpha chains and two gamma chains, and as gamma chains have a lower affinity for 2,3-DPG than beta chains, fetal haemoglobin has a leftward curve in comparison to adult haemoglobin (e.g. cord blood has a P50 of 20 mmHg, c.f. adult blood which has a P50 of 26.6 mmHg).29 Factors affecting oxygen affinity of haemoglobin are RBC intracellular, H+ ion activity (i.e. Bohr effect), carbon dioxide tension, Cl- ion concentration, temperature and 2,3-DPG concentration.30,31,32 While all phosphates have an effect on oxygen affinity, only 2,3-DPG and ATP are in sufficient concentrations to exert an effect. The major effect is due to 2,3 DPG, because the molar concentration of ATP is onequarter that of 2,3-DPG and its effect on haemoglobin oxygen affinity is less than that of 2,3DPG.30,33 ,34 The 2,3-DPG also remains inside the RBC as it cannot permeate the normal RBC membrane. Increasing any of the above factors shifts the curve to the right and decreasing any of the above factors shifts the curve to the left. Abnormal haemoglobins have also been described which have either rightward or leftward curve shifts when compared to normal.35 Propranolol also shifts the curve to the right by unknown mechanisms.36 The Bohr effect The immediate decrease in oxygen affinity of haemoglobin when the pH of the blood falls (i.e. shift of the curve to the right) is known as the Bohr effect. While the original Bohr description referred to the immediate effect of carbon dioxide on the oxygen-haemoglobin dissociation curve placement, it was soon realised that the H+ ion concentration was a more important physiological factor (although when carbon dioxide is the acid variable, about 20% of the Bohr effect is due to a carbon dioxide effect independent of pH).37 The Bohr effect is related to the decrease in RBC intracellular pH. The normal RBC-plasma pH gradient is 0.2 (i.e. at a plasma pH of 7.4 the RBC pH is 7.2). The gradient may be reduced in citrate stored blood, and increased in blood of critically ill patients.33 Increasing oxygenation of haemoglobin reduces its affinity for carbon dioxide (Haldane effect), increasing the PCO2 and decreasing the pH (i.e. deoxygenated blood is a better buffer than oxygenated blood). 2,3 Diphosphoglycerate In the red blood cell, 2,3-DPG is produced from 1,3-diphosphoglycerate in the RapoportLuebering shuttle. This shuttle bypasses the ATP-producing phosphoglycerate kinase step of the Embden Myerhof pathway, and so the pathways compete for 1,3-diphosphoglycerate, producing either ATP or 2,3 DPG. Normally 20% of the 1,3-diphosphoglycerate is metabolised through the Rapoport-Luebering shuttle, although with an increase in the ADP:ATP ratio, ATP may be increased by increasing the amount of substrate metabolised through the phosphoglycerate kinase step, at the expense of 2,3 DPG.29 A decrease in RBC pH reduces the 9 RBC Production and Haemoglobin Function 2,3 DPG levels by inhibiting phosphofructokinase (i.e. reducing glycolysis) and inhibiting 2,3DPG mutase and increasing 2,3-DPG phosphatase activity (i.e. decreasing synthesis and increasing metabolism of 2,3-DPG, respectively), reducing the P50 and shifting the oxygenhaemoglobin dissociation curve to the left.38 This is opposite to the effect of an acute reduction in pH (i.e. Bohr effect) which shifts the curve to the right. As P50 is measured under standard conditions of pH and PCO2, the effect of a chronic acidosis is to reduce the P50.29 The Bohr effect occurs immediately, whereas the pH effect on 2,3 DPG may take up to 12 - 24 hr, acting in vivo to normalise the position of the oxygen-haemoglobin dissociation curve. Intracellular pH has the strongest control over 2,3-DPG synthesis.39 The increase in 2,3DPG associated with elevation of normal subjects to high altitudes is due to hyperventilation and respiratory alkalosis, as the 2,3 DPG levels do not alter in spite of hypoxia if the associated pH changes are inhibited by acetazolamide.40 The 2,3-DPG levels are influenced by many factors, being reduced in chronic acidosis and hypophosphataemia, and increased in chronic hypoxia, alkalosis, anaemia (detectable at Hb 100 g/L or less), and treatment with cortisol, aldosterone, androgens, triiodothyronine, and inosine. The P50 The P50 is the partial pressure of oxygen of a whole blood sample at which haemoglobin is 50% saturated, at a pH of 7.4, temperature 37º C and carbon monoxide level less than 2%. This is sometimes refered to as the standard P50, with the in vivo P50 being defined as the partial pressure of oxygen, at which haemoglobin is 50% saturated at the pH, PCO2, temperature and carboxyhaemoglobin concentration of the blood in the subject. While the in vivo P50 may reflect the oxygen-haemoglobin affinity better in vivo than the standard P50, the oxygen-haemoglobin dissociation curve is constantly (and rapidly) changing in vivo (and from organ to organ39) in response to PCO2, pH and temperature, so even this (particularly when it is calculated from a peripheral blood sample) has limitations when used to assess organ oxygenation. The P50 (i.e standard P50) is used largely to assess chronic changes in the oxygen-haemoglobin dissociation curve. The P50 is increased if the oxygen-haemoglobin dissociation curve is shifted to the right, and is decreased if the curve is shifted to the left. The P50 can be estimated with an accuracy of + 1 mmHg between saturations of 20% to 90%, from a measurement of blood PO2 and SO2, using a calculation that assumes that the shape of the oxygen-haemoglobin dissociation curve remains constant.41 While the Siggaard-Andersen algorithm improved the accuracy of P50 when calculated from arterial blood with saturations up to 97%,42 in critically ill patients the accuracy has has been found to be suspect when arterial blood with saturations > 92% are used.43 When severe abnormalities of acid-base balance or 2,3-DPG concentrations exist, the shape of the oxygen-haemoglobin dissociation curve is changed significantly,44 and accurate P50 estimations may require construction of the oxygen-haemoglobin dissociation curve. For a normal adult, the P50 is 26.6 mmHg + 2 mmHg. The oxygen-haemoglobin dissociation curve The normal arterial oxygen tension of 90 - 100 mmHg at sea level corresponds to a saturation of approximately 97%. If the PaO2 is decreased by 40% to 60 mmHg, the saturation falls by 6% to 91%. A decrease of the PaO2 by a further 10 mmHg to 50 mmHg produces a further 6% fall in saturation to 85%. With the mixed venous PO2 at 40 mmHg (SO2 75%), a fall of a further 5 mmHg to 35 mmHg the saturation falls by 10% from 75% to 65%. The more precise SO2 values at PO2 values ranging from 10 - 100 mmHg, of the normal oxygenhaemoglobin dissociation curve at pH 7.40 and a temperature of 37ºC, are listed in Table 1.4.45 10 RBC Production and Haemoglobin Function Table 1.4 The PO2 and SO2 values of the normal oxygen-haemoglobin dissociation curve at a pH of 7.4, PCO2 40 mmHg and temp 37ºC PO2 (mmHg) 10 20 30 40 50 60 70 80 90 100 % Saturation 9.58 32.12 57.54 74.69 85.08 90.85 94.06 95.84 96.88 97.49 The oxygen-haemoglobin dissociation curve in disease When oxygen delivery (DO2) is impaired, one of the compensatory mechanisms by which oxygen consumption (VO2) is maintained is a decrease in haemoglobin’s oxygen affinity (i.e. increase in P50)34,46,47, which is largely effected by an increase in RBC 2,3 DPG concentration. While an increase in 2,3-DPG, and thus P50, is often reported in patients with chronic clinical disorders of low cardiac output,46,48 cyanotic congenital heart disease,49 anaemia,50 chronic lung disease,51 thyrotoxicosis33 and cirrhosis,52 both increases and decreases in P50 values have been found in patients with acute illness. In acute myocardial infarction the P50 has been reported to increase, to improve VO2, as DO2 decreases with a decrease in cardiac output.53 The increase in P50 indicating a precarious oxygen transport-requirement balance in peripheral tissues of these patients, which was reflected by a poor outcome, even with adequate DO2 and VO254 values. The P50 has also been used as a marker for evaluating adequacy of tissue oxygenation in patients with cardiopulmonary disease,55 with the severity of tissue hypoxia being reflected by the magnitude of the compensatory increase in P50. On the other hand, in other acute disorders, particularly in association with massive transfusion,56,57 hypophosphataemia29,58,59,60 or shock,61 and in critically ill patients,62 low levels of 2,3 DPG and a reduction in P50 have been reported. The rise in 2,3 DPG that occurs in vivo in transfused stored blood cells has a half-life of 4 8 hr,35 and 18 - 36 hr may elapse before the 2,3-DPG levels are fully restored. Studies in trauma patients receiving massive transfusion of stored blood have shown that the P50 and 2,3-DPG levels may take up to 4 days before they are restored to normal.56 In shock, a reduction in 2,3 DPG may be due to a decrease in RBC pH, which can occur in the presence of a normal plasma pH, due an increase in the plasma-RBC pH gradient33 or an increase in the RBC ADP:ATP ratio, both of which reduce RBC 2,3 DPG levels.62 In some acutely ill patients in whom the P50 and 2,3 DPG values have been measured, low P50 values occurred in the presence normal 2,3-DPG levels,58,63,64 indicating that the increase in haemoglobin affinity for oxygen in critically ill patients is probably multifactorial. Clinical effects of shifts in the oxygen-haemoglobin dissociation curve Acute shift in the oxygen-haemoglobin dissociation curve. This is caused largely by the Bohr effect, and change in temperature: 11 RBC Production and Haemoglobin Function 1. If the curve is shifted to the left, it is easier to load oxygen in the lung at a given partial pressure. On the other hand, the blood would unload less oxygen at a given venous oxygen partial pressure. 2. If the curve is shifted to the right, then there is a greater oxygen delivery at a given venous oxygen partial pressure, but presumably it would be more difficult to load oxygen at the lung, particularly when breathing hypoxic mixtures. In vivo, carbon dioxide and heat are generated in the peripheral tissues, shifting the curve to the right allowing more oxygen to be delivered at the same partial pressure. In the lung the reverse occurs, i.e. unloading of the carbon dioxide and reducing the temperature shifts the curve to the left facilitating oxygen uptake.65 Chronic shift in the oxygen-haemoglobin dissociation curve (i.e. change in P50) 1. Shift to the right (increase in P50): during exercise, subjects with increased P50 values meet metabolic oxygen demands predominantly by increasing the oxygen extraction with only modest increase in cardiac output; on the other hand, if the P50 values are decreased, then at the same oxygen consumption the cardiac output may more than double to meet the oxygen demand.66 Nevertheless, it would seem that oxygen affinity is not commonly a critical parameter in the delivery of oxygen.65 2. Shift to the left (decrease in P50): a decrease in P50 appears not to be harmful to animals breathing low oxygen mixtures. However, if they are exchanged-transfused first to the point of anaemia with blood with low 2,3-DPG, then mortality is increased.33 While studies in hypoxaemic hypoxia have shown that a decrease in P50 improves pulmonary uptake of oxygen and tissue oxygenation when PaO2 is less than 30 - 35 mmHg67 (and therefore may be of value to individuals living at high altitudes), this does not occur if hypoxaemia is due to venous admixture caused by congenital heart disease, in which a rightward shift is still advantageous, even with severe hypoxaemia, because increasing haemoglobin affinity for oxygen does not increase the oxygen content of shunted blood.68 Haemoglobin binding of nitric oxide Haemoglobin scavanges free circulating nitric oxide by binding with high affinity ferrous sites on haem (with an affinity for nitric oxide 8000 times the affinity for oxygen). There is also a binding site on the globin molecule (β93 cystine residue), where nitric oxide binds in the form of S-nitrosothiol (which protects the nitric oxide from being scavanged by the high affinity ferrous sites).69 As haemoglobin binds to oxygen in the lungs, its affinity for Snitrosothiol is increased. As haemoglobin releases oxygen in the periphery, its affinity for Snitrosothiol is reduced, and nitric oxide is released into the tissues. Thus haemoglobin acts as a carrier of nitric oxide, releasing it in areas of hypoxia to cause vasodilation and improvement of blood flow to hypoxic tissues.70 REFERENCES 1. Erslev A. Erythropoietin coming of age. N Engl J Med 1987;316:101-103. 2. Weatherall DJ. The treatment of thalassemia - slow progress and new dilemmas. N Engl J Med 1993;329:877-879. 3. Lucarelli G, Galimberti M, Poichi P, Angelucci E, Baronciani D, Giardini C, Andreani M, Agostinelli F, Albertini F, Clift RA. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med 1993;329:840-844. 4. Lowrey CH, Nienhuis AW. Brief report: treatment with azacitidine of patients with endstage β-thalassemia. N Engl J Med 1993;329:845-848. 12 RBC Production and Haemoglobin Function 5. 6. 7. 8. 9. 10. 11 . 12 . 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. Kauppinen R. Porphyrias. Lancet 2005;365:241-252. Becker DM, Kramer S. The neurological manifestations of porphyria: a review. Medicine 1977;56:411-423. McColl, KE, Wallace AM, Moore MR, et al. Alterations in haem biosynthesis during the human menstrual cycle: Studies in normal subjects and patients with latent and active acute intermittent porphyria. Clin Sci 1982;62:183-191. Pain RW, Phillips PJ, Harley HAJ, Beare JH. A simple screeing strategy for diagnosing the porphyrias. Med J Aust 1979;2:474-477. Pimstone NR, Gandhi SN, Mukerji SK. Therapeutic efficacy of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 1987;316:390-393. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LC, Kass EH. Beta-carotine as a photoprotective agent in erythropoietic protoporphyria. N Engl J Med 1970;282:12311234. Robert TL, Varella L, Meguid MM. Nutrition management of acute porphyria. Nutrition 1994;10:551-555. Doss M, Sixel-Dietrich F, Verspohl F. “Glucose effect” and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatic culture: relationship with human acute hepatic porphyrias J Clin Chem Clin Biochem 1985;23:505-512. Lamon JM, Frykholm BC, Hess RA, Tschudy DP. Hematin therapy for acute porphyria. Medicine 1979;58:252-269. Laiwah ACY, McColl KEL. Management of attacks of acute porphyria. Drugs 1987;34:604-616. Goetsch CA, Bissell DM. Instability of hematin used in the treatment of acute hepatic porphyria. N Engl J Med 1986;315:235-238. Elder GH, Hift RJ, Meissner PN. The acute porphyrias. Lancet 1997;349:1613-1617. Moore MR. International review of drugs in acute porphyria-1980. Int J Biochem 1980;12:1089-1097. Weir PM, Hodkinson BP. Is propofol a safe agent in porphyria? Anaesthesia. 1988;43:1022-1023. Bloomer JR, Bonkovsky HL. The porphyrias. Dis Mon 1989;35:1-54. Soonawalla ZF, Orug T, Badminton MN, Elder GH, Rhodes JM, Bramhall SR, Elias E. Liver transplantation as a cure for acute intermittent porphyria Lancet 204;363:705-706. Betke K. Methaemoglobinaemia. In: Advanced haematology. ed, Huntsman RG, Jenkins GC. Butterworths. London 1974, p56. Mayo W, Robertson B. Intraoperative cyanosis: a case of dapsone-induced methaemoglobinaemia. Can J Anaesth 1987;34:79-82. Rosen PJ, Johnson C, McGehee W, Beutler E. Failure of methylene blue treatment in toxic methemoglobinemia. Ann Intern Med 1971;75:83-86. Karim A, Ahmed S, Siddiqui R, Mattana J. Methemoglobinemia complicating topical lidocaine used during endoscopic procedures. Am J Med 2001;111:150-153. Slaughter MS, Gordon PJ, Roberts JC, Pappas PS. An unusual case of hypoxia from benzocaine-induced methemoglobinemia. Ann Thorac Surg 1999;67:1776-1778. Ward KE, McCarthy MW. Dapsone-induced methemoglobinemia. Ann Pharmacother 1998;32:549-553. Park CM, Nagel RL. Sulphemoglobinaemia. Clinical and molecular aspects. N Engl J Med 1984;310:1579-1584. Strier L. CH 7 Oxygen-transporting proteins: myoglobin and haemoglobin. In: Strier L, ed. Biochemistry, 3rd Ed. New York: WH Freeman and Company, 1988:143-176. 13 RBC Production and Haemoglobin Function 29. Bellingham AJ, Grimes AJ. Red cell 2,3-diphosphoglycerate. Br J Haematol 1973;25:555562. 30. Perutz MF. Hemoglobin structure and respiratory transport. Sci Amer 1978;239:68-86. 31. Harken AH. The surgical significance of the oxyhemoglobin dissociation curve. Surg Gynecol Obstet 1977;144:935-955. 32. Finch CA, Lenfant C. Oxygen transport in man. N Engl J Med 1972;286:407-415. 33. McConn. The oxyhemoglobin dissociation dissociation curve in acute disease. Surg Clin N Amer 1975;55:627-658. 34. Thomas HM III, Lefrak SS, Irwin RS, Fritts HW Jr, Cardwell PRB. The oxyhemoglobin dissociation curve in health and disease. Am J Med 1974;57:331-348. 35. Adamson JW, Finch CA. Hemoglobin function, oxygen affinity, and erythropoietin. Ann Rev Physiol 1975;37:351-369. 36. Schrumpf JD, Sheps DS, Wolfson S, Aronson AL, Cohen LS. Altered hemoglobinoxygen affinity with long-term propranolol therapy in patients with coronary artery disease. Am J Cardiol 1977;40:76-82. 37. Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol 1979;46:599-602. 38. Bellingham AJ, Detter JC, Lenfant C. Regulatory mechanisms of hemoglobin oxygen affinity in acidosis and alkalosis. J Clin Invest 1971;50:700-706. 39. Klocke RA. Oxygen transport and 2,3-diphosphoglycerate (DPG). Chest 1972;62(suppl):79S-85S. 40. Lenfant C, Torrance JD, Raynafarje C. Shift of the O2-Hb dissociation curve at altitude: mechanism and effect. J Appl Physiol 1971;30:625-631. 41. Aberman A, Cavanilles JM, Weil MH, Shubin H. Blood P50 calculated from a single measurment of pH, PO2, and SO2. J Appl Physiol 1975;38:171-176. 42. Siggaard-Andersen O, Siggaard-Andersen M. The oxygen status algorithm: a computer program for calculating and displaying pH and blood gas data. Scand J Clin Lab Invest 1990;50(Suppl 203):29-45. 43. Anstey C. The accuracy of in vivo P50 at high haemoglobin saturation. Anaesth Intensive Care 2000;28:31-36. 44. Morgan TJ, Endre ZH, Kanowski DM, Worthley LIG, Jones DM. Siggaard-Andersen algorithm-derived p50 parameters: perturbation by abnormal hemoglobin-oxygen affinity and acid-base disturbances. J Lab Clin Med 1995;126:365-372. 45. Roughton FJW, Severinghaus. JW. Accurate determination of O2 dissociation curve of human blood above 98.7% saturation with data on O2 solubility in unmodified human blood from 0o to 37o. J Appl Physiol 1973;35:861-869. 46. Metcalfe J, Dhindsa DS, Edward MJ, Mourdjinis A. Decreased affinity of blood for oxygen in patients with low-output heart failure. Circ Res 1969;25:47-51. 47. Woodson RD, Torrance JD, Shappell SD, Lenfant C. The effect of cardiac disease on hemoglobin-oxygen binding. J Clin Invest 1970;49:1349-1356. 48. Woodson RD, Torrance JD, Lenfant C. Oxygen transport in low cardiac output hypoxia. The Physiologist 1969;12:399-410. 49. Oski FA, Gottlieb AJ, Delivoria-Papadopoulos M, Miller W. Red cell 2,3 diphosphoglycerate levels in subjects with chronic hypoxaemia. N Engl J Med 1969;280:1165-1166. 50. Torrance J, Jacobs P, Restrepo A. Intra erythrocytic adaption to anemia. N Engl J Med 1970;283:165-169. 14 RBC Production and Haemoglobin Function 51. Lenfant C, Ways P, Aucutt C. Effect of chronic hypoxic hypoxia on the 02-Hb dissociation and respiratory gas transport in man. Resp Physiol 1969;7:7-29. 52. Astrup P, Rorth M. Oxygen affinity of haemoglobin and red cell 2,3 DPG in hepatic cirrhosis. Scand J Clin Invest 1973;31:311-317. 53. Lichtman MA, Cohen J, Young JA, Whitbeck AA, Murphy M. The relationships between arterial oxygen flow rate, oxygen binding by hemoglobin, and oxygen utilization after myocardial infarction. J Clin Invest 1974;54:501-513. 54. Sumimoto T, Takayama Y, Iwasaka T, Sugiura T, Takeuchi M, Tarumi N, Takashima H, Inada M. Oxygen delivery, oxygen consumption and hemoglobin-oxygen affinity in acute myocardial infarction. Am J Cardiol 1989;64:975-979. 55. Valeri CCR, Fortier NL. Red cell 2,3-diphosphoglycerate and creatine levels in patients with red-cell mass deficits or with cardiopulmonary insufficiency. N Engl J Med 1969;281:1452-1455. 56. McConn R, Derrick JB. The respiratory function of blood; transfusion and blood storage Anesthesiology 1972;36:119-127. 57. Collins J. Problems associated with the massive transfusion of stored blood. Surgery 1974;75:274-295. 58. Watkins GH, Rabeto A, Plzak LF, Sheldon GF. The left-shifted oxyhemoglobin curve in sepsis: a preventable defect. Ann Surg 1974;181:213-219. 59. Lichtman MA, Miller DR, Cohen J, Waterhouse C. Reduced red cell glycolysis, 2,3 diphosphoglycerate and adenosine triphosphate concentration and increased hemoglobin oxygen affinity caused by hypophosphatemia. Ann Intern Med 1971;74:562-566. 60. Travis SF, Sugerman HJ, Ruberg RL, Dudrick SJ, Delivoria-Papadopoulos M, Miller LD, Oski FA. Alterations of red cell glycolytic intermediates and O2 transport as a consequence of hypophosphatemia in patients receiving intravenous hyperalimentation. N Engl J Med 1971;285:763-766. 61. Chillar RK, Slawsky P, Desforges JF. Red cell 2,3 diphosphoglycerate and adenosine triphosphate in patients with shock. Br J Haemat 1971;21:183-187. 62. Myburgh JA, Webb RK, Worthley LIG. The P50 is reduced in critically ill patients. Intens Care Med 1991;17:355-358. 63. McConn R. 2,3 DPG - What role in septic shock? In: Lillehie R, Stubbs S, ed. Shock in low and high flow states. International congress series, 247. Excerpta Medica, Amsterdam, 1972 pp 28-41. 64. McConn R, Derrick JB. The respiratory function of blood in the acutely-ill patient and the effect of steriods. Ann Surg 1971;174:436-450. 65. Hlastala MP. Physiological significance of the interaction of oxygen and carbon dioxide in blood. Crit Care Med 1979;7:374-379. 66. Oski FA, Marshall BE, Cohen PJ, et al. Exercise with anemia. The role of the left-shifted or right-shifted oxygen-hemoglobin equilibrium curve. Ann Intern Med 1971;74:44-46. 67. Woodson RD. Physiological significance of oxygen dissociation curve shifts. Crit Care Med 1979;7:368-375. 68. Rossoff L, Zeldin R, Hew E, Aberman A. Changes in blood P50: Effects on oxygen delivery when arterial hypoxaemia is due to shunting. Chest 1980;77:142-146. 69. Jia L, Bonaventura C, Stamler JS. S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 1996;380:221-226. 70. Stamler JS, Jia L, Eu JP, McMahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulated by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997;276:2034-2037. 15 16 Chapter 2 ANAEMIAS and POLYCYTHAEMIAS ANAEMIAS Normal haemoglobin concentrations vary from 135 - 175 g/L in males and 120 - 160 g/L in females. An anaemia is a reduction in the haemoglobin concentration below 120 g/L in females and 135 g/L in males. In some circumstances, the blood haemoglobin values do not reflect alterations in the red blood cell (RBC) mass. For example, in patients who have sustained an acute reduction in plasma volume owing to extensive burns, pancreatitis, anaphylaxis or acute histamine release reactions, the haemoglobin values may be high when the RBC mass is either normal or low. By contrast, haemoglobin values may be low when the RBC mass is normal or high in patients who have expanded blood volumes with excessive intravenous infusions or during pregnancy. Classification of anaemias Anaemias may be caused by an increased loss or decreased production of haemoglobin (Table 2.1) and are often classified as microcytic, macrocytic or normocytic (Table 2.2). The use of hypochromia or normochromia to differentiate the anaemias has been lost with the current automatic machines that have revealed the mean corpuscular haemoglobin concentration (MCHC) is usually constant in all conditions (apart from hereditary spherocytosis where the MCHC is usually greater than 36%).1 Table 2. 1 Causes of an anaemia Increased loss or destruction Blood loss Haemolytic anaemias Impaired formation Deficiency of substances essential for erythropoiesis iron, B12, folate, copper or vitamin C deficiency Defective porphyrin synthesis lead poisoning, sideroblastic anaemias Defective or unbalanced globin synthesis thalassaemias, haemoglobinopathies Bone marrow failure absolute (e.g. leukaemia, aplastic anaemia) relative (i.e., chronic infection, renal failure, hepatic failure) The common anaemias are blood loss or iron deficiency (microcytic), megaloblastic (macrocytic), and secondary or haemolytic (normocytic). 17 Anaemias and Polycythaemias Table 2.2 Classification of anaemias Microcytic Iron deficiency Others (i.e., thalassaemia minor, sideroblastic anaemia) Macrocytic Nonmegaloblastic (alcoholism, chronic liver disease, myxoedema, haemolysis (due to reticulocytosis), scurvy) Megaloblastic (B12, folate deficiencies) Normocytic Secondary anaemias chronic infections and chronic inflammation chronic renal failure rheumatoid arthritis, SLE, polyarteritis nodosa malignancy endocrine failure (Addison’s disease, hypogonadism, panhypopituitarism) Aplastic anaemia Primary disorders of the bone marrow leukaemias, myelofibrosis MICROCYTIC ANAEMIA Iron deficiency The normal adult daily requirements for iron are 1 mg for males and 1.5 mg for females. The diet normally contains about 10 - 15 mg of iron per day, so only 10 - 15% is absorbed. Approximately 25 - 35 mg of iron is released daily by the reticuloendothelial system (RES) from the breakdown of RBCs. Because ionic iron is poorly soluble, it is transported in the circulation bound to transferrin, a transport protein with a molecular weight of 80,000 that can bind two atoms of iron per molecule. Iron is stored attached to ferritin. Serum iron and transferrin levels reflect transport iron, and serum ferritin reflects storage iron (Table 2.3).2 Table 2.3 Normal adult serum iron values Males Females Serum ferritin Serum iron Serum transferrin Transferrin saturation 20 - 250 8 - 35 25 - 50 10 - 50 10 - 150 8 - 27 25 - 50 10 - 35 µg/L µmol/L µmol/L % Approximately 2500 mg of iron exists as haemoglobin, 100 - 1000 mg exists as storage iron (females low, males high), 300 mg exists as tissue iron containing enzymes (i.e. myoglobin, cytochromes, etc.), and 4 mg exists in the plasma pool. A serum ferritin level of 1 µg/L is equivalent to 10 mg of storage iron (i.e. tissue ferritin). 18 Anaemias and Polycythaemias When iron deficiency develops, the iron stores fall first, followed by the serum iron level and finally the haemoglobin level. While iron deficiency can deplete cytochromes, myoglobin and iron-containing enzymes, there is no evidence that these effects are important clinically. Causes. Iron deficiency is caused by increased requirements (commonest cause is due to blood loss), inadequate intake, or both (Table 2.4). Table 2. 4 Causes of iron deficiency Increased requirements physiological (pregnancy, puberty) excess blood loss peptic ulceration, diverticulitis, hiatus hernia carcinoma (particularly gastrointestinal carcinoma) hereditary haemorrhagic telangiectasia parasitic infestations Inadequate intake or poor GIT absorption gastrectomy, achlorhydria, intestinal malabsorption dietary Clinical features.3 Chronic anaemia will often not be associated with symptoms unless it is below 70 - 80 g/L. Symptoms include lassitude, weakness, pica (with a craving for ice), dysphagia, anorexia, nausea, menorrhagia, angina and pulmonary oedema. The signs of the anaemia include pallor, (the hand should be compared with the examiners hand; the crease colour changes to white when the haemoglobin is less than 100 g/L), angular stomatitis, atrophic tongue, tender mouth and tongue. Koilonychia is present in only 18% of patients with iron deficiency anaemia and brittle nails with longitudinal ridging may be more common. A bounding arterial pulse, with a large pulse pressure and prominent dicrotic notch (it may feel as though there is a double pulse), a systolic ejection bruit (often heard loudest over the pulmonary area) and a cervical venous hum may be present. Investigations. These include: 1. Tests for occult blood loss: the commonest cause of an iron-deficient anaemia in men or postmenopausal women is chronic occult blood loss and the site is commonly gastrointestinal (e.g. peptic ulceration, carcinoma of the colon).4 On 3 successive days, 2 - 5 g of faeces are collected and tested for blood using the faecal human haemoglobin test. Endoscopy, radiological contrast and radiolabelled RBC studies may also be required. 2. Complete blood picture: chronic iron deficiency classically produces a microcytic anaemia. An acute blood loss causes a normocytic anaemia. 3. Iron-binding proteins: serum ferritin, iron and transferrin measurements should be performed on a specimen of blood from a patient who has fasted overnight. Low serum iron with high transferrin levels characteristically indicates iron deficiency. A serum ferritin level of less than 100 µg/L in anaemic patients should always be taken to indicate depleted iron stores. Occasionally, serum ferritin levels may be normal or even elevated in the presence of reduced tissue iron stores;5 therefore, if iron deficiency is suspected and the serum ferritin is normal, a bone marrow aspirate will be required to determine the status of iron stores. High serum ferritin levels can be caused by conditions other than iron overload, although low serum ferritin levels are always indicative of low iron stores and obviates the need to perform a tissue estimate. 19 Anaemias and Polycythaemias Treatment. If iron deficiency is due to a poor oral intake, then ferrous sulphate 300 mg (35 mg of elemental iron) one to two tablets 8-hourly for 4 - 10 weeks, may be prescribed. The total iron requirement (i.e. 1 - 2 grams) may also be administered as an intravenous infusion of an iron-dextran complex, after giving a test dose of 1 - 5 mg to asses whether any adverse allergic reactions will occur. Transfusions (500 ml of blood contains about 250 mg of iron), and are indicated only if surgery is contemplated or the patient is experiencing cardiovascular symptoms of cardiac failure or ischaemia. In the presence of an adequate supply of folate and B12, a reticulocytosis, thrombocytosis and leucocytosis usually begins after 4 days and peaks at 10 days. The reticulocyte count increases from 3 to 15% (increasing the MCV to 95 - 105 fl) and the haemoglobin usually increases by 10 g/L per week. If iron deficiency is due to excessive blood loss the disorder causing the excessive blood loss (e.g. peptic ulcer, colon carcinoma, menorrhagia, etc.) should also be treated. Excessive blood loss due to epistaxis or gastrointestinal blood loss caused by hereditary haemorrhagic telangectasia may respond to fibrinolytic inhibitors (e.g. epsilon aminocaproic acid 2 g orally daily).6 Haemochromatosis Cause. Haemochromatosis is an iron-storage disorder, in which an inappropriate increase in gastrointestinal iron absorption results in excess iron deposition (iron stores of 20 - 25 g may occur with haemochromatosis), and functional abnormalities of the liver, heart, pancreas and pituitary. It may be inherited as an autosomal recessive (i.e. genetic haemochromatosis which is associated with mutations in the histocompatability antigen HLA-H, as is porphyria cutanea tarda7) or an acquired disorder (e.g. transfusion siderosis) . While an increase in iron stores may also occur in alcoholic subjects with chronic liver disease, these individuals do not have haemochromatosis. Haemochromatosis occurring in a heavy drinker may be distinguished from alcoholic liver disease by studying relatives of the patient and by measuring the hepatic iron content, which is within normal limits in patients with alcoholic liver disease. Clinical features. The male:female ratio for homozygosity is 1:1 although the disease is five times more frequent in males than females (probably due to the effect of increased physiological iron loss during menstruation and pregnancy in females8) and often develops during the ages of 40 - 60 years. The symptoms include lethargy and weakness (75%), arthralgia (45%), loss of libido (30%), and abdominal pain (40%); the signs include hepatomegaly (70%), skin pigmentation (80%), hypogonadism (30%), arthropathy (70%), and signs of diabetes mellitus and hepatic and cardiac impairment. Hepatic and cardiac damage may lead to cirrhosis and cardiomyopathy respectively. Hepatocellular carcinoma develops in 30% of untreated cases. Investigations. The investigations include serum iron studies (revealing an increase in fasting serum transferrin saturation of > 60% for males and > 50% for females,9 and an increase in serum ferritin levels), chest X-ray or abdominal X-Rays (showing an increase in hepatic density) and an MRI,10 or liver biopsy, to measure the hepatic iron content and to confirm the diagnosis. Treatment. As the patient usually has 20 - 25 g of excess iron, weekly (even twice-weekly) phlebotomy of 500 mL of blood is required for 2 - 3 years, keeping the haemoglobin at 100 110 g/L. This is followed by one phlebotomy every 1 - 3 months to maintain low normal serum ferritin levels (i.e. 50 – 100 ug/L).11 Patients are advised not to take vitamin or mineral preparations containing iron or vitamin C supplements and moderation with red meat and alcohol. Desferrioxamine is not used because it removes only 10 - 20 mg of iron per day, at best, compared with venesection of 500 ml of blood which removes 200 - 250 mg of iron. All immediate relatives of the patient (i.e. brothers, sisters) should be screened. 20 Anaemias and Polycythaemias MACROCYTIC ANAEMIA Nonmegaloblastic The commonest cause of macrocytosis in the absence of an anaemia and folate or B12 deficiency is chronic ethanol excess. An anaemia in an alcoholic may be due to folate deficiency, iron deficiency (usually acute or chronic blood loss, as iron absorption is often increased), hypersplenism, pyridoxal phosphate deficiency (i.e. sideroblastic anaemia), or haemolysis (i.e., Zieve’s syndrome).12,13 Megaloblastic The megaloblastic anaemias are caused by an impaired DNA synthesis due to folate or vitamin B12 deficiency. Vitamin B12 Vitamin B12 has a structure similar to the porphyrins with cobalt being in the position occupied by iron in the haem molecule, the cyanide or hydroxyl ion filling the unsatisfied valence of the cobalt ion for cyanocobalamin and hydroxocobalamin, respectively. Both cyano- and hydroxocobalamin are present in the body in trace amounts only; hydroxocobalamin binds more firmly to proteins and remains longer in the body than cyanocobalamin. Twenty-four hours after parenteral administration, only 55% of 100 µg and 15% of 1000 µg of cyanocobalamin is retained whereas 90% of 100 µg and 30% of 1000 µg of hydroxocobalamin is retained.14 Both cyano- and hydroxocobalamin are rapidly converted to the two physiologically active forms of vitamin B12, i.e. methyl and 5-deoxyadenosylcobalamin which cannot themselves be used for therapy because they are rapidly destroyed by light. The minimum daily requirement of vitamin B12 is 2.5 µg. Intestinal absorption of vitamin B12 is mediated by receptor sites in the ileum that require cobalamin to be bound by the highly specific glycoprotein intrinsic factor (molecular weight 50,000), secreted by parietal cells of the gastric mucosa. As the cobalamin-intrinsic factor complex crosses the ileal mucosa, the intrinsic factor is released and the vitamin is transferred to a plasma transport protein, transcobalamin II. Other cobalamin-binding proteins, including transcobalamin I, exist in the plasma and liver to provide an effective storage of cobalamin (a unique situation for a water-soluble vitamin). Two milligrams are stored in the liver and 2 mg are stored elsewhere in the body, thus supply for 3 - 6 years is available to the body if B12 absorption ceased abruptly. Folic acid Folic acid is the common name for pteroylmonoglutamic acid, and uncooked fruits and vegetables constitute the primary source of the vitamin. It is absorbed from the duodenum and jejunum and changed within the intestinal cell to 5-methyltetrahydrofolic acid which is carried in the plasma. The minimum daily requirement is normally 50 µg, but requirements may increase during pregnancy or disease, up to 300 - 500 µg/day. The total body stores normally consists of 5 - 20 mg which provides the body with a 3 month supply of folate, although, in the absence of folate supplementation in critically ill patients, a deficiency with thrombocytopenia, hypersegmented neutrophils and macrocytosis, may develop within 3 to 4 days.15 Folate and B12 reactions There are only two human enzymatic reactions that require cobalamin as a coenzyme: 1. Isomerisation of L-methylmalonyl-CoA to succinyl-CoA by methylmalonyl-CoA mutase, utilising 5-deoxyadenosylcobalamin as the coenzyme. 21 Anaemias and Polycythaemias 2. Methylation of homocysteine to methionine by methionine synthetase utilising methyl cobalamin as the coenzyme and 5-methyltetrahydrofolate as the methyl source. Methionine synthetase is inhibited by nitrous oxide (which is 50% inactivated after 1 hour of nitrous oxide exposure16), as nitrous oxide converts the cobalt in methyl cobalamin from the monovalent to the divalent form (in a manner which is similar to the conversion of haemoglobin to methaemoglobin), causing B12 to no longer act as a methyl carrier, decreasing the formation of tetrahydrofolate (THF) and methionine (Figure 2.1).17,18 This effect is irreversible (or at best slowly reversible over 4 days19) and does not effect the isomerisation of L-methylmalonyl-CoA by methylmalonyl-CoA mutase.20,21 Figure 2.1 Folate and vitamin B12 reactions Myelin (and other methylations) ↑ S-adenosyl homocysteine ← S-adenosyl-methionine ↑ ↓ Methionine Homocysteine synthase Methionine → Proteins + + ←THF ← GIT→ 5-Methyl THF B12 ↑ ↑ formate methylene serine DHF THF glycine reductase reductase histidine ← 5,10 methylene ← Folinic → Tetrahydrofolate → acid → dihydrofolate ↓ Deoxyuridine → Thymidilate → DNA DHF = dihydrofolate; THF = tetrahydrofolate; GIT = gastrointestinal tract The decrease in methionine reduces the formation of S-adenosyl-methionine which is a direct methyl group donor for many methylation reactions (e.g. myelination). It also reduces homocysteine, which is derived entirely from methionine, and an intracellular THF deficiency also occurs.22 In the case of B12 deficiency (or inhibition) or methionine deficiency, administering folate (to enhance protein and DNA metabolism) will reduce the methionine, further reducing myelination and precipitating neurological disorders of subacute combined degeneration of the spinal cord and peripheral neuropathy. In the experimental model the development of subacute combined degeneration of the spinal cord due to B12 deficiency is inhibited by methionine supplementation23. Subacute combined degeneration of the spinal cord may also be precipitated by nitrous oxide in B12 deficient patients.24 S-adenosyl-methionine is a powerful inhibitor of methylene-THF reductase; therefore, when B12 and methionine deficiency exists, THF (when it is converted to 5,10 methylene THF, with formate, serine, glycine and histidine oxidations) is converted to, and 'trapped', as 5-methyl 22 Anaemias and Polycythaemias THF. Both B12 and methionine can release the ‘trapping’, by increasing S-adenosyl methionine, inhibiting the formation of 5-methyl TFH. 5,10 methylene THF provides the methyl group to deoxyuridine to form thymidine which is a necessary precursor of DNA synthesis. The dihydrofolate so formed is reduced by the enzyme, dihydrofolate reductase (trimethoprim, pentamidine and pyrimethamine are selective inhibitors of this enzyme in bacteria; methotrexate inhibits both the human and bacterial enzymes) to reform THF. Folate deficiency reduces the amount of 5,10 methylene THF available for DNA synthesis (as does B12 and methionine deficiency due to the ‘trap’), causing megaloblastosis (Table 2.1). Folinic acid is a stable form of THF that can be administered orally or parenterally to provide reduced folate without first being required to be acted on by dihydrofolate reductase. In normal individuals, 50% nitrous oxide administered to patients for less than 5 - 6 hr does not affect haemopoiesis. However, exposure for 6 hr produces mild, and exposure for 24 hr severe, signs of megaloblastic depression (i.e. pancytopenia) of the bone marrow.25 In critically ill patients megaloblastosis may be evident after 2 hr exposure, although it has been suggested that exposures of nitrous oxide in excess of 45 min will be significant in compromised patients and require the use of folinic acid therapy.26 Long-term neurological effects may occur with prolonged administration of nitrous oxide.27 The marrow effects are reversed by folinic acid, 60 mg in 24 hr28 or 30 mg daily for 5 days;29 and, in the short-term methionine and B12 (in the absence of B12 deficiency) are usually not required. Causes, clinical features, investigations and treatment of megaloblastic anaemia Causes 1. Pernicious anaemia: this anaemia is due to B12 malabsorption and deficiency, secondary to atrophy of the gastric mucosa with absence of intrinsic factor.30 This may also occur after gastrectomy. 2. Folate deficiency: deficient states often occur with inadequate dietary intake (e.g. in the elderly, alcoholic or mentally disturbed), malabsorption (e.g. steatorrhoea) or excess demands (e.g. pregnancy, chronic haemolytic anaemia). Clinical features. Symptoms of B12 or folate deficient megaloblastic anaemia include weakness, lassitude, sore atrophic tongue, angular stomatitis, and diarrhoea. Signs include pallor, weakness, jaundice, and, in the case of B12 deficiency (not folate deficiency), neurological disorders which may not remit with treatment and which may be provoked by folic acid administration. Classically posterior column signs of joint position sense defects are observed with a positive Romberg sign, and abnormal vibration and joint position sense. Peripheral neuropathy may be found with signs of, numbness, paraesthesia, weakness and ataxia. Dementia has also been described. Occasionally the neurological symptoms and signs may occur in the absence of haematological defects and with serum B12 levels at low normal levels (i.e 200 - 350 ng/L or 150 -250 pmol/L).31 Investigations. The investigations include: 1. Complete blood picture: this will reveal a macrocytic anaemia (MCV > 100 fl), thrombocytopenia with hypersegmented polymorphs and, occasionally, agranulocytosis 2. Bone marrow: this will reveal a megaloblastosis. 3. Serum folate and B12 levels: an overnight fasting serum specimen for folate (normal 3.0 15 µg/L or 6.8 - 34 µmol/L) and B12 (normal 200 - 1000 ng/L or 150 -750 pmol/L), are taken. In pernicious anaemia, B12 values are almost invariably below 100 ng/L, although a physiologically adequate serum level is above 258 pmol/L as clinical evidence of B12 deficiency can exist below this value.32 While vegetarians often have low serum levels of B12, a deficient state does not usually occur. 23 Anaemias and Polycythaemias 4. Intrinsic factor antibody: patients who have an antibody to intrinsic factor with low serum concentrations of B12 have pernicious anaemia, and absorption tests (e.g. Shilling test) are not needed to confirm the diagnosis33. 5. Plasma biochemical tests: the indirect bilirubin and LDH-1 are often elevated due to marrow destruction of megaloblastic erythroid cells. Treatment. Parenteral hydroxocobalamin 1000 µg monthly is used for vitamin B12 deficient states34,35 and should be considered for all elderly patients if folate supplementation is given.36 Large doses of oral cobalamin (1000 µg daily) will also produce successful long term results in patients with pernicious anaemia, due to a vitamin B12 transport system that is independent of intrinsic factor and the terminal ileum.37 Rarely, patients may exhibit an allergy to hydroxocobalamin (e.g. pruritis, utricaria, bronchospasm, angio-oedema) with no crossreaction to cyanocobalamin.38 If a folic acid deficiency exists then this is usually corrected by oral or intravenous folic acid 5 - 15 mg/day. Folinic acid (30 - 60 mg daily) is administered when folate inhibitors have caused the deficient state. Following replacement therapy, the reticulocyte count usually increases up to a maximum of 10-20% by the 10th day. NORMOCYTIC ANAEMIA The secondary anaemias Anaemia associated with chronic infections or chronic inflammation An anaemia (Hb 90 - 110 g/L) is often associated with an inflammatory (e.g. systemic lupus erythematosus, polyarteritis, rheumatoid arthritis) or infective process that has been present for longer than 1 month. If the haemoglobin is less than 80 g/L then it is likely that another process is present (e.g. blood loss). The reticulocyte count is normal, the serum iron and transferrin levels are reduced, the saturation is normal and the serum ferritin is raised. It appears that hepatic transferrin synthesis is depressed, iron is less freely released from the RES, and some of the suppression of RBC production is due to the decreased availability of iron. The RBC survival time is also about 85% shorter than in normal subjects.39 It has been suggested that the decrease in serum iron associated with chronic infection increases the body resistance to infection because it reduces the iron available to support the growth of microorganisms.40 Anaemia associated with chronic renal failure While uraemic toxins, hyperparathyroidism, hypersplenism, folate deficiency and iron deficiency may play a role in causing the anaemia of end-stage renal disease, the anaemia is largely due to a persistent mild haemolysis and decreased levels of erythropoietin.41,42,43 The RBC morphology often reveals distorted and fragmented cells (e.g. schistocytes, burr, tear-drop, and helmet cells). The haemoglobin concentration usually falls to 50 - 80 g/L, with a linear relationship existing between the haematocrit and the creatinine clearance. Recombinant erythropoietin has been used to correct the anaemia of chronic renal failure in patients on long-term haemodialysis, which improves the patient's wellbeing and physical capacity.44,45 The patient's maximum oxygen consumption is increased after two months, and a 30% reduction in the left ventricular mass occurs after 12 months of treatment.46 A dose of 25 50u (up to 200 u) is usually administered three times weekly, or 2 -12 mg every year.47 However, it appears that thrombosis is more likely (e.g. the AV shunts often clot48), particularly if the haemoglobin response is too rapid, therefore it is recommended that the dose be tailored so that the monthly haemoglobin rise is no greater than 20 g/L.49 24 Anaemias and Polycythaemias Haemolytic anaemias Haemolytic anaemias are caused by the premature destruction of RBCs due to disorders that cause either intravascular or extravascular haemolysis (Table 2.5). Table 2. 5 Causes of haemolytic anaemias Intravascular haemolysis Incompatible blood transfusion Hypotonic intravenous fluids Cardiac prosthesis, march haemoglobinuria Arteriopathies thrombotic thrombocytopenic purpura haemolytic uraemic syndrome, scleroderma, malignant hypertension DIC Envenomation Extravascular haemolysis Autoimmune haemolytic anaemia (warm antibody, cold antibody) Physical abnormalities of the RBC RBC membrane disorders, enzyme defects thalassaemias, haemoglobinopathies Hypersplenism Intravascular haemolysis The causes of intravascular haemolysis include, incompatible blood transfusion, hypotonic intravenous fluids, RBC trauma (march haemoglobinuria, cardiac prosthesis), paroxysmal nocturnal haemoglobinuria (caused by an acquired genetic disorder which enhances RBCs sensitivity to complement and characterised by chronic haemolytic anaemia, nocturnal haemolysis and thrombosis50) and the arteriopathies. 1. Hypotonic intravenous fluids: normal RBCs do not begin to haemolyse unless they are suspended in a solution with an osmolality of 160 mosmol/kg (e.g. 0.5% saline), and complete haemolysis occurs when the RBCs are suspended in a solution with an osmolality of 110 mosmol/kg (e.g. 0.35% saline). In clinical practice, solutions down to an osmolality of 143 mosmol/kg (e.g. 0.45% saline solutions) can be infused through a peripheral vein without causing haemolysis, and, due to rapid mixing, even sterile water can be infused through a central venous catheter without causing intravascular haemolysis.51 2. Arteriopathies a. Thrombotic thrombocytopenic purpura (TTP) is a disease caused by an acquired reduction in plasma von Willebrand factor – cleaving protease activity (due to an IgG autoantibody),52,53 leading to the binding of unusually large multimers to platelets and results in platelet microthrombi that characterise the disorder. It has been described following the administration of chemotherapeutic agents (e.g. cyclosporine, mitomycin),54 ticlopidine,55 clopidogrel,56 and has been associated with HIV infection57, systemic lupus erythematosis, scleroderma and Sjögren’s syndrome.58 25 Anaemias and Polycythaemias b. c. It is characterised by intravascular fibrin deposition on the damaged surface of small blood vessels, causing a thrombocytopenia (< 20,000), microangiopathic haemolytic anaemia (haemoglobin < 55 g/L in 30%; RBCs are fragmented and nucleated), elevated plasma LDH, renal failure and fluctuating neurological manifestations. The coagulation tests are often normal (if they indicate a DIC then the diagnosis is most likely doubtful). A positive antinuclear antibody is present in 20% of cases. The disease may span days to months; and, while arthralgias, abdominal pain, purpura and fever are common, as the disease progresses the brain and kidney become progressively involved and the clinical picture usually becomes predominantly neurological, with confusion, disorientation, seizures, hemiparesis and aphasias. TTP is a clinical diagnosis, because biopsy tissue (e.g. renal) may not contain arterial thrombi. The most consistently effective form of treatment is plasmapheresis (to remove the IgG autoantibody) using 7 exchanges of FFP in 9 days (to replenish the plasma von Willebrand factor – cleaving protease activity),59 and may be associated with reversal of coma.60 Variable success has been reported with, corticosteroids, antiplatelet agents (e.g. aspirin, dipyridamole), fresh frozen plasma, prostacyclin and cytotoxic agents (e.g. vincristine 1 mg per 1-4 weeks for 2-5 doses, cyclophosphamide or azathioprine).61 The haemolytic uraemic syndrome (HUS) characterised by a triad of microangiopathic haemolytic anaemia, thrombocytopaenia and renal failure, is thought to be a variant of TTP (although unlike TTP it does not have a reduction in von Willebrand factor – cleaving protease activity and has less CNS involvement, and more renal involvement). It exists in a diarrhoeal-associated epidemic form, and may follow an Escherichia coli (particularly the Shiga toxin producing serotypes O157:H7 and O103:H2),62 Shigella, Salmonella, Streptococcus pneumoniae, Campylobacter, Yersinia, coxsackie, influenza or Epstein-Barr infection,63 as well as nondiarrhoeal sporadic or rare familial forms. The diarrhoeal-form is more common in children of 3 - 10 years and they often recover. The sporadic and non-infective forms usually affects adults and generally carries a worse prognosis. An overactivity of the alternative complement pathway has been reported in the familial form of HUS,64 suggesting that an abnormality of factor H (with an increase in complement activation by the alternative pathway) may be involved in the aetiology of all cases of HUS. Treatment of HUS is commonly plasmapheresis (e.g. 7 exchanges of FFP in 9 days). Antibiotics early during the course of the disease (e.g. beta-lactams, fluroquinolones, tetracyclines) do not alter the course of the disease and may even worsen it.65 A TTP-like syndrome may also occur with malignant hypertension, eclampsia, transplantation, scleroderma and systemic lupus erythematosus; these are discussed elsewhere. Clinical features. The symptoms and signs of an intravascular haemolysis depends on the rate of haemolysis. For example, intravenous haemolysis due to an incompatible blood transfusion presents with shock, rigors, urticaria, and dyspnoea, followed by haemoglobinuria, excessive bleeding and oliguria, whereas haemolysis due to in intravascular prosthesis may present with features of an anaemia (e.g. tiredness, weakness, angina, cardiac failure). 26 Anaemias and Polycythaemias Investigations. The investigations include: 1. Complete blood picture: the features of an intravascular haemolysis include an anaemia, reticulocytosis and altered RBC morphology. The bone marrow can increase RBC production by eight times before an anaemia occurs, which will present when the RBC life span is reduced to less than 20 days. At this stage the reticulocyte count will be approximately 20 - 30%. The RBC morphology reveals spherocytosis, polychromasia and (in the case of microangiopathic haemolytic anaemia), fragmented cells. 2. Plasma haptoglobin, haemopexin, methaemalbumin and free haemoglobin levels, and urinary haemoglobin and haemosiderin excretion: haptoglobin is an alpha-globulin acute-phase reactant, with a normal half-life of 4 days. Half the circulating pool of haptoglobin is renewed daily. It combines specifically and tightly with the globin moiety of free haemoglobin, being able to bind 500 - 1500 mg of free haemoglobin per litre of plasma, which is cleared rapidly from the circulation, with a half-life of 9 - 30 min. An intravascular haemolysis, with a RBC half-life of 17 days or less, is associated with an undetectable plasma level of haptoglobin.66 Haemopexin is a plasma beta-globulin which binds specifically to haem and becomes depleted in patients with moderate to severe haemolysis. In addition, some of the free haemoglobin may combine with albumin to form methaemalbumin when haptoglobin and haemopexin are depleted. Once the protein binding capacity of the plasma is exceeded, free haemoglobin is filtered at the glomerulus, which is reabsorbed by the proximal tubule and stored as haemosiderin and ferritin. The presence of haemosiderin in the urine indicates that a significant amount of haemoglobin has been filtered by the kidneys. When the absorptive capacity of the proximal tubule is exceeded, haemoglobinuria occurs, producing a red colour in alkaline urine (i.e. oxyhaemoglobin) and a black colour in an acidic urine (i.e. methoxyhaemoglobin). 3. Plasma bilirubin and LDH levels: significant intravascular haemolysis is associated with an elevated unconjugated bilirubin level (often no greater than twice normal unless hepatic disease is also present), acholuria (i.e. the unconjugated bilirubin is bound to albumin and so is not excreted in the urine), increased urobilinogen excretion (although faecal measurement is difficult and urinary excretion is unreliable because it is dependent upon urinary pH) and an elevation in the plasma LDH (isoenzymes 1 and 2). 4. RBC survival studies: the demonstration of a reduced RBC life span is the definitive test of a haemolytic anaemia. This can be performed using chromium 51 labelled RBCs, measuring the rate of disappearance of the labelled RBCs from the circulation and is usually coupled with an estimation of organ uptake to assess the major sites of RBC destruction. Extravascular haemolysis In these disorders RBCs are taken up and destroyed by the RES of the liver and spleen. Extravascular haemolysis is not associated with release of free haemoglobin into the circulation. Extravascular haemolysis may be caused by an autoimmune haemolytic anaemia (AIHA), RBC enzyme defect or hypersplenism. Autoimmune haemolytic anaemia.67 1. Warm antibody: warm antibody AIHA is often due to an IgG, and occasionally an IgA, RBC antibody which may be idiopathic or associated with lymphomas, SLE or drugs.68 The drug induced AIHA may be one of three types: 27 Anaemias and Polycythaemias a. 2. Alpha methyldopa may induce an IgG antibody to the RBC surface. Approximately 10% of patients taking 2 g of alpha-methyl-dopa have a positive Coombs' test. Procainamide may induce a similar antibody.69 b. Penicillin may associate with the RBC surface and induce an IgG antibody against the RBC-penicillin complex. This is usually found only in patients taking 15 - 20 million units of penicillin daily, and occurs 7 - 10 days after therapy begins. Cephalosporins may also cause this type of haemolytic anaemia. c. Quinidine forms a complex with plasma protein, to which an IgG or IgM antibody forms. The quinidine-protein-AB complex then settles on RBCs or platelets causing the 'innocent bystander' AIHA (or thrombocytopenia). Other drugs to cause this type of AIHA include, quinine, sulphonamides, quinolones, isoniazid, and phenacetin. Cold antibody: cold agglutinins are IgM RBC antibodies which may be associated with acute diseases (i.e. mycoplasma, infectious mononucleosis) or chronic diseases (i.e. lymphoma, idiopathic). The agglutination of RBCs by IgM cold agglutinins occur at low temperatures (less than 32ºC); disagglutination occurs with rewarming. Most cold agglutinins are inefficient in fixing complement to the cell surface and so agglutination and haemolysis in vivo may be only mild. Clinical features of AIHA. These are similar to the features of any chronic anaemia. Investigation of AIHA. The Coombs' Test is used to detect sensitisation of RBC or antibody in plasma. 1. Direct Coombs' test: this is performed to detect sensitisation of red blood cells (i.e. the process of adherence of protein molecules to the surface of the RBC) by an antibody. The RBCs under investigation are washed thoroughly, then mixed in equal amounts with the Coombs' reagent. The Coombs' reagent is prepared by injecting rabbits repeatedly with either whole human serum or with pure components, until an antiserum of sufficient anti IgG and anti complement titre can be harvested. If whole serum has been used, certain components have to be removed to make the test specific. The Coombs' test is generally accepted to work by bridging the gap between incomplete antibodies, thus linking RBCs and therefore causing agglutination. After an incompatible blood transfusion, the Coombs' test will be positive on the post-transfusion specimen, showing sensitisation of RBCs 2. Indirect Coombs' test: this is performed to detect the presence of an antibody in the serum (e.g. to detect rhesus antibody). In this case the RBCs containing the appropriate antigen, are used as indicators only. Suitable RBCs are mixed with serum under investigation for 30 60 min then washed and then treated as for the direct Coombs' test. Treatment of AIHA. The warm antibody autoimmune haemolytic anaemias are treated by treating the precipitating factors (i.e. cease drugs, removal of thymoma or ovarian tumour). Oral or intravenous corticosteroids improve the survival of the antibody-coated cells without dramatically changing antibody levels or production. Prednisolone 1 - 2 mg/kg/day (60 - 120 mg/day) will produce an effective remission in 60% of patients, (40% of whom are able to be controlled by low doses, i.e. < 20 mg/day, and 60% are controlled by intermediate doses, i.e. 20 - 40 mg/day). The remaining 40% are either controlled by unacceptably high steroid administration or are steroid resistant. The variable response to splenectomy and its long term complications such as overwhelming sepsis makes the introduction of immunosuppressive agents of azathioprine and cyclophosphamide the next option. These have a slow onset and have been reported to be successful in 60 - 70% of steroid resistant AIHA patients. 28 Anaemias and Polycythaemias Plasmapheresis is considered to be relatively ineffective for AIHA. Splenectomy or immunoglobulin may be considered for steroid and immunosuppression-resistant patients. The cold antibody autoimmune haemolytic anaemias are treated by treating the underlying disease (e.g. lymphoma, chronic lymphatic leukaemia), otherwise treatment is largely supportive as it is usually unresponsive to glucocorticoids. For example, avoidance of cold, folic acid and transfusions of packed, warmed (i.e. infused through a warming coil) and washed RBC (to remove any extra source of complement). Physical abnormalities of the RBC: RBC enzyme defects. The RBC, at maturity, retains non-oxygen utilising metabolic pathways (i.e. the glycolytic pathway, hexose monophosphate shunt and the Rapoport-Luebering shuttle). The glycolytic pathway generates ATP, 50% of which is used to drive the cell-wall cation pump. Much of the remaining energy is used for renewal of membrane phospholipids. The Hexose monophosphate shunt forms reduced nicotinamide adenine dinucleotide, which in turn is used to maintain levels of reduced glutathione needed to protect haemoglobin and the membrane from exogenous oxidants. The protection is afforded by the continual availability of the thiol (-SH) groups of reduced glutathione, which are used in preference to the -SH groups of haemoglobin and the cell membrane. The normal RBC protects itself against oxidant stress by increasing the amount of glucose metabolised by the hexose monophosphate shunt (which is normally only 10%) to increase the regeneration of reduced glutathione. Also the oxidation of Fe2+ to Fe3+ (methaemoglobin) is reversed by this system. Defects of the glycolytic pathway (i.e. pyruvate kinase deficiency) present with haemolytic anaemias in early childhood. Defects in the hexose-monophosphate shunt (i.e. GPD deficiency) inhibits the formation of reduced glutathione, resulting in oxidation of haemoglobin sulphydryl groups and causing some of the haemoglobin to precipitate within the RBC and form Heintz bodies. Patients with GPD deficiency may also present with an acute haemolytic crisis within 1 h of ingesting an oxidant (e.g. drug-induced haemolysis; Table 2.6), causing hypotension, a rapid drop in haematocrit, a rise in plasma haemoglobin and a fall in haptoglobin. As the disorder is self-limiting the treatment is largely supportive (i.e. discontinue the drug, correct shock, anaemia and dehydration) Table 2. 6 Drugs which may cause haemolysis in G6PD deficient individuals Sulphonamides Primaquine, chloroquine Quinine, quinidine and chloramphenicol Methylene blue, vitamin K, nalidixic acid, nitrofurantoin Nitrates Hypersplenism. This term is applied to any clinical situation in which the spleen removes excessive quantities of circulating cellular elements. The criteria for its diagnosis include splenomegaly (Table 2.7), splenic destruction of one or more of the circulating cellular elements, normal or hyperplastic cellularity of the bone marrow, and evidence of increased turnover of the depleted cell line with evidence of increased splenic uptake. POLYCYTHAEMIA Polycythaemia is diagnosed in the presence of a packed cell volume (PCV) of greater than 52% for males or greater than 47% for females (i.e. haemoglobin > 180 g/L for males and > 29 Anaemias and Polycythaemias 165 g/L for females), and may be primary (polycythaemia rubra vera) or secondary (e.g. hypoxia). Polycythaemia rubra vera Cause. While polycythaemia rubra vera is characterised by overproduction of all myeloid elements, the disease is usually dominated by an elevated haemoglobin concentration. Clinical features. The symptoms include, headache, dizziness, vertigo, tinnitus, weakness, pruritus (particularly with warm bath or shower, which is histamine mediated and may be corrected with cimetidine),70 sweating and a predilection to thrombosis and haemorrhage. The signs include ruddy cyanosis, injected conjunctiva, engorged retinal veins, splenomegaly and hepatomegaly. Table 2. 7 Causes of splenomegaly Infections infectious mononucleosis, septicaemia, endocarditis tuberculosis, malaria, hydatid, AIDS, viral hepatitis, brucellosis leishmaniasis, histoplasmosis, trypanosomiasis, typhoid, paratyphoid Immunoregulation diseases rheumatoid arthritis, SLE, AIHA, serum sickness Portal hypertension cirrhosis, congestive heart failure hepatic, splenic or portal vein obstruction RBC diseases thalassaemia, sickle cell disease Infiltrative diseases of the spleen amyloidosis, lipid storage diseases leukaemias, lymphomas, myelofibrosis, polycythaemia rubra vera Miscellaneous thyrotoxicosis, sarcoidosis Investigations. An elevated RBC volume in males greater than 36 ml/kg and females greater than 32 ml/kg, in the presence of a normal arterial blood saturation (or greater than 91%) and in the absence of carboxyhaemoglobin, is usually diagnostic (i.e. in the absence of a secondary polycythaemia). Serum or urinary erythropoietin levels are reduced or absent, serum uric acid is increased, the ESR is low and leucocyte alkaline phosphatase is often elevated. The neutrophil and platelet counts and the serum vitamin B12 binding capacity (i.e. transcobalamin I and II levels) are elevated in 75% of cases. Treatment. Without treatment, survival is often reduced to 2 years. With treatment survival may be extended to 10 - 12 years. Treatment consists of phlebotomy, which is best used initially to reduce RBC mass, and for young patients with mild disease (to reduce the haematocrit to below 45%), or myelosuppressive therapy, consisting of radiation, 32P, or hydroxyurea, which is best used in the elderly who have extreme symptomatic thrombocytosis, a rapidly enlarging spleen or symptoms of hypermetabolism. 30 Anaemias and Polycythaemias Secondary polycythaemia Causes. Causes of secondary polycythaemia include disorders that increase erythropoietin secondary to hypoxia or ectopic production, and disorders that reduce plasma volume, i.e. spurious polycythaemia. (Table 2.8) Treatment. In patients who have COPD and polycythaemia, a reduction in PCV down to 50-55% reduces pulmonary vascular resistance and right ventricular stroke work (particularly during exercise). Further reduction of PCV is of no benefit, thus a reduction in PCV in COPD patients is only considered if it is greater than 55%.71 In patients with cyanotic congenital heart disease, if PCV values are above 60%, a reduction in PCV by 10% is associated with increased oxygen uptake and reduction in oxygen debt; these patients may also benefit from venesection to no lower than 55%. Table 2. 8 Causes of secondary polycythaemia Hypoxaemia chronic pulmonary diseases, sleep apnoea chronic carboxyhaemoglobinaemia (i.e., smoking) cyanotic cardiac diseases haemoglobinopathy with an abnormal 'shift to the left' Ectopic erythropoietin production renal carcinoma, hepatoma, cerebellar haemangioma Reduced plasma volume diuretics REFERENCES 1. Fischer SL, Fischer SP. Mean corpuscular volume. Arch Intern Med 1983;143:282-283. 2. Worwood M. Serum ferritin. Clin Sci 1986;70:215-220. 3. Elwood PC, Waters WE, Greene WJW, Sweetnam PM, Wood MM. Symptoms and circulating haemoglobin. J Chronic Diseases 1969;21:615-628. 4. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with iron deficiency anaemia. N Engl J Med 1993;329:1691-1695. 5. Editorial. Serum-ferritin. Lancet 1979;i:533-534. 6. Saba HI, Morelli GA, Logrono LA. Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 1994;330:1789-1790. 7. Beutler E. Genetic irony beyond haemochromatosis: clinical effects of HLA-H mutations. Lancet 1997;349:296-297. 8 . Olynyk JK. Genetic haemochromatosis - preventable rust. Aust NZ J Med 1994;24:711716. 9. Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med 1993;328:16161620. 10. Y Gandon, D Olivié, D Guyader, C Aubé, F Oberti, V Sebille, Y Deugnier. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004:363:357-362. 11. Burt MJ, George DK, Powell LW. Haemochromatosis - a clinical update. Med J Aust 1996;164:348-351. 12. Editorial. Alcohol and the blood. Br Med J 1978;1:1504-1505. 13. Chanarin I. Alcohol and the blood. Br J Haematol 1979;42:333-336. 14. Chanarin I. The megaloblastic anaemias. 2nd ed. Oxford: Blackwell Scientific Publications, 1979. 31 Anaemias and Polycythaemias 15. Beard MEJ, Hatipov CS, Hamer JW. Acute onset of folate deficiency in patients under intensive care. Crit Care Med 1980;8:500-503. 16 . Guttormsen AB, Refsum H, Ueland PM. The interaction between nitrous oxide and cobalamin. Biochemical effects and clinical consequences. Acta Anaesthesiol Scand 1994;38:753-756. 17. Skacel PO, Hewlett AM, Lewis JD, Lumb M, Nunn JF, Chanarin I. Studies on the haemopoietic toxicity of nitrous oxide in man. Br J Haematol 1983;53:189-94. 18. Nunn JF, Sharer NW, Bottiglieri T, Rossiter J. Plasma methionine concentrations during elective surgery and nitrous oxide. Br J Anaesth 1986;57:342-349. 19. Editorial. Nitrous oxide and acute marrow failure. Lancet 1982;ii:856-857. 20. Chanarin I. Nitrous oxide and the cobalamins. Clin Sci 1980;59:151-154. 21. Nunn JF. Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br J Anaesth 1987;59:3-13. 22. Scott JM, Weir DG. The methyl folate trap. Lancet 1981;ii:337-340. 23. Scott JM, Dinn JJ, Wilson P, Weir DG. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981;ii:334-337. 24. Flippo TS, Holder WD Jr. Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch Surg 1993;128:1391-1395. 25. Amess JAL, Burman JF, Rees GM, Nancekievill DG, Mollin DL. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 1978;ii:339-345. 26. Gillman MA. Folinic acid prevents megaloblastic changes associated with nitrous oxide. Anesth Analg 1988;67:1018-1019. 27. Ng J, Frith R. Nanging. Lancet 2002;360:384. 28. Amos RJ, Amess JAL, Nanckievill DG, Rees GM. Prevention of nitrous oxide-induced megaloblastic changes in bone marrow using folinic acid. Br J Anaesth 1984;56:103-107. 29. Nunn JF, Chanarin I, Tanner AG, Owen ERTC. Megaloblastic bone marrow changes after repeated nitrous oxide anaesthesia. Br J Anaesth 1986;58:1469-1470. 30. Toh B-H, van Driel IR, Gleeson PA. Pernicious anaemia. N Engl J Med 1997;337:14411448. 31. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler S, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994;60:211. 32. Spence D. Uses of error: knowledge gaps. Lancet 2001;358:1934. 33. Dawson DW. Diagnosis of vitamin B12 deficiency. Br J Med 1984;289:938. 34. Hoffbrand AV, Lavoie A. Blood and neoplastic diseases: megaloblastic anaemia. Br Med J 1974;2:550-553. 35. Linnell JC, Matthews DM. Cobalamin metabolism and its clinical aspects. Clin Sci 1984;66:113-121. 36. Allen LH, Casterline J. Vitamin B-12 deficiency in elderly individuals: diagnosis and requirements. Am J Clin Nutr 1994;60:12-14. 37. Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998;352:1721-1722. 38. Heyworth-Smith D, Hogan PG. Allergy to hydroxocobalamin, with tolerance to cyanocobalamin. Med J Aust 2002;177:162-163. 39. Wallerstein RO. Role of the laboratory in the diagnosis of anemia. JAMA 1976;236:490493. 40. Editorial. Iron and resistance to infection. Lancet 1974;ii:325-326. 41. Editorial. Anaemia of chronic renal failure. Lancet 1983;i:965-966. 32 Anaemias and Polycythaemias 42. Eschbach JW, Adamson JW. Anemia of end-stage renal disease (ESRD). Kidney Int 1985;28:1-5. 43. Dodds A, Nicholls M. Haematological aspects of renal disease. Anaesth Intens Care 1983;11:361-368. 44. Winearls CG, Oliver DR, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;ii:1175-1178. 45. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anaemia of end-stage renal disease with recombinant human erythropoietin: results of a phase I and phase II clinical trial. N Engl J Med 1987;316:73-78. 46. MacDougall IC, Lewis NP, Saunders MJ, Cochlin DL, Davies ME, Hutton RD, Fox KAA, Coles GA, Williams JD. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990;335:489-493. 47. Cotes PM. Erythropoietin: the developing story. Br Med J 1988;296:805-806. 48. Raine AEG. Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin therapy. Lancet 1988;i:97-100. 49. Firkin F. Recombinant human erythropoietin enters the pharmacopeia. Aust NZ J Med 1989;19:279-280. 50. Schwartz RS. PIG-A - the target gene in paroxysmal nocturnal hemoglobinuria. N Engl J Med 1994;330:283-284. 51. Worthley LIG. Hyperosmolar coma treated with intravenous sterile water - a study of three cases. Arch Intern Med 1986;146:945-947. 52. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lammle B. Von Willebrand factor - cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. New Engl J Med 1998;339:1578-1584. 53. Tsai H-M, Lian EC-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585-1594. 54. Moake JL. TTP - desperation, empiricism, progress. N Engl J Med 1991;325:426-428. 55. Kupfer Y, Tessler S. Ticlopidine and thrombotic thrombocytopenic purpura. N Engl J Med 1997;337:1245. 56. Bennett CL, Connors JM, Carwile JM, Moake JL, Bell AJ, Tarantolo SR, McCarthy LJ, Sarode R, Hatfield AJ, Feldman MD, Davidson CJ, Tsai H-M. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342:17731777. 57. Stewart GJ. Could it be HIV? 1. The challenge: clinical diagnosis of HIV. Med J Aust 1993;158:31-34. 58. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:589-600. 59. Moake JL. Moschcowitz, multimers, and metalloprotease. N Engl J Med 1998;339:16291631. 60. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA, and the Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991;325:393-397. 61. Schmidt JL. Thrombotic thrombocytopenic purpura: successful treatment unlocks etiologic secrets. Mayo Clin Proc 1989;64:956-961. 62. Rondeau E, Peraldi M-N. Escherichia coli and the hemolytic-uremic syndrome. N Engl J Med 1996;335:660-662. 33 Anaemias and Polycythaemias 63. Ferris TF. Preeclampsia and postpartum renal failure: examples of pregnancy induced microangiopathy. Am J Med 1995;99:343-347. 64. Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 1998;53:836-844. 65. Todd WTA. Prospects for the prevention of haemolytic-uraemic syndrome. Lancet 2001;357:1636-1638. 66. Hershko C. The fate of circulating haemoglobin. Br J Haematol 1975;29:199-204. 67. Gibson J. Autoimmune hemolytic anemia: current concepts. Aust NZ J Med 1988;18:625637. 68. Garratty G, Petz LD. Drug-induced immune hemolytic anemia. Am J Med 1975;58:398407. 69. Kleinman S, Nelson R, Smith L, Goldfinger D. Positive direct antiglobulin tests and immune hemolytic anaemia in patients receiving procainamide. N Engl J Med 1984;311:809-812. 70. Easton P, Galbraith PR. Cimetidine treatment of pruritus in polycythaemia vera. N Engl J Med 1978;299:1134. 71. Editorial. Polycythaemia due to hypoxaemia: advantage or disadvantage? Lancet 1989;i:20-22. 34 Chapter 3 HAEMOSTASIS, PLATELET FUNCTION and COAGULATION HAEMOSTASIS There are four processes which maintain haemostasis and arrest bleeding after injury, vascular smooth muscle constriction, platelet adhesion and aggregation (i.e. primary haemostasis), fibrin generation by intrinsic and extrinsic coagulation pathways (i.e. secondary haemostasis), and fibrinolysis and re-endothelialisation of the vascular surface. The haemostatic function of the microvasculature and platelets are closely linked and vascular disorders that cause bleeding often have similar clinical presentations to the thrombocytopenic disorders and are often classified as non thrombocytopenic purpuras. The causes of non thrombocytopenic purpuras are listed in Table 3.1. Table 3.1 Nonthrombocytopenic purpuras Age, idiopathic Allergic or Henoch-Schönlein purpura Septicaemia Scurvy Paraproteinaemias Thrombocythaemia Prolonged corticosteroid administration Fat embolism PLATELET FUNCTION Platelets are non-nucleated cytoplasmic fragments with a diameter of 2 - 4 µm. They are derived as cytoplasmic fragments from megakaryocytes and have a lifespan of 8 - 10 days. While thrombopoietin is the dominant hormone controlling megakaryocyte development many cytokines and other hormones are involved including IL-3, IL-6 and IL-11.1 Normally about 30% of platelets are sequestrated in the spleen, a percentage which is increased during hypothermia (which may cause thrombocytopenia), and returned on rewarming.2 While the platelet factor nomenclature has largely been abandoned, platelet factor 3 (PF-3) is still used to describe the platelet phospholipid procoagulant activity necessary for the coagulation cascade, and platelet factor 4 is still used to describe the cationic alpha-granule protein which has the capacity to neutralise heparin. The endothelial cell products of nitric oxide and prostacyclin, maintain quiescent platelet activity as they traverse intact vessels. With disruption of the endothelium, the platelet performs its haemostatic function by the events; adhesion, activation, release and aggregation. 35 Haemostasis, Platelet function and Coagulation Adhesion Platelet adhesion is triggered by damage to the vascular endothelium and exposure of the subendothelial matrix. Coverage of the exposed site by platelets depends on the recognition of adhesive proteins by specific platelet-membrane glycoproteins, some of which are integrins (e.g. glycoprotein Ia/IIa which binds to collagen, glycoprotein Ic/IIa which binds to fibronectin) and others are not (e.g. glycoprotein Ib which binds to von Willebrand factor and Glycoprotein IV which binds to thrombospondin as well as collagen, Figure 3.1). The platelet membrane glycoprotein IIb/IIIa integrin, in addition to its function in platelet aggregation, also has a role in platelet adhesion.3 Figure 3.1 Binding of von Willebrand factor (vWF) and fibrinogen to platelet membrane glycoproteins. Fibrinogen binds to the glycoprotein IIb/IIIa-Ca2+ complex, in the presence of ADP. vWF can either bind to glycoprotein Ib, in the absence of ADP or bind to the glycoprotein IIb/IIIa-Ca2+ complex, in the presence of ADP (Reproduced, and modified, with permission, from Stein B, Fuster V, Israel DH, Cohen M, Badimon L, Badimon JJ, Chesebro JH. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol 1989;14:813-836). Activation A variety of platelet stimuli (e.g. collagen, thrombin, adrenaline, serotonin) bind to their specific platelet surface receptors and function in concert to trigger a cascade of intracellular reactions that lead to the release reaction. Shear stress can also directly activate platelets. Release There are two classes of secretory granules; dense granules and alpha granules. Following platelet activation, the dense granules secrete ADP and calcium to reinforce platelet aggregation and platelet-surface coagulation reactions.4 The alpha granules secrete a large array of proteins including, platelet factor 4, fibronectin, thrombospondin, platelet-derived growth factor, fibrinogen, plasminogen, factors V and VIII and vWF) to the exterior, and the arachidonate products of prostaglandin G2 (PGG2), prostaglandin H2 (PGH2) and TxA2 (the formation of which is blocked by aspirin), are also released causing platelet contraction. Aggregation Contact with collagen, and with thrombin formed from tissue injury, triggers platelet liberation of ADP (ADP binding to its platelet receptor is inhibited by ticlopidine and 36 Haemostasis, Platelet function and Coagulation clopidogrel) and serotonin, and formation of thromboxane A2 (TxA2) from platelet-membrane phospholipids (blocked by aspirin), stimulating vasoconstriction, fibrin deposition and platelet aggregation. The aggregation of platelets is mediated by membrane glycoproteins IIb/IIIa and a fibrinogen link (Figure 3.1).Glycoprotein IIb/IIIa antagonists inhibit platelet aggregation by blocking fibrinogen binding to activated glycoprotein IIb/IIIa receptors. Platelet aggregation does not occur in the absence of divalent cations or fibrinogen, which explains why a prolonged bleeding time occurs in patients with hypofibrinogenaemia. PLATELET DISORDERS Thrombocytopenia The circulating platelet count normally ranges from 150,000 to 400,000/µL. Thrombocytopenia is usually defined as a platelet count less than 100,000/µL. Causes. The causes of thrombocytopenia include those disorders listed in Table 3.2. Clinical features. The main clinical feature is bleeding. Patients who have platelet counts: - Below 100,000 /µL have an abnormal bleeding time and an abnormal Hess test - Below 80,000 /µL have prolonged bleeding with trauma or surgery - Below 40,000 /µL have spontaneous purpuric spots - Below 20,000 /µL have spontaneous bleeding (e.g. haematemesis, epistaxis). The characteristic feature of thrombocytopenic bleeding is that it occurs immediately after injury. Spontaneous bleeding may present with purpura (i.e., capillary haemorrhages, the size of a pinhead, into subcutaneous tissues on legs, conjunctival or buccal mucosa), ecchymoses, mucosal bleeding (e.g. epistaxis, menorrhagia) and cerebrovascular haemorrhage. In women, menorrhagia may be the first sign. Table 3.2 Causes of thrombocytopenia Reduced production neoplasia, aplastic anaemia drugs, severe sepsis, radiation, chemicals folate or B12 deficiency Reduced survival antibody-induced idiopathic thrombocytopenic purpura, SLE, CLL, haemolytic anaemias drugs (quinidine, quinine, heparin, sulphonamides, penicillins, cephalosporins) nonantibody induced prosthetic cardiac valves, DIC, massive transfusion thrombotic thrombocytopenic purpura hypersplenism Sequestration of platelets hypothermia Investigations. The investigations include: 1. Platelet count 2. Bone marrow: the megakaryocyte count is reduced if there is a decreased production of platelets, and increased if there is a reduced platelet survival. 37 Haemostasis, Platelet function and Coagulation 3. Hess (or tourniquet) test: this is performed by inflating a tourniquet on the patient's arm, midway between the systolic and diastolic pressures, for 5 min. The cuff is then deflated and the number of petechiae in a circle of 3 cm diameter and 1 cm below the antecubital fossa are counted. If there are more than 20 petechiae, the test is positive. If the count is less than 10, the test is normal. Between 10 - 20 the test is borderline. The test is positive in thrombocytopenia and in conditions that cause nonthrombocytopenic purpuras. 4. Bleeding time: this is performed by inflating a blood pressure cuff on the arm to be tested to a pressure of 40 mmHg. An incision 9 mm long and 1 mm deep on the anterior surface of the midforearm is made with a scalpel. The incision is touched at exactly 30 s intervals with a piece of absorbent paper, and the time interval until blood no longer moistens the paper is recorded. The normal bleeding time is 5 + 3 min (2 - 8 min). The bleeding time is prolonged with thrombocytopenia, aspirin and other NSAIDs, a packed cell volume less than 30%,5 (as a low packed cell volume reduces normal platelet margination6, thus bleeding times should be standardised to a haematocrit of greater than 35%),7 uraemia (some of which may be due to a reduced haematocrit), hypothyroidism, vWD, penicillins, cephalosporins and massive transfusion.8 While the bleeding time is often described as the best single test for platelet function, it has not been shown to be an accurate predictor of surgical bleeding.9 5. Other platelet function tests: platelet aggregation and secretion function tests are only performed when a specific platelet disorder is suspected. Treatment. The treatment may include: 1. Platelet concentrate: administered through a clean standard blood giving set, platelet concentrate (i.e. platelets harvested from six donors) will raise the platelet count by about 30,000/µL, and should be used in postoperative patients or patients who are bleeding and have a platelet count of less than 50 - 100,000/µL. Platelet concentrate should also be given to patients who have platelet counts less than 5 - 20,000/µL who may not be bleeding, because they are at risk of spontaneous haemorrhage.10,11 However, appropriateness of platelet transfusion also depends on platelet function, timing and nature of an invasive procedure, presence of an infection or coagulopathy, or the administration of chemotherapy. The half-life of transfused platelets is usually 2 - 3 days. Platelet viability may be assessed by measuring the platelet count 1 h after the platelet transfusion.12,13 2. DDAVP: desmopressin (DDAVP) is a vasopressin analogue which has a pronounced antidiuretic action (i.e. a high affinity for V2 receptors), but virtually no pressor activity (i.e. no affinity for V1 receptors). Intravenous desmopressin (0.3 µg/kg over 30 min or 300 µg intranasally14), has been used to decrease the bleeding in patients with renal failure,15,16 cirrhosis,17,18 vWD.19 platelet defects (NSAID-induced and congenital platelet defects20,21) and postoperative cardiac22,23 and orthopaedic surgery.24 It increases circulating plasma levels of VIII/vWF complex by three- to five- fold (reaching a maximum at 60 - 120 min) and tissue plasminogen activator, by releasing endothelial stores of these factors.25 It also increases plasma levels of XII.26 It should be given with caution in patients with cerebral or coronary atherosclerosis as there is an increased risk of coronary and cerebral artery thrombosis with its use. 3. Fibrinolytic inhibitors: fibrinolytic inhibitors of epsilon-aminocaproic acid (15 mg/kg/hr) or tranexamic acid (10 mg/kg 8-hourly) are sometimes given following DDAVP to inhibit the activity of the associated increase in plasminogen activator. Also EACA may reduce bleeding in patients with immune and nonimmune thrombocytopenia.27 4. Specific treatment: this involves the treatment of the underlying cause. For example, folic acid and B12 repletion in deficient states, withdrawal of an offending toxin or drug (platelet count usually returns to normal in 7-10 days), splenectomy in some instances of hypersplenism, 38 Haemostasis, Platelet function and Coagulation and corticosteroids, immunosuppressants or plasmapheresis for autoimmune (i.e. antibody induced) thrombocytopenias. 5. Recombinant human megakaryocyte growth and development factor: Pegylated recombinant human megakaryocyte growth and development factor (0.03 - 1 µg/kg subcutaneously for up to 10 days) has been used sucessfuly in the management of thrombocytopenia in patients with advanced cancer.28 Platelet defects in disease Renal failure Haemostatic abnormalities occur in renal failure due to abnormal platelet adherence and aggregation, and abnormal vasoconstriction; and nitric oxide (which inhibits collagen-induced platelet aggregation29) may be partly responsible for the bleeding tendency.30 Treatment with DDAVP (0.3 µg/kg or 20 µg/70 kg, in 50 mL of saline infused over 30 minutes) may give temporary relief (i.e. 4 - 12 hr), whereas cryoprecipitate produces an effect which lasts for 24 36 h. Conjugated oestrogens (intravenous 'Premarin' 0.6 mg/kg daily for 5 days, i.e. 40 mg daily for a standard man, or a total of 200 mg31) may also restore bleeding time in renal failure patients for 3 - 14 days. Erythropoietin may be used to increase the PCV and thus reduce the PCV effect on the bleeding time. Hepatic failure Haemostatic defects occur in hepatic failure due to a reduction in all coagulation factors (apart from factor VIII), fibrinolysis and thrombocytopenia (which may be due to folate deficiency, hypersplenism or marrow depression). Desmopressin (DDAVP, 0.3 µg/kg) has been used to reduce the bleeding time in these patients. Antiplatelet agents Antiplatelet agents have been used to target the various steps of platelet function Aspirin (acetyl-salicylic acid) Action. For antiplatelet therapy, aspirin is the agent of choice. It inhibits platelet aggregation mediated through activation of the arachidonic-thromboxane pathway (but not platelet aggregation induced by ADP, collagen or low levels of thrombin). Aspirin irreversibly acetylates and inactivates platelet and megakaryocyte cyclooxygenase (prostaglandin G/H synthase), directly inhibiting conversion of arachidonic acid to prostaglandin G2 which reduces prostaglandin H2 and ultimately TxA2 production (and its platelet effects of aggregation and vasoconstriction)32. The antiplatelet effect is maximal in 20 minutes and it prolongs bleeding time for the life of the platelet (i.e. 5 - 7 days)33. While long-term aspirin administration in doses as low as 20 mg/day depress the platelet thromboxane formation by 90%, larger doses are needed to prevent the thromboxane-induced platelet activation in vivo,34 with 100 mg almost completely suppressing the biosynthesis of TxA2 in normal subjects and in patients with atherosclerotic vascular disease. The effect of aspirin on endothelial cyclooxygenase is only transient (i.e. lasts for only 2 - 4 hr35) because the endothelial cyclooxygenase is less sensitive to aspirin and is able to be resynthesised (unlike platelet cyclooxygenase) between doses of aspirin. Prostacyclin inhibition (and therefore inhibition of vasodilation) with aspirin therapy is minimal36.. Indications. Aspirin is used to:37,38,39,40,41 - Prevent myocardial infarction and reduce mortality in patients with stable and unstable angina and evolving myocardial infarction. 39 Haemostasis, Platelet function and Coagulation - Preserve coronary artery vein grafts (if administered 48 h postoperatively, although the usual recommendation is 325 mg to start 6 hr after surgery42) and reduce morbidity and mortality associated with coronary artery bypass grafting.43 Reduce abrupt closure (but not restenosis) following coronary artery angioplasty. Prevent thromboembolic complications of cardiac valve disease. Reduce the incidence and mortality of stroke in patients with TIAs, and in patients with previous stroke. Prevent occlusion in obliterative arterial disease of lower limbs. Prevent colorectal cancer, particularly in patients with familial adenomatous polyposis, or to prevent recurrence of gastrointestinal cancer in these patients after colectomy.44 However, the reduction in colorectal cancer requires regular aspirin use for 10 (or more) years.45 It has also been used to: - Reduce preeclampsia in nulliparous women who have a systolic blood pressure that is persistently 120 mmHg or greater.46,47 However, in a large prospective, randomised, doubleblind, placebo-controlled trial, low-dose aspirin started between the 13th and 26th week of gestation did not reduce the incidence of preeclampsia or improve perinatal outcomes in pregnant women at high risk for preeclampsia.48 Dosage. Aspirin is usually administered in a dose ranging from 100 - 325 mg/day,49 (e.g. a loading dose of 325 mg with a daily dose of 100 mg). To reduce the incidence of a stroke, a dose of 30 - 75 mg/day is as effective as a daily dose of 325 mg. Side-effects. These include peptic ulceration, gastrointestinal haemorrhage, asthma and angio-oedema. Sulphinpyrazone, indomethacin and other NSAIDs The effect of these agents on platelet cyclooxygenase, unlike aspirin, is usually reversible after 24 - 48 hr. Dipyridamole Dipyridamole is a phosphodiesterase inhibitor (predominantly phosphodiesterase V)50 which increases platelet cAMP, and is often combined with aspirin to gain an additive antiplatelet effect. The antiplatelet effect has only been demonstrated when higher levels of dipyridamole than that attained by conventional oral doses are achieved. In a comprehensive review of all studies in which dipyridamole or dipyridamole plus aspirin were used, it was concluded that there was little evidence to support its use as an antiplatelet agent.51 Dazoxiben Theoretically drugs that inhibit thromboxane synthetase, such as dazoxiben, should be superior to aspirin as antiplatelet agents. In addition to inhibiting TxA2 production they should augment prostacyclin release by diverting platelet endoperoxide to serve as substrate for prostacyclin synthesis in the vascular endothelium. However the prostaglandin endoperoxides are proaggregatory in their own right and the thromboxane synthetase inhibitors have not been found to prevent platelet aggregation as efficiently as aspirin. Thienopyridines (Ticlopidine and Clopidogrel) Action. Ticlopidine and its chemical analogue clopidogrel (which is six times as potent as ticlopidine) are antagonists of ADP-induced platelet aggregation. They selectively and irreversibly (i.e. noncompeditively) inhibit ADP binding to its platelet receptor thereby 40 Haemostasis, Platelet function and Coagulation inhibiting ADP dependent activation of glycoprotein IIb/IIIa complex which is the major receptor for fibrinogen on the platelet surface.52 They have no effect on phospholipase A activity or thromboxane A2 and prostacyclin synthesis, and no direct effect on either cyclic AMP-phosphodiesterase or adenylyl cyclase.53 Both ticlopidine and clopidogrel are inactive when tested in vitro, thus the antiplatelet activity of both agents is produced by unidentified metabolites, and their onset of action is delayed for hours or days, depending on the dose.54 Ticlopidine also reduces plasma fibrinogen, increases RBC deformity, inhibits platelet adhesion, prolongs bleeding time, and blocks the release reaction of platelets. The antiplatelet effect is associated with a twofold to fivefold prolongation of the bleeding time. As clopidogel has a better adverse reaction profile when compared with ticlopidine it has largely replaced ticlopidine in clinical practice.55 Indications. Clopidogrel and ticlopidine have a role in the primary and secondary prevention of cerebrovascular infarctions and other thromboembolic complications in patients who have suffered transient or reversible cerebral thromboembolic events.56,57 They reduce the incidence of stroke, myocardial infarction and death in patients who have previously had a stroke or TIAs.58 Clopidogrel also reduces the combined incidence of myocardial infarction, stroke and vascular deaths in patients with atherosclerotic vascular disease, and in this regard both of these agents are better than aspirin.59 Currently, they are administered for the prevention of stroke, myocardial infarction, or vascular death in patients with atherosclerotic vascular disease who are intolerant of aspirin.60 Dosage. An oral dose of 250 mg of ticlopidine twice daily is often administered. It has a bioavailability of 80 - 90%. Its onset of activity is after 24 - 48 hr, with maximal activity occurring after 3 - 5 days and activity still detectable 10 days after the last dose. The elimination half-life for this agent is not known. An oral dose of clopidogrel 75 mg daily is equivalent to an oral dose of ticlopoidine of 250 mg twice daily. Maximal inhibition of ADP induced platelet aggregation occurs after 3 – 5 days after the initiation of the standard dose (e.gt. 75 mg clopidogrel) but an oral loading dose of 300 – 600 mg of clopidogrel produces detectable inhibition of ADP-induced aggregation after 2 hours, which is maximal at 4-6 hours.61 Side-effects. The side effects of ticlopidine include nausea, vomiting or diarrhoea in up to 10%, skin rash in 4% and reversible neutropenia in 2% of patients. The adverse effects of neutropenia, thrombocytopenia or pancytopenia appear within the first three months of treatment (requiring haemotological monitoring every two weeks for the first three months of therapy) and are readily reversible (if neutrophil count < 1200) upon withdrawal of the drug. Persistent diarrhoea necessitating discontinuation of the drug occurs in up to 5% of patients. It also may cause cholestatic jaundice, an increase in serum cholesterol and thrombotic thrombocytopenic purpura.62 Ticlopidine reduces phenytoin metabolism, and may lead to phenytoin toxicity in previously stable patients.63 Clopidogel, at 75 mg/day, appears to have no toxic bone marrow effects (or a similar rate of severe neutropenia to aspirin i.e. 0.05%) with a lower incidence of skin rash and diarrhoea when compared with ticlopidine (although a higher incidence when compared with aspirin) and a lower incidence of thrombotic thrombocytopaenic purpura (and usually within the first two weeks of treatment64). It also has a lower incidence of severe gastrointestinal haemorrhage when compared with aspirin (e.g. 0.49% cf. 0.71%).59 Glycoprotein IIb/IIIa receptor inhibitors The final step leading to the formation of the platelet plug is platelet aggregation, which is mediated by the binding of adhesive proteins to the glycoprotein IIb/IIIa receptor. Drugs that inhibit glycoprotein IIb/IIIa receptors (e.g abciximab - developed from murine monoclonal 41 Haemostasis, Platelet function and Coagulation antibody Fab fragments to the IIb/IIIa receptor, trigramin - from snake venom, and natural and synthetic peptides or disintegrins such as integrelin, lamifiban and tirofiban) prevent the binding of fibrinogen to these receptors and, unlike aspirin, inhibit platelet aggregation irrespective of the pathway responsible for initiating aggregation.65 These drugs have been used in clinical studies in patients with unstable angina to reduce myocardial infarction, and during coronary angioplasty to reduce restenosis. Abciximab produces a dose dependent irreversible blockade of the IIb/IIIa receptor, and an effect of > 80% blockade occurs with 0.25 mg/kg as an intravenous bolus followed by an intravenous infusion at 10 ug/min for 12 hours (this degree of receptor blockade is required to prevent ischaemic complications in response to thrombotic provocations of balloon angioplasty-induced damage to a stenotic atherosclerotic blood vessel, until the surface is no longer highly reactive to platelets. A receptor blockade of 50% is not effective).66 While the drug is cleared rapidly from the circulation, platelet-bound drug persists for several days. Abciximab also binds to the vitronectin receptor (unlike the other peptide and nonpeptide antagonists) an effect which may be important in its action in preventing thrombin generation and restenosis following PTCA and coronary artery stenting.67 Bleeding is the major side effect (particularly from venous and arterial access sites) and can only be overcome by platelet transfusions. Thrombocytopaenia (which may be profound i.e. less than 10,000 /µL)68 and alveolar haemorrhage69,70 may also occur, requiring platelet transfusion and discontinuation of all antiplatelet and anticoagulant therapy.71 Platelet counts should be performed 2-4 hours after initiation of abciximab therapy and 24 hours later, to monitor this rare complication.71 While human-antichimaeric antibodies develop in about 6% of patients,72 in one study of approximately 500 patients, abciximab was readministered with a similar efficacy and incidence of allergic reactions and thrombocytopaenia as with first-time abciximab recipients.73 Tirofiban and lamifiban produce a rapidly reversible inhibition of the IIb/IIIa receptor. With normal renal function tirofiban has a half life of 1.9 hours and lamifiban two hours. Other agents While, agents that block glycoprotein Ib/vWF interaction (e.g. monoclonal antibodies to vWF or glycoprotein Ib) have been used experimentally, there is no experience with these agents in humans.74 Prostacyclin has also been used to suppress platelet activity, although largely in extracorporeal circuits where heparin cannot be used.75 Antiplatelet activity has also been reported with many other agents including, beta-lactam antibiotics (e.g. penicillins, cephalosporins), calcium-channel blockers, EACA, heparin, tricyclic antidepressants, phenothiazines, dextrans, ketanserin, radiographic contrast agents and halothane,76,77 although they are not commonly used for their antiplatelet effect. COAGULATION Coagulation activation Coagulation consists of a sequence of amplifying zymogen activations via an extrinsic or intrinsic pathway, generating factor X activator to convert prothrombin to thrombin which converts fibrinogen to fibrin (Figure 3.2).78 1. The intrinsic pathway: the exposure of blood to a negatively charged surface causes factor XII to attach to the surface and form two activated factor XII molecules known as alphaXIIa and beta-XIIa. Alpha-XIIa remains bound to the surface and activates factor XI, and factor XIa activates factor IX. Exposure to a negatively charged surface also causes high molecular weight (HMW) kininogen to attach to the surface with prekallikrein. Beta-XIIa 42 Haemostasis, Platelet function and Coagulation (which is not retained on the surface) activates prekallikrein (but not factor XI) to kallikrein. Kallikrein splits bradykinin (a potent peripheral arteriolar vasodilator - due to endothelial release of NO and prostacyclin79 - with a half-life of 20 s) from HMW kininogen, reciprocally activates factor XII and activates plasminogen to plasmin. It is suggested that perhaps the net effect of activation of Hageman factor to its fragments is not to promote clotting by activating factor XI but, via the action of kallikrein and plasmin, favour vessel patency by initiating vasodilation and fibrinolysis,80 particularly as patients who have an autosomal recessive hereditary deficiency of one of the contact factors (i.e. factor XII, prekallikrein or HMW kininogen), despite having a prolonged APTT, do not bleed abnormally even after trauma. Figure 3.2 A diagram of blood coagulation reactions. HMWK = high molecular weight kininogen, KAL = kallikrein, PLAT. LIPID = platelet procoagulant phospholipid, PREK = prekallikrein, TF = tissue factor (Reproduced, with permission, from Rapaport SI. Chapter 25 Haemostasis. In: West JB ed. Best and Taylor's Physiological Basis of Medical Practice, 11th Ed. Baltimore: Williams and Wilkins, 1985:409-436). 2. The extrinsic pathway: factor VII is activated by tissue phospholipid. 3. Factor X activation: factor X is activated by either a complex (from the intrinsic pathway) consisting of factor VIIIa (activated by thrombin), platelet phospholipid, Ca2+ and factor IXa, or a complex (from the extrinsic pathway) consisting of tissue phospholipid, Ca2+ and factor VIIa. 43 Haemostasis, Platelet function and Coagulation 4. Thrombin formation: activated factor X then forms a complex with platelet phospholipid, Ca2+ and factor Va (activated by thrombin) to form a prothrombin activator, which converts prothrombin to thrombin. 5. Fibrin formation: thrombin is a proteolytic enzyme with a molecular weight of 30 000 36 000; it cleaves fibrinogen to form fibrin and activates factor XIII to convert fibrin to a stable cross-linked fibrin polymer. Fibrin adsorbs large amounts of thrombin at the site of its production and this property is given the term 'antithrombin I' although the thrombin so adsorbed is not inactivated and may reappear during clot retraction or fibrinolysis. While a single extrinsic or intrinsic pathway activation explains the in vitro coagulation tests [i.e. the APTT and the International Normalised Ratio (INR) assesses the intrinsic and extrinsic systems, respectively], there are many interactions between the intrinsic and extrinsic systems, indicating that both pathways act during in vivo coagulation. In particular, factor VIIa activates factor IX; factors IXa, Xa, XIIa and thrombin activate factor VII; factor Xa activates VII; and thrombin activates platelet aggregation, factors I, XIII, VIII and V, Protein C (with the endothelial thrombomodulin as a cofactor) and plasminogen81 (Figure 3.3). Figure 3.3 The many actions of thrombin in blood coagulation. Prot C = Protein C, Prot Ca = activated Protein C (Reproduced, with permission, from Rapaport SI. Chapter 25 Haemostasis. In: West JB ed. Best and Taylor's Physiological Basis of Medical Practice, 11th Ed. Baltimore: Williams and Wilkins, 1985:409-436). Coagulation factors Fibrinogen (factor I) Fibrinogen is an acute phase reactant that circulates in the plasma as a gamma-globulin at a concentration of 2 - 4 g/L. It is made up of two pairs of three nonidentical polypeptide chains (i.e. alpha, beta and gamma chains) which are held together by disulphide bonds. Thrombin cleaves two pairs of arginine-glycine peptide bonds in fibrinogen, producing small peptides known as fibrinopeptide A and B from both the alpha and beta chains, and converts fibrinogen to fibrin monomer. Fibrin monomers are composed of a small central E domain connected to two larger D domains (Figure 3.4), and they spontaneously polymerise (catalysed by factor XIIIa) with covalent cross-linking of the adjacent D domains to form fibrin. 44 Haemostasis, Platelet function and Coagulation Vitamin K factors (i.e. factors II, VII, IX, and X, and Proteins C, S and Z) The metabolic role of vitamin K is to serve as a cofactor for an hepatic microsomal enzyme that converts specific glutamyl residues in the protein precursors of factors II, VII, IX and X (and Protein C, S and Z), to gamma-carboxyglutamyl residues.82 Vitamin K deficiency takes up to 3 weeks to develop after ceasing intake. With 10 - 50 mg of intravenous vitamin K, haemostatic levels of the vitamin K factors (i.e. > 30%) are achieved within 3 - 4 hr, although if oral anticoagulation is once again required, if these doses of vitamin K are used, it may take 1 - 3 weeks before satisfactory anticoagulation is again achieved. Figure 3.4 A diagrammatic representation of fibrin polymerisation and degradation. (Reproduced, with permission, from Shafer KE, Santoro SA, Sobel BE, Jaffe AS. Monitoring activity of fibrinolytic agents. a therapeutic challenge. Am J Med 1984;76:879-886). 45 Haemostasis, Platelet function and Coagulation Proaccelerin (factor V) Factor V is synthesised in the liver. Its properties are listed in Table 3.3. Antihaemophiliac factor (factor VIII) Factor VIII is a large complex protein that circulates in close association with vWF,83 both of which arise from the endothelium. Adrenaline, vasopressin and its analogue DDAVP, all increase the plasma concentration of factor VIII and have been used to aid haemostasis in patients with haemophilia A. Factor VIII refers to the protein which is deficient or abnormal in haemophilia A. Factor VIIIC refers to the biological activity of factor VIII as measured by conventional blood coagulation assays. Factor VIII clotting antigen (VIIICAg) describes the antigenic determinants of factor VIII as assayed by immunoradiometric assay. von Willebrand factor (vWF) vWF refers to the protein which is deficient or abnormal in von Willebrand's disease; vWF antigen (vWFAg) describes the antigenic determinants of vWF. The factor forms by far the largest portion of the factor VIII/vWF complex, occurring with factor VIII in a ratio of 50:1.84 The VIII/vWF complex circulates in multimeric forms. Its larger multimers are essential for platelet adhesive activities (von Willebrand’s disease is usually associated with a prolonged bleeding time, and a normal Hess test), as the lower molecular weight multimers have a reduced capacity to induce platelet adhesion.85 Endothelial cells are the source of plasma vWF. An acquired vWD can be caused under conditions of high fluid shear stress (e.g. AS, VSD or patent ductus) causing the metalloprotease (ADAMTS 13 ) to cleave the large vWF multimers and create inactive derivatives.86 The antibiotic ristocetin facilitates binding of the vWF to platelets and agglutinates platelets in normal plasma but not platelets suspended in plasma from a patient with von Willebrand’s disease. Table 3.3 Factor XII XI IX VII VIII V X II I XIII Properties of coagulation factors Biological Minimum Synonym molecular weight Half life (Da) (days) Hageman factor 80,000 Prekallikrein Fletcher factor 88,000 HMW kinogen Fitzgerald factor 120,000 Plasma thromboplastin 160,000 antecedent (PTA) Christmas factor 57,000 Proconvertin 50,000 Antihaemophilic factor (AHF) 100,000-2,000,000 Proaccelerin 330,000 Stuart factor 57,000 Prothrombin 70,000 Fibrinogen 340,000 Fibrin-stabilizing factor (FSF) plasma (tetrameric) 320,000 platelet (diameric) 160,000 46 haemostatic level (%) 2 0 0 2.5 0 1 (20 h) 0.2 ( 5 h) 0.5 1.5 1.5 (40 hr) 3 (70 hr) 4.5 40 20 30 10 30 30 1 g/L 7 7 5 20 Haemostasis, Platelet function and Coagulation Factors XII and XI Factor XII and factor XI are synthesised in the liver. Their properties are listed in table 3.3. Factor XI circulates in the plasma as a complex with HMW kininogen.87 An elevated level of factor XI is a risk factor for venous thrombosis due to a sustained generation of thrombin.88 Factor XIII Plasma factor XIII is a tetramer with a molecular weight of 320,000 and is activated by thrombin (in the presence of Ca2+) to catalyse the formation of covalent bonds between the polymerising fibrin molecules. Factor XIIIa also participates in the cross-linking of fibrin molecules to fibronectin and to an alpha 2-plasmin inhibitor as well as cross-linking fibronectin to collagen. Platelets contain 30-50% of the total blood factor XIII in a diameric form (mol. wt 160,000), the function of which is not completely understood. Severe ulcerative colitis is associated with factor XIII deficiency and intravenous factor XIII concentrate for 10 days has been reported to reduce bloody diarrhoea and increase body weight in these patients.89 Coagulation inhibition Antithrombin I refers to the capacity of fibrin to adsorb thrombin, antithrombin II has been found to be the same as antithrombin III, antithrombin VI represents the inhibitory effects of FDPs and antithrombin IV and V are of uncertain physiological significance.90 Antithrombin III Antithrombin III (AT III) is an alpha-2-globulin with a half-life of 70 hr and a molecular weight of 58,200. It is synthesised largely in the liver by hepatocytes, although a portion is also synthesised by the endothelium.91,92 The normal plasma level is 150 mg/L. AT III is the principal antagonist of the serine proteases (i.e. XIIa, XIa, Xa, IXa, VIIa, thrombin, plasmin and kallikrein) and accounts for 85% of plasma inhibition of thrombin. An arginine reactive centre of the AT III molecule is responsible for the AT III inhibition of the active serine centre of the serine proteases. Heparin binds to lysine sites on AT III and produces a conformational change at the arginine reactive centre, to potentiate the serine protease inhibition of AT III. The potentiation is greatest for thrombin and factor Xa inactivation.93 The half-life and serum levels are reduced with heparin infusions because the heparin-AT III complex has a higher rate of removal from the circulation94 (i.e. the half-life is reduced from 70 to 50 hr). The AT III levels return to normal 2 - 3 days after ceasing the heparin infusion. Heparin cofactor II Heparin cofactor II is a plasma antiprotease with a molecular weight of 65,600 which is activated by heparin and (unlike AT III) dermatin sulphate. Heparin cofactor II also differs from AT III in that it only inhibits thrombin. Protein C anticoagulant pathway Protein C is a vitamin K dependent glycoprotein with a molecular weight of 62,000, a half life of 5 hr, which is activated to a serine protease by a thrombin-thrombomodulin complex on the endothelial surface (Figure 3.5).95 Thrombomodulin is an endothelial cell membrane glycoprotein (mol. wt. of 75,000) which contains thrombosis by binding and inactivating the procoagulant effect of thrombin (converting it from a procoagulant enzyme into a potent activator of protein C) generating activated Protein C (i.e. Protein Ca). In the presence of phospholipid and Ca2+, Protein Ca inactivates thrombin, factors Va and VIIIa, inhibits the conversion of prothrombin to thrombin by platelet-bound Va and Xa, and stimulates fibrinolysis by neutralising a tissue plasminogen activator inhibitor.96 Protein S is a vitamin K47 Haemostasis, Platelet function and Coagulation dependent plasma glycoprotein (mol. wt. 69,000) which acts as a cofactor for the protein Ca inactivation of factors Va and VIIIa.97 Figure 3.5 A diagram depicting the conversion of Protein C to Protein Ca (which in turn inactivates factors VIIIa and Va) by a thrombin-thrombomodulin complex on the endothelial cell surface (Reproduced, with permission from Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986;314:1298-1304). A familial thrombophilia characterised by an autosomal dominant inheritance, poor anticoagulant response to activated protein C and an incidence 5-10 times that of thrombophilia caused by deficiencies in ATIII, protein C or protein S, has recently been described.98,99 The condition is diagnosed by the activated protein C resistance (APCR) test, where a standard amount of activated protein C (APC) is added to the patient's plasma and the prolongation (i.e. a normal response), or resistance to prolongation (i.e. an abnormal response), of the APTT is assessed.100 The APCR test is usually expressed as a ratio (i.e. APTT with APC/APTT without APC). The ratio is normally 1.9 to 4.0 and APC resistance is present if the ratio is greater than 4.0. The disorder is thought to be due to a selective defect in factor V (i.e. factor V Leiden, which has a replacement of arginine with glutamine at position 506 thereby eliminating the protein C cleavage site in factor V),101 which is resistant to inactivation by activated protein C,102 as the defect is corrected by the addition of normal unactivated factor V.103 Other plasma coagulation inhibitors An alpha-2-macroglobulin accounts for 15% of plasma inhibition of thrombin.104 Factor Xa is inhibited by AT III, but in contrast to thrombin is less sensitive to alpha-2-macroglobulin although is markedly inhibited by alpha-1-antitrypsin (although a deficiency in alpha-1antitrypsin is not associated with excessive thrombosis). Tissue factor pathway inhibitor is a serine protease inhibitor (mol. wt. 34,000, the majority of which is bound to endothelium), which is synthesised by endothelial cells and 48 Haemostasis, Platelet function and Coagulation megakaryocytes.105 It is a factor Xa-dependent inhibitor. First it complexes with and inactivates factor Xa, then factor VIIa is inactivated within the factor Xa/tissue factor complex. Protein Z-dependent protease inhibitor. Protein Z forms a Ca2+- dependent complex with activated factor X (Xa) at a phospholipid surface and serves as a cofactor to enhance (by more than 1000 x) the inhibition of Xa by a protein-Z-dependent protease inhibitor (ZPI).106 Coagulation Blood Products Fresh frozen plasma Fresh frozen plasma (FFP) is the anticoagulated plasma prepared from the collection of one unit of blood (i.e. approximately 250 ml or 8% of the plasma volume), that is frozen (and stored below -30ºC) within 4 - 6 hr of collection. It is preferable to administer FFP within the recipient's ABO blood group, and to use it within 2 - 6 hr of thawing. If it is used for: 1. factor VIII replacement, then as each unit contains 0.7 u/ml (i.e. 70% of factor VIII is retained, or 175 u/250 ml), 6 units (i.e. 1.5 L) will be needed to increase factor VIII by 30%. 2. factor XII, XI, X, IX, VII, V and II replacement, then as each unit contains 1 u/mL (i.e. 100% of these factors are retained), 4 units (i.e. 1 litre) will be needed to increase these factors by 30%. 3. factor I (fibrinogen) replacement, then as each unit contains 600 mg of fibrinogen, 5 u (i.e. 1.25 L) will be needed to increase fibrinogen by 1 g/L (each unit raises the fibrinogen level by 0.2 g/L). Cryoprecipitate Cryoprecipitate is prepared by thawing FFP at 4ºC and recovering the cold precipitate. This contains 20% of the fibrinogen and 30% of factor VIII, factor XIII, vWF and fibronectin from the original plasma to provide 10 - 15 mL with 80-100 u of factor VIII and 150 mg of fibrinogen from each unit. The plasma of 5 u of blood are commonly pooled to give 50-80 mL with 400 u of factor VIII and factor XIII and 0.6 g of fibrinogen. Cryoprecipitate may be used up to 6 hr after thawing. ABO group compatibility is preferred but not essential. Recombinant Factor VIIa (rFVIIa) Recombinant factor VIIa (rFVIIa) has a half-life of about 2 h and been used empirically in patients with traumatic bleeding (60µg/kg i.v),107 haemophilia A or B with inhibitors108 (100 µg /kg 2-hourly until haemostasis is achieved)109, thrombocytopaenia110 and renal failure with aspirin and low molecular weight heparin (bolus dose of 120 µg /kg).111 The advantage of intravenous rFVII in the management of coagulopathic haemorrhage, is that it appears to enhance haemostasis at the site of injury, without systemic activation of the coaculation cascade112 and as such is being used more and more in the critically ill haemorrhagic patient.113 In patients with severe coagulopathy with intractable bleeding the dose is usually 100 µg/kg (and rounded to the nearest 1.2 mg) as a single bolus (over 2-5 minutes) every 2-3 hours until the bleeding is controlled. Recombinant Factor VIII (rFVIII) Recombinant Factor VIII is comparable to plasma-derived factor VIII (e.g. has a similar half-life) and is effective in treating bleeding disorders. Factor IX complex (Prothrombinex-HT, CSL) Prothrombinex contains 600 u of factor X, 500 u of factor IX and 550 u of factor II in a vial of freeze dried product, and thus will raise each of these factors by approximately 15% of the 49 Haemostasis, Platelet function and Coagulation normal amount. If it is used in patients who have vitamin K deficiency (e.g. acute or chronic liver disease or warfarin overdosage) then FFP should also be given to supply factor VII. Coagulation tests Apart from fibrinogen, all factors are measured in terms of activity, as a percentage of control plasma. Bleeding tends to occur if the fibrinogen level is less than 1 g/L, or the activity of a factor is less than 30% (Table 3.3). A reduction in plasma ionised Ca2+ commensurate with life is not associated with excess bleeding. Coagulation tests are usually indicated if there is a disease commonly associated with bleeding problems (e.g. acute or chronic liver failure, massive transfusion, DIC), malnutrition or malabsorption, a history of a bleeding disorder (e.g. easy bruising, prolonged bleeding with tooth extraction, tonsillectomy or surgical procedure) or a need to monitor anticoagulant therapy114. Prothrombin time (PT) Tissue thromboplastin is added to recalcified platelet-poor plasma and the time for a clot to appear is compared with the time for a clot to appear with normal plasma. The result may be expressed in seconds, as a percentage or as a ratio. This test reflects the function of the extrinsic pathway and therefore the combined activity of factors VII, X, V, II and I, and is prolonged in the presence of a deficiency (or antagonism) of any of these factors. The test is sensitive to three of the four vitamin K-dependent clotting factors. At usual therapeutic doses, heparin has no effect on the prothrombin time;115 also, factors I and V have to be very low before the prothrombin time is affected. If the prothrombin time is prolonged and the APTT is normal an isolated factor VII deficiency exists. To standardise the estimation of prothrombin activity and correct for the differences in reagents and methods, a unit of measurement known as the International Normalised Ratio (INR) has been recommended.116 To calculate the INR the laboratory must first calibrate its own prothrombin method against a standard material which is provided by the Community Bureau of Reference in Brussels, Belgium. The laboratory can then translate its prothrombin ratios (patients prothrombin time : control's prothrombin time) into an INR, the INR being that prothrombin ratio that would be obtained if the WHO reference thromboplastin were used to test the sample. Activated partial thromboplastin time (APTT) A contact activating agent and phospholipids are added to recalcified platelet poor plasma and the time is measured (in seconds) for a clot to form. The result is compared with the time for normal control plasma to clot. This test reflects the combined activities of factors XII, HMW kininogen, prekallikrein, XI, X, IX, VIII, V, II, I, and is prolonged in the presence of a deficiency or antagonism (e.g. heparin, FDPs, warfarin or lupus anticoagulant) of these factors. The test is independent of factor VII. False-positive results are often obtained if a sample of blood is obtained from an intravascular catheter which is continually flushed with heparin or through a preheparinised syringe needle. Thrombin time This test determines the time plasma takes to clot after adding a solution of thrombin. The test is prolonged in the presence of hypofibrinogenaemia or thrombin inhibitors (e.g. heparin and FDPs). 50 Haemostasis, Platelet function and Coagulation Fibrinogen assay Plasma fibrinogen levels are normally 2 - 4 g/L, and bleeding does not usually occur unless levels are less than 1 g/L. Fibrin degradation products (FDPs) These are formed by plasmin degradation of fibrin and fibrinogen and are elevated in the presence of intravascular fibrinolysis. They are measured in serum using a latex agglutination test (normal < 10 µg/mL). Cross-linked fibrin derivatives (XDPs or D-dimer) These are formed exclusively by plasmin degradation of mature cross linked fibrin (not by fibrinogen degredation) and are elevated in the presence of thrombolysis. They are measured in the plasma by latex agglutination or by the more sensitive enzyme-linked immunosorbent assay (normal < 200 ng/mL). Euglobulin clot lysis time (ECL) As the euglobulin fraction of plasma concentrates plasminogen activators and is relatively free of inhibitors of fibrinolysis, the lysis time of the clot formed from this fraction measures overall plasminogen activator activity. Normally, the lysis time is greater than 120 min, with times less than this indicating significant plasminogen activator activity (e.g. effective thrombolytic therapy).117 Thromboelastography (TEG) Thromboelastography provides a global assessment of coagulation within 20-30 min, measuring the interaction between platelets and the protein coagulation cascade from the initial platelet-fibrin interaction, to platelet aggregation and clot strengthening with fibrin cross linking, to fibrinolysis.118 Blood is placed in a heated (37ºC) cuvette which is oscillated. A pin is suspended from a wire into the blood and the forces transmitted from the oscillating cuvette to the pin (by fibrin strands) are amplified to give an TEG trace recorded on a paper moving at 2 mm/min (Figure 3.6). Abnormal TEG patterns occur with thrombocytopenia, coagulation factor defects, and fibrinolytic abnormalities (Figure 3.7). While there is some correlation between TEG abnormalities and the standard coagulation tests, in hepatic transplantation, cardiac surgery and massive transfusion, the TEG more reliably predicts abnormalities that are associated with perioperative bleeding. In hepatic transplantation, fresh frozen plasma (2 - 4 u) are given if the 'r' time is greater than 15 min, platelets 1 u/10 kg are given if the MA is less than 40 mm (even if the platelet count is normal) and cryoprecipitate 6-12 u is given for persistent poor clot formation (alpha angle < 40º) with normal MA.119 Generally, coagulation returns towards normal within 1 - 2 h after hepatic reperfusion.120 Coagulation disorders Coagulation disorders are characterised by bleeding, which may be delayed 3 - 6 hr after injury, with deep bruising and large surgical haematomas. Spontaneous retroperitoneal or mesenteric haemorrhage, subdural haemorrhage and haemarthroses (ankles, knees, elbows) are also common. There may also be a history of continuous bleeding (e.g. for up to 3 - 6 weeks) after a dental extraction. Causes The coagulation defects that cause bleeding are listed in Table 3.4. Congenital deficiencies of factors I, II, VII and X are extremely rare. Congenital deficiency of factor V (i.e. Owren's 51 Haemostasis, Platelet function and Coagulation disease) is also rare and may be associated with duplex system and patent ductus arteriosus. An acquired inhibitor of factor V may occur in patients with autoimmune disease121 Figure 3.6. A diagrammatic representation of the TEG variables. r = Reaction time (time from placement of blood into the cuvette until tracing reaches an amplitude of 2 mm. Normal range is 6 - 8 minutes) and is prolonged with coagulation factor deficiencies and anticoagulants. A small r value may occur with hypercoagulable states. K = clot formation time (time taken for the amplitude to increase from 2 mm to 20 mm. Normal range is 3 - 6 minutes), this is prolonged with coagulation defects. The alpha angle = angle formed by the slope of the TEG tracing from the r to the K value (normal value 50 - 60º) and is reduced with coagulation defects. Maximum amplitude (MA) is the greatest amplitude on the TEG trace and is a direct function of the strength of the clot (reduced with functional abnormalities of coagulation and platelets. Normal range 50-60 mm). A60 = the amplitude of the tracing 60 minutes after MA is achieved (normal range = MA - 5 mm). It is a measure of clot lysis and decreased with fibrinolysis. The clot lsis index = A60/MA x 100 (normal value is > 85%) is a measure of loss of clot integrity as a result of lysis (Reproduced with permission from Mallett SV, Cox DJA. Thromboelastography. Br J Anaesth 1992;69:307-313). Figure 3.7 Characteristic thromboelastographic patterns. A = normal trace, B = haemophilia, C = thrombocytopenia, D = fibrinolysis, E = hypercoagulability (Reproduced with permission from Mallett SV, Cox DJA. Thromboelastography. Br J Anaesth 1992;69:307-313). 52 Haemostasis, Platelet function and Coagulation Table 3.4 Causes of coagulation defects Congenital X-linked recessive causes (i.e. carried by X chromosome) Haemophilia A (factor VIII) Haemophilia B (factor IX) Autosomal dominant causes von Willebrand's disease Factor XI deficiency Dysfibrinogenaemias Autosomal recessive causes Deficiencies of factors I, II, V, VII, X Acquired Massive blood transfusion (factor dilution) Disseminated intravascular coagulation (factor consumption) Vitamin K malabsorption and deficiency (e.g. steatorrhoea, obstructive jaundice) inhibition (e.g. oral anticoagulants, salicylate intoxication) Liver disease Heparin Haemophilia A This is an x-linked disease that causes low or undetectable levels of factor VIII measured either as VIIIC or VIIIAg (some haemophiliacs may have normal or elevated VIIIAg, whereas others may have normal VIIIC with undetectable VIIIAg). Levels of vWF are normal or even raised and consequently the bleeding time is normal. An acquired anti-factor-VIII antibody may occur in 5-10% of haemophilia A patients (contrasting with haemophilia B patients who very rarely develop anti-factor-IX antibodies) which may also occur spontaneously in autoimmune disorders or in the post partum period. The infusion of 1u of factor VIII per kilogram of body weight will increase the plasma level of factor VIII by approximately 20 u/L. A minimal haemostatic level of 300u/l is usually necessary to treat relatively mild bleeding episode, a level of 500/l is generally considered the minimum for serious bleeding into joints or muscles, and in cases of major surgery or life threatening bleeding, normal factor VIII levels are maintained. Treatment of a patient with haemophilia A who has: 1. A minimal spontaneous bleeding, requires one dose of factor VIII of 10 u/kg (i.e. 2 bags of cryoprecipitate or factor VIII concentrate from 10 units of blood). 2. A moderate bleed (e.g. a fully developed haemarthrosis), requires 20 - 25 u/kg of factor VIII (i.e. four bags of cryoprecipitate), with a repeated dose, 12 and 24 hr later. 3. A severe bleed (e.g. a head injury or major trauma or surgery), requires 40 - 50 u/kg of factor VIII (i.e. eight bags of cryoprecipitate) with a 12-hourly dose of 20 - 25 u/kg of factor VIII (i.e. four bags of cryoprecipitate) for 7 - 10 days or until the bleeding is controlled. 4. An anti-factor-VIII antibody; the bleeding may be controlled by plasmapheresis and infusing plasma-derived or recombinant factor VIII.122 53 Haemostasis, Platelet function and Coagulation 5. Treatment with rFVIIa (35 - 70 µg/kg) appears to be treatment of choice in patients with acquired haemophilia or patients with anti-factor VIII antibody. The main disadvantages are a short half life (requiring application 2 - 3 hourly) and as there is no laboratory tests currently available to monitor the effectiveness of rFVIIa monitoring is largely clinical. Apart from factor VIII replacement, DDAVP (0.3 µg/kg intravenously over 30 min), followed by EACA (15 mg/kg/hr) or tranexamic acid (10 mg/kg 8-hourly), to inhibit the associated increase in plasminogen activator release with DDAVP, has also been used to aid haemostasis in patients with Haemophilia A and von Willebrand’s disease. Although, patients who have severe deficiencies of factor VIII do not respond to DDAVP. Three patients with haemophilia A who underwent hepatic transplantation, achieved haemostatic levels of factor VIII within 6 - 18 hr of the procedure. Recent advances in gene-replacement therapy indicates that a cure for coagulation factor deficiencies (particularly factor VIII and IX deficiencies) will soon be available.123 von Willebrand's disease von Willebrand's disease is inherited as an autosomal dominant with deficient or abnormal vWF and reduced levels of factor VIII (e.g. 1 - 50% of normal factor VIII levels). It may also be acquired with hypothyroidism, SLE, lymphoma or aortic stenosis.124,125,126 For surgical cover (and with major trauma), one donor unit of cryoprecipitate per 10 kg per day is used (i.e. 1 bag/50 kg), with the first dose being given the day prior to surgery and continued for 7 - 10 days postoperatively. Factor IX deficiency (Haemophilia B) Haemophilia B is an x-linked disease (i.e. virtually all will be males) with low or undetectable levels of factor IX. An acquired inhibitor may occur in patients with autoimmune disease. One litre of FFP daily (i.e. 1000 u or 15 u/kg factor IX) is usually enough to stop minor bleeding in patients who have factor IX deficiency. Patients with severe haemarthrosis and during minor surgery (e.g. dental extractions), 20 - 25 u/kg of monocomponent factor IX therapy is usually required. During major surgery, facilities to monitor factor IX levels should be available. A preoperative dose of 40 to 65 u/kg should be infused to raise the factor IX level to at least 400 u/L of plasma and further doses are given at 6 - 8 hr intervals to maintain the concentration of factor XI greater than 250 u/L plasma. Treatment should be continued for 7 to 10 days. Treatment with rFVIIa is also the treatment of choice in patients with anti-factor VIII antibody. Factor XIII deficiency Patients with a factor XIII deficiency have a moderate to severe bleeding disorder as well as having an impairment of wound healing. Because an effective level of factor XIII is above 0.5% and as its half-life is 12 days, long-term prophylaxis may be obtained by infusing 1 donor unit of cryoprecipitate per 10 kg (i.e., 1 bag/50 kg) every 2 - 3 weeks. Disseminated intravascular coagulation127,128 Disseminated intravascular coagulation (DIC) is a syndrome characterised by an acute or chronic intravascular coagulation and consumption of platelets and clotting factors with clinical features of microvascular thrombosis and haemorrhage. It often complicates a variety of disorders and therefore is considered to be an intermediary mechanism of disease In chronic DIC, the factor levels may be normal and the only abnormality may be thrombocytopenia. 54 Haemostasis, Platelet function and Coagulation Causes. The causes of DIC are listed in Table 3.5. Disorders causing intrinsic or extrinsic activation of the coagulation system often do so through the thrombogenic effects of TNFalpha and circulating IL-6 and IL-8 (e.g. activation of coagulation factors and inhibition of protein-C and protein-S pathway).129 In patients who develop DIC, the maintenance of the coagulopathy occurs with, circulatory stasis (which prevents the circulating inhibitors from reaching the coagulants) and RES blockade (inhibiting clearance of thromboplastins and activated procoagulants from the thrombin generation), and is more likely to occur with pregnancy, cirrhosis, or septicaemia. Table 3.5 Causes of DIC Endothelial cell injury (i.e. intrinsic pathway activation) Heat stroke, hyperthermia, malignant hyperpyrexia Viral, rickettsia or tubercle bacilli infections Haemangioma, aneurysms Shock, hypoxia, burns Intravascular tissue thromboplastin release (i.e. extrinsic pathway activation) Amniotic fluid embolism, death in utero. Tumour cells, antigen-antibody complexes Tissue from trauma and surgery Intravascular haemolysis Incompatible blood transfusion Mixed intrinsic and extrinsic pathway activation Bacterial sepsis Neoplasia (adenocarcinoma, lymphoma, leukaemia) Pre-eclampsia Envenomation While treatment with cytotoxic agents in leukaemic patients often induces rapid cell lysis and DIC, treatment of promyelocytic leukaemia with all-trans retinoic acid has a different effect as it induces a functional maturation of leukaemic promyelocytes and a progressive reduction in the leukaemic chromosomal translocation.130 However, in up to 25% of patients from 2 - 21 days after starting treatment, a ‘retinoic acid syndrome’ may develop, which is characterised by fever, headache, nausea, vomiting, tachypnoea, haemoptysis, interstitial and alveolar pulmonary infiltrates (i.e. ARDS, due to maturing myeloid cells invading lung parynchyma and in severe cases pulmonary capillaritis131), pleural and pericardial effusions, peripheral oedema, thromboembolism, cerebral haemorrhage, hypotension and renal failure.132,133 Laboratory findings include, leukocytosis, disseminated intravascular coagulation, hyperbilirubinaemia, hypertriglyceridaemia and elevated creatinine. The treatment includes resuscitation (i.e. oxygen, mechanical ventilation) and intravenous dexamethasone 10 mg 12-hourly for three days. While ceasing the all-trans retinoic acid appears to be reasonable, anecdotal evidence from one report appeared to support its continuation. One review concluded that discontinuation of the all-trans retinoic acid is probably not effective.134 55 Haemostasis, Platelet function and Coagulation Clinical features. The clinical features include symptoms and signs due to factor deficiency and ischaemia. Factor deficiency will commonly cause mucosal haemorrhage (i.e. gastrointestinal tract haemorrhage, haemoptysis) and wound haemorrhage. Vascular microthrombi will commonly cause organ ischaemia and multiple organ failure (i.e. renal, respiratory, hepatic, and cerebral failure). Investigations. The investigations include: 1. Coagulation tests: these tests often reveal a coagulation deficiency (e.g. thrombocytopenia, hypofibrinogenaemia, and prolonged INR, APTT and thrombin time). 2. Fibrinolysis testing: secondary fibrinolysis is often present which is reflected in a shortened euglobulin lysis time. 3. Fibrin degradation products: the plasma fibrin and fibrinogen degradation products (i.e. FDPs, XDPs) are elevated. 4. Complete blood picture: the fibrin mesh occluding the blood flow in the microcirculation produces RBC deformation (e.g. helmet cells, schistocytes, spherocytes, RBC fragmentation), intravascular haemolysis, an increase in reticulocyte count and an anaemia. Treatment. Findings consistent with DIC may occur in many diseases, although the disorder is often of no clinical significance. Severe and therefore clinically significant DIC may be defined as that which is associated with hypofibrinogenaemia. 1. Identification and treatment of the underlying disorder: is the cornerstone of management of DIC (i.e. correct circulatory failure, for example, shock and drain and remove dead or septic tissue), once this is underway then if the patient is bleeding, coagulation factor and platelet therapy may be administered. Once the precipitating cause has been removed the clotting factors usually return to normal within 24 hr, although the thrombocytopenia may persist for several days. 2. Coagulation factors: If the fibrinogen level is less than 1 g/L, 0.5 - 1 L of FFP (i.e. 0.6 1.2 g fibrinogen) and 1 - 2 packs of cryoprecipitate (i.e. 0.6 - 1.2 g of fibrinogen), are administered and FFP or cryoprecipitate are administered thereafter to keep plasma fibrinogen levels greater than 1 g/L. Intravenous vitamin K 10 - 20 mg and folic acid 15 mg are also given. Coagulation factor replacement therapy and the progress of DIC are monitored by APTT, INR, platelet count and FDP levels. 3. Platelets: If the patient is bleeding and the platelet count is below 80,000/µL, six packs of platelets are infused, and are administered thereafter depending on clinical evidence of bleeding and the platelet count. 4. Anticoagulants: Heparin. Inhibition of thrombin generation with heparin at standard anticoagulant doses has been used in patients where the thrombin generation is unable to be removed by treating the underlying disorder, although, even in this group, heparin has not been associated with an improvement in survival. Treatment of the DIC with heparin and factor replacement, without management of the underlying disorder, has not been associated with improved survival, and therefore is not recommended. 5. Coagulation inhibitors: Antithrombin III. Antithrombin III infusions have been reported to be of use in patients with severe DIC,135,136 although no significant reduction in mortality has been observed.137 While one study of ATIII infusions in critically ill patients without severe DIC but who had acquired low levels of ATIII, appeared to be without benefit,138 another double blind placebo controlled study of patients requiring respiratory and/or hemodynamic support because of severe sepsis and/or post-surgery complications found that antithrombin III infusions to 56 Haemostasis, Platelet function and Coagulation normalise plasma antithrombin activity had a net beneficial effect on 30-day survival.139 However, a recent multicentre, placebo controlled trial of 2300 patients with severe sepsis high dose antithrombin III (6000 IU as a bolus followed by 6000 IU for 4 consecutive days) was not associated with a reduction in 28-day all cause mortality.140 Protein C. Protein C infusions (100 IU/kg 8-hourly for 24 hr and thereafter according to plasma protein C levels) have also been used to treat patients with sepsis-induced DIC141 (particularly when associated with meningococcal disease, as it has been associated with beneficial effects,142,143,144 although currently there are no prospective randomised trials that have shown that it improves outcome in meningococcal disease).145 However, in a recent trial in patients with severe sepsis and one or more acute organ failures, an infusion of activated protein C (drotrecogin alfa) 24 µg/kg/hr for 96 hours was associated with a reduction in the 28 day all cause mortality from 30.83% to 24.72% (i.e. 1 additional life saved for every 16 patients treated), regardless of whether the patients had a low level of protein C or not (indicating that it did not just correct a protein C deficiency). 146 However, it was associated with an increased risk of bleeding and patients who had trauma or had undergone recent surgery, had a CVA within the previous 3 months, platelet count of < 30,000, acute pancreatitis without an established source of infection, chronic liver disease, dialysis dependent renal failure, anticoagulated with heparin or warfarin or were < 18 years of age - were excluded.146 Thrombomodulin. 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Anaesth Intens Care 1994;22:659-665. 121. Brandt JT, Britton A, Kraut E. A spontaneous factor V inhibitor with unexpected laboratory features. Arch Pathol Lab Med 1986;110:224-227. 122. Editorial. Anti-factor-VIII inhibitors in haemophilia. Lancet 1989;ii:363-364. 123. Mannucci PM, Tuddenham EGD. The hemophilias - from royal genes to gene therapy. N Engl J Med 2001;344:1773-1779. 124. Dalton RG, Dewar MS, Savidge GF, Kernoff PBA, Matthews KB, Greaves M, Preston FE. Hypothyroidism as a cause of aquired von Willebrand's disease. Lancet 1987;i:10071009. 125. Warkentin TE, Moore JC, Morgan DG. Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's disease the link? Lancet 1992;340:35-37. 126. Warkentin TE, Moore JC, Morgan DG. Gastrointestinal angiodysplasia and aortic stenosis. N Engl J Med 2002;347:858-859. 127. Colman RW, Robboy SJ, Minna JD. Disseminated intravascular coagulation: a reappraisal. Ann Rev Med 1979;30:359-374. 62 Haemostasis, Platelet function and Coagulation 128. Mant MJ, King EG. Severe, acute disseminated intravascular coagulation. A reappraisal of its pathophysiology, clinical significance and therapy based on 47 patients. Am J Med 1979;67:557-563. 129. Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993;270:975-979. 130. Gillis JC, Goa KL. Tretinoin. A review of its pharmacodynamic and pharmacokinetic properties and use in the management of acute promyelocytic leukaemia. Drugs 1995;50:897-923. 131. Nicolls MR, Terada LS, Tuder RM, Prindiville SA, Schwartz MI. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. Am J Resp Crit Care Med 1998;158:1302-1305. 132. Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP Jr. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 1992;117:292-296. 133. Chanarin N, Smith GB, Green A, Andrews MIJ. Retinoic acid syndrome. Lancet 1993;341:1289-1290. 134. Warrell RP Jr, de The H, Wang ZY, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993;329:177-189. 135. Schipper HG, Jenkins CSP, Kahle LH, ten Cate TW. Antithrombin III transfusions in disseminated intravascular coagulation. Lancet 1978;I:854-856. 136. Blauhut B, Kramar H, Vinazzer H. Substitution of antithrombin III in shock and DIC: a randomised study. Thromb Res 1985;39:81-89. 137. de Jonge E, Levi M, Stoutenbeek CP, van Deventer SJ. Current drug treatment strategies for disseminated intravascular coagulation. Drugs 1998;55:767-777. 138. Díaz-Cremades JM, Lorenzo R, Sánchez M, Moreno MJ, Alsar MJ, Bosch JM, Fajardo L, González D, Guerrero D. Use of antithrombin III in critical patients. Intens Care Med 1994;20:577-580. 139. Giudici D, Baudo F, Palareti G, Ravizza A, Ridolfi L, D' Angelo A. Antithrombin replacement in patients with sepsis and septic shock. Haematologica 1999;84:452-460. 140. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-1878. 141. Esmon CT, Schwartz HP. An update on clinical and basic aspects of the protein C anticoagulant pathway. Trends Cardiovasc Med 1995;5:141-148. 142. Rintala E, Seppälä O-P, Kotilainen P, Rasi V. Protein C in the treatment of coagulopathy in meningococcal disease. Lancet 1996;347:1767. 143. Rivard GE, David M, Farrell C, Schwarz HP. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr. 1995;126:646-652. 144. Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet. 1997;350:1590-1593. 145. Leclerc F, Leteurtre S, Cremer R, Fourier C, Sadik A. Do new strategies in meningococcemia produce better outcomes? Crit Care Med. 2000;28(9 Suppl):S60-S63. 146. Bernard GR, Vincent J-L, Laterre P-F, LaRosa SP, Dhainaut J-F, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, for the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. 63 Haemostasis, Platelet function and Coagulation 147. de Jonge E, Dekkers PE, Creasey AA, Hack CE, Paulson SK, Karim A, Kesecioglu J, Levi M, van Deventer SJ, van Der Poll T. Tissue factor pathway inhibitor dosedependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood. 2000;95:1124-1129. 64 TRAINEE PRESENTATIONS Each registrant has prepared a five minute talk and summary on the topics listed below. The summaries that were received in time for publication have been included (unedited). 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Discuss the advantages and disadvantages of the various sedation regimens in the intensive care patient. Define and list the causes and management of platypnoea and orthodeoxia. What are the factors causing, and treatment of, an acute subclavian vein thrombosis. Discuss the difference in aetiology, diagnosis and treatment of portopulmonary hypertension and hepatopulmonary syndrome. Discuss the management of a patient who has an asystolic cardiac arrest. Discuss the causes and management of acute paralytic ileus. Discuss the causes, clinical features and management of a patient with D-lactic acidosis. Discuss the clinical features and management of a patient who has the ‘Retinoic acid syndrome’. How would you manage a patient who has an acute post-operative colonic pseudo-obstruction? Discuss the management of a patient with AF, hypotension and hypertrophic obstructive cardiomyopathy. Discuss all the methods used to improve the likelihood of a successful canulation of a central vein. Discuss the clinical features and the management of a patient with a TIA. Discuss your management of a patient with chest trauma who is mechanically ventilated and who develops a broncho-pleural fistula. A patient has been referred to you following a nephrectomy for a hypernephroma performed 7 days ago for management of pyrexia, oliguria and now hyperkalemia. He has been confused during the past three days with episodes of hypoglycaemia and the numerous glucose infusions has caused him to develop hyponatremia. how would you manage him? Discuss how you would manage a patient who has developed blindness with serum sodium of 122 mmols/L and measured osmolality of 290 mosm/kg 1 hour following a TURP. 65 Dr. M. Reade page 67 Dr. M. Davey 70 Dr. S. Sane 72 Dr. S. Simpson 76 Dr. M. Ibrahim 80 Dr. G. Kwan 82 Dr. T. Fraser 84 Dr. D. Moxon 86 Dr. W. Newman 87 Dr. A. Holley 89 Dr. B. Cheung 92 Dr. H. Ramaswamykanive 95 Dr. M. Sanap 98 Dr. P. Dubey 102 Dr. S. Vergese 105 16. Discuss the ideal properties of a predictive scoring system for severity of illness in the intensive care unit. 17. Discuss your management of a mechanically ventilated postoperative coronary artery bypass patient who has just developed AF and who is hypotensive. 18. Discuss the indications for and complications of intravenous sodium bicarbonate 19. Discuss the antibiotic management of a patient with MRSA aortic valve endocarditis with vancomycin allergy 20. Do you use selective decontamination of the gastrointestinal tract in your intensive care unit? If so why? If not why not? 21. What are the indications for and complications of Nacetylcysteine 22. Discuss the indications and contraindications of morphine in the treatment of acute pulmonary oedema 23. Discuss the clinical presentation and management of a patient who has an acute Budd-Chiari syndrome 24. Discuss the diagnosis and management of gout in a critically ill patient with acute renal failure 25. Discuss the management of the Guillain Barre syndrome 66 Dr. S. Senthuran 107 Dr. D. Gardiner 109 Dr. R. Ramadoss 111 Dr. A. MacCormick 115 Dr. G. Ding 117 Dr. L. Min 120 Dr. M. Heaney 122 Dr. J. Lewis 125 Dr. D. Corcoran 128 Dr. D. Rigg 131 DISCUSS THE ADVANTAGES AND DISADVANTAGES OF THE VARIOUS SEDATION REGIMENS IN THE INTENSIVE CARE PATIENT Dr. M. Reade. Intensive Care Unit, The Austin Hospital, Victoria There are three related but distinct therapeutic goals in the management of cognitive function and awareness in critically ill patients: analgesia; control of delirium; and sedation. Many of the drugs employed to control one aspect of this triad will have effects (beneficial or detrimental) on the other two. Sedation cannot therefore be considered in isolation, but a discussion of analgesic and psychotropic pharmacology and regimens is beyond the scope of this paper. The need for sedation can be reduced by minimisation of sleep deprivation, reducing delirium (by frequent reorientation and appropriate medications), use of appropriate analgesia, optimisation of the temperature and use of a suitable ventilation strategy. Hypoxaemia, hypercapnoea, hypoglyceamia and withdrawal from alcohol or benzodiazepines can also be treated. The effectiveness of any sedation strategy must be adequately assessed. There are a number of scoring systems to allow this, though few have been properly validated. The most commonly used scores are the Ramsay,1 Riker2 and Motor Activity Assessment Scale (MAAS),3 though others exist.4 The Ramsay score is used most frequently in clinical trials.5 There are few (if any) disadvantages in incorporating these simple measures into a sedation regimen. In patients who are receiving mechanical ventilation, daily interruption of sedative-drug infusions decreases the duration of mechanical ventilation and the length of ICU stay.6 This practice potentially exposes the patient to unpleasant awareness and to the risk of self harm by removal of intravenous catheters etc. The need for nursing care is greater. Routine daily interruption of sedatives is not universally practiced. Allowing nurses to titrate the doses of sedatives and analgesics according to a protocol reduced the duration of mechanical ventilation, the intensive care unit and hospital lengths of stay and the need for tracheostomy among critically ill patients with acute respiratory failure.7 The only disadvantage of such a regimen is the extra training required of nursing staff. The choice of medication used to primarily produce sedation is only a small part of the overall sedation regimen. The ideal sedative agent would reduce anxiety, facilitate patient care, produce anterograde amnesia and reduce psychomotor agitation. Pharmacologically, it would be easy to titrate, haemodynamically stable, not produce tachyphylaxis and be cheap. Each drug class has a number of theoretical advantages and disadvantages, as listed in Table 1. Comparison of medications whose primary action is sedative. The most commonly studied benzodiazepines in the ICU are midazolam, lorazepam and diazepam. Intravenous midazolam and diazepam have an effect after 2 - 5 minutes, whereas lorazepam takes 5 - 20 minutes. Midazolam has the shortest half life, but has an active hepatic metabolite which accumulates in renal failure. Lorazepam has a longer elimination half life, making it less titratable by infusion, though it has no active hepatic metabolites, possibly making it more suitable in renal failure. Diazepam has a very long half life and an active hepatic metabolite. In intravenous form its solvent causes phlebitis, restricting its use by many to the enteral form. Midazolam and lorazepam have been compared in a number of trials:4 lorazepam infusions may be easier to manage (with fewer dose adjustments), and while there was no difference in the time to recovery, there was less variability with lorazepam. For this reason, the SCCM recommendation is that midazolam is indicated for short term use only, as it produces unpredictable awakening after infusions of 48 - 72 hours. Lorazepam is preferred in 67 this situation, unless very rapid awakening is required, in which case propofol in indicated.4 Unfortunately, IV lorazepam is not available in Australia. Table 1. Properties of the commonly used ICU sedative agents Benzodiazepines Propofol Amnesia produced Yes As effective as midazolam in one study but not another Tolerance? Yes No Opioid sparing? Yes, mildly No – thought to have no analgesic effect Withdrawal effect? Yes No Side effects Paradoxical Hypertriglyceridaemia. agitation in low Hypotension/bradycardia. doses Pancreatitis. Lactic acidosis. Cardiac arrest. Possible sepsis due to contamination. Myoclonus. Accumulation in renal failure Midazolam and diazepam – yes; lorazepam – no. No Titratable? Midazolam – yes, if short term. Lorazepam – no Diazepam - no Highly Haemodynamically stable? Yes No – reduces cardiac contractility; causes vasodialtion Cost Inexpensive Moderately expensive Alpha agonists No Yes, markedly No Hypotension. Hypertension. Bradycardia. Dry mouth. Nausea. Somnolence. Corneal dryness. No (though kinetics of metabolites are not fully established) Yes – though not directly compared to propofol. Likely to have a larger effective dose range with fewer side effects than propofol. Transient hypertension then hypotension; reported to not be clinically significant. Very expensive Clonidine, an alpha-2 agonist, has been employed as a sedative, but its use is limited by hypotension. With seven times less hypotensive effect, dexmedetomidine has only recently become available, licensed in Australia for use in the first 24 postoperative hours. Two large (n = 353 and 401) placebo controlled trials found patients given dexmedetomidine needed very little ‘rescue’ sedative (either propofol or midazolam) and also required approximately half the amount of morphine for analgesia.8 A trial in 295 postoperative patients compared the sedative effects of dexmedetomidine with propofol. Dexmedetomidine alone was sufficient to achieve satisfactory sedation in 89% of patients. Eighty eight percent of patients receiving propofol, but only 50% of patients receiving dexmedetomidine, required morphine for analgesia. Ninety eight percent of patients receiving dexmedetomidine were extubated without discontinuation of the study drug, whereas this was true for only 6% of those receiving propofol, highlighting 68 dexmedetomidine’s ability to produce rousable sedation with little respiratory depression.8 Longer infusions have been used successfully in other case series and published trials.9,10 Which pharmacological sedative regimen produces optimal sedation, the shortest time to extubation, and the shortest length of ICU stay has recently been systematically reviewed.5 The majority of trials compared propofol with midazolam, finding propofol to be at least as effective while allowing faster time to extubation, but with increased risk of hypotension and increased cost. Dexmedetomidine was not included in this review. There is no one pharmacological sedation regimen known to be superior in all circumstances. Any discussion of sedation must include evaluation of analgesics and major tranquilizers, which have both sedative effects, and by their primary action can also reduce the requirement for sedation. Sedation requirement is also affected by the administration protocol followed and the environment of the patient. Only when all of these factors are addressed can the drugs be compared and the most effective selected. References 1. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974;2:656-659. 2. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med 1999;27:1325-1329. 3. Devlin JW, Boleski G, Mlynarek M, Nerenz DR, Peterson E, Jankowski M, et al. Motor Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med 1999;27:12711275. 4. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119-141. 5. Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ. Sedation in the intensive care unit: a systematic review. JAMA 2000;283:1451-1459. 6. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:14711477. 7. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999;27:2609-2615. 8. MIMS Annual. St Leonards: MediMedia Australia Pty Limited, 2004. 9. Romero C, Bugedo G, Bruhn A, Mellado P, Hernandez G, Castillo L. Experiencia preliminar del tratamiento con dexmedetomidina del estado confusional e hiperadrenergia en la unidad de cuidados intensivos. Revista Espanola de Anestesiologia y Reanimacion 2002;49:403-6. 10. Perioperative sympatholysis. Beneficial effects of the alpha 2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. McSPI--Europe Research Group. Anesthesiology 1997;86:346-63. 69 DEFINE AND LIST THE CAUSES AND MANAGEMENT OF PLATYPNOEA AND ORTHODEOXIA Dr. M. Davey. Intensive Care Unit, The Canberra Hospital, ACT Definitions Platypnoea: dyspnoea aggravated in the erect position and relieved in the supine position. Orthodeoxia: is oxygen desaturation aggravated in the erect position and relieved in the supine position. The precise cause of the syndrome is unclear but patients develop right to left intracardiac shunting, often in the presence of normal right sided cardiac pressures (Cheng 1999). Causes Common • ASD or PFO (Rao 2001, Kubler 2000, Patel 2003) with position-dependent shunting, often in combination with one of the conditions below. Rare • Other Cardiac o Pericardial effusion o Constrictive pericarditis o Aortic aneurysm • Pulmonary o Multiple pulmonary emboli (Hussain 2004) o Pulmonary emphysema o Radiation-induced bronchial stenosis (Awan 1999) o Hepatopulmonary syndrome (Gomez 2004) o Amiodarone toxicity of the lungs o Pulmonary A-V communications • Autonomic o Parkinson disease (Hussain 2004) o Bilateral thoracic sympathectomy (van Heerdon 2004) • Abdominal o Hepatic cirrhosis o Ileus Management • Closure of the ASD or PFO • The case associated with Parkinson’s disease (Hussain 2004) was attributed to postural hypotension, and improved with fludrocortisone. • The case associated with radiation-induced bronchial stenosis (Awan 1999) was relieved by bronchial dilation initially, and later by bronchial stenting. • The case associated with bilateral thoracic sympathectomy (van Heerdon 2004) was treated initially with noradrenaline and almitrine. References 1. Awan AN. Ashraf R. Meyerson MB. Dunn TL. (1999) Radiation-induced bronchial stenosis: a new cause of platypnea-orthodeoxia. Southern Medical Journal. 92:720-4. 2. Cheng TO. (1999) Platypnea-orthodeoxia syndrome: etiology, differential diagnosis, and management. Catheterisation & Cardiovascular Interventions. 47:64-6. 70 3. 4. 5. 6. 7. 8. Gomez FP. Martinez-Palli G. Barbera JA. Roca J. Navasa M. Rodriguez-Roisin R. (2004) Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology. 40:660-6. van Heerden PV. Cameron PD. Karanovic A. Goodman MA. (2003) Orthodeoxia—an uncommon presentation following bilateral thoracic sympathectomy. Anaesthesia & Intensive Care. 31:581-3. Hussain SF. Mekan SF. (2004) Platypnea-orthodeoxia: report of two cases and review of the literature. Southern Medical Journal. 97:657-62. Kubler P. Gibbs H. Garrahy P. (2000) Platypnoea-orthodeoxia syndrome. Heart. 83:2213. Patel AD. Abo-Auda WS. Nekkanti R. Ahmed S. Razmi RM. Pohost GM. Nanda NC. (2003) Platypnea-orthodeoxia in a patient with ostium primum atrial septal defect with normal right heart pressures. Echocardiography. 20:299-303. Rao PS. Palacios IF. Bach RG. Bitar SR. Sideris EB. (2001) Platypnea-orthodeoxia: management by transcatheter buttoned device implantation. Catheterization & Cardiovascular Interventions. 54:77-82. 71 WHAT ARE THE FACTORS CAUSING, AND TREATMENT OF, AN ACUTE SUBCLAVIAN VEIN THROMBOSIS Dr. S. Sane. Department of Critical Care Medicine, Flinders Medical Centre, South Australia Acute subclavian vein thrombosis is a component of a broader group of diseases grouped under upper extremity deep vein thrombosis (UEDVT). UEDVT occurs in two forms: 1. Effort induced thrombosis, also called as Paget-von Schrötter syndrome,1 or Primary UEDVT which accounts for 25% cases of UEDVT& is the most common vascular problem in athletes.2 2. Secondary UEDVT which accounts for 75 % cases of UEDVT. Aetiology: Primary UEDVT Underlying chronic venous compressive abnormality caused by musculoskeletal structures in costoclavicular space at the thoracic outlet or inlet. Pathophysiology: Virchow’s triad of stasis, hypercoaggulability & intimal damage, for thrombosis, plays an important part. Axillosubclavian vein is exposed to repeated trauma [with vigorous or unaccustomed arm movements, 3,4 due to its relatively fixed position in the thoracic outlet/inlet which leads to intimal hyperplasia causing venous stenosis. Secondary UEDVT CVC catheters Permanent pacemakers Hypercoagulable states Mediastinal tumour/nodes Mediastinal radiation & surgery Trauma (e.g. fracture clavicle) IV drug abuse Contributory anatomic abnormalities: 1. Presence of cervical rib. 2. Posttraumatic deformity of surrounding bony structures. 3. Anomalous musculoskeletal bands. Horrates et al found that 65% of catheter induced thromboses were left sided.5 Schillinger et al found in a study of hundred patients who underwent CVC for dialysis, 42% of their subclavian veins & only 10 % jugular veins developed stenosis.6 Therefore the authors recommended right internal jugular vein for CVC canulation. Management: Relevant history (recent trauma, iv drug abuse or unaccustomed exercise etc) 72 Physical examination (signs of venous obstruction in the form of oedema, venous collaterals, tenderness, warmth) Acute management & prevention in future. Investigations: 1. Colour flow duplex imaging: sensitivity- 78 to100% specificity- 90 to 100% 2. Venography: gives accurate diagnosis. Position of arm: abduction , external rotation & extension especially to diagnose effort induced vein thrombosis. Patient should undergo bilateral venograms with provocative maneuvers even if signs & symptoms of venous compression are unilateral. Diagnosis made by visualising intraluminal defect & venous collaterals. False positives - compression features with provocative measures can also occur in asymptomatic patients. 3. X ray: Can give suggestion of the diagnosis by evidence of fracture clavicle / 1st rib or presence of a cervical rib. 4. CT scan:9 UEDVT is seen as hypoattenuating defect in contrast enhanced CT scan. Cross section can detect soft tissue pathology such as tumour or lymphadenopathy surrounding the vein in question. Especially good diagnostic quality can be obtained with 3D images. 5. Magnetic Resonance venograms:9 It has shown good accuracy in diagnosing subclavian, brachiocephalic & SVC thrombosis, an area that is poorly visualised by ultrasound. 6. Ultrasound: Advantage- rapid, noninvasive & easily available. Diagnosis made by absence of colour flow signals & augmentation or visualisation of thrombus. Morbidity & mortality: Major complications of UEDVT can be:7 1. Pulmonary embolism2. The prevalence of PE in UEDVT is about 10-30% which is similar to lower limb DVT. Catheter induced thrombosis has higher risk of causing pulmonary embolism. 3. Superior vena cava syndrome. 4. Sepsis especially with staphylococcus aureus secondary to septic thrombophlebitis. 5. Chronic disability. 6. Removal of a CV canula in a critically ill patient results in IV access problems. Interventions: Primary UEDVT “ Machleder algorithm” (10) which is as follows: A. Thrombolysis“ Golden Week”- greatest benefits are obtained if thrombolysis is started within about seven days of symptoms,8 even though a period of 10 to 14 days is considered reasonable. 73 Thrombolytic agents used are- urokinase, alteplase, reteplase. Contraindications for thrombolysis areAbsolute: 1. active internal hemorrhage 2. recent GI hemorrhage 3. CNS tumour, aneurysms or AV malformations. 4. recent CVA. Relative contraindications: 1. trauma 2. post partum (<10 days) 3. uncontrolled hypertension 4. hemorrhagic retinopathy 5. left sided cardiac thrombus Current mechanical thrombectomy devices can facilitate clot removal & thus decrease thrombolytic dose & infusion period. B. Anticoagulation is recommended for 6 to 12 weeks after thrombolysis. C. Surgical thoracic outlet decompression is indicated in case of significant persistent disability or persistence of venous abnormality &can be achieved by trans axillary or trans thoracic resection of first rib. D. Follow up venography & angiography is done to detect residual venous stenosis after decompression surgery. Use of vascular stents is relatively contraindicated in this position due to low patency rates. Secondary UEDVT A. Traditional conservative measures include, removal of CV catheter, bed rest, limb elevation, application of heat & anticoagulation. Symptomatic relief is achieved because of development of collaterals & prevention of clot propagation. B. Surgical thrombectomy is sometimes required. C. Catheter directed thrombolysis: most thrombosed veins reanalyse within 24 hours. If underlying vein is normal after thrombolysis, short-term anticoagulation is needed, however if it is abnormal anticoagulation for 10 to 12 weeks is warranted. References 1. Hughes ESR: Venous obstruction in the upper extremity, Int Abst Surg, 949;88(2):89-127 2. Sotta RP: Vascular problems in the proximal upper extremity. Clin Sports Med 1990;9(2):379-388 3. Rutherford RB et al. Primary subclavian-axillary vein thrombosis:Cardiovascular Surg 1996; 4(4):420-423 4. Adams JT et al: PUEDVT Arch Surg 1965; 91:29-42 5. Horrates et al: Changing concepts of deep venous thrombosis of the upper extremity-report of a series and review of the literature. Surgery 1988 Sep; 104(3): 561-7 6. Schillinger et al: Post-catheterization venous stenosis in hemodialysis: comparative angiographic study of 50 subclavian and 50 internal jugular accesses. Nephrology 1992; 13(3): 127-33 74 7. Pradoni et al: Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med 1997 Jan 13; 157(1): 57-62 8. Adelman MA et al. A multidisciplinary approach to the treatment of Paget –Schrotter syndrome, Ann Vasc Surg 1997;11(2):149-154 9. Rose SC: Systemic central veins of the thorax and neck. In: Noninvasive vascular imaging with ultrasound, computed tomography, and magnetic resonance. 1997: 163-74 10. Craig et al: Deep vein thrombosis, upper extremity, May 2003, www.emedicine.com. 75 DISCUSS THE DIFFERENCE IN AETIOLOGY, DIAGNOSIS AND TREATMENT OF PORTOPULMONARY HYPERTENSION AND HEPATOPULMONARY SYNDROME Dr. S. Simpson. Intensive Care Unit, Women’s and Children’s Hospital, South Australia Introduction Cardiopulmonary abnormalities are common in patients with advanced liver disease, resulting from malnutrition, immunosuppression, and the effects of severe portal hypertension (eg. pneumonia, pleural effusion, atelectasis), or from the underlying disease (eg cystic fibrosis, alpha-1-antitrypsin deficiency).1 There are also two distinct pulmonary syndromes pathogenically linked to the presence of portal hypertension. Hepatopulmonary syndrome (HPS) is characterised by pulmonary vasodilation, with anatomical shunt and an alveolar diffusion defect. Conversely, portopulmonary hypertension (PPHTN) results in pulmonary vasoconstriction with arterial remodelling.1-5 Each entity requires a unique management approach, and has different prognostic relevance, especially in relation to liver transplantation. Common features Both HPS and PPHTN occur in the presence of portal hypertension, defined as portal pressure >10mmHg. Although more commonly associated with parenchymal liver disease, nonhepatic causes of portal hypertension can lead to either syndrome.1-5 There is no correlation between the severity of portal hypertension and the development of either HPS or PPHTN. Both have a poor prognosis if untreated. Hepatopulmonary syndrome (HPS) The classic triad2 • Hepatic dysfunction • Arterial hypoxaemia in air (PaO2 < 70mmHg, or Alveolar-arterial gradient >20mmHg) • Intrapulmonary vascular dilatations (IPVD’s) The incidence of HPS ranges between 4-47% of patients with chronic liver disease.1-3 Pathogenic theories centre upon the circulatory consequences of portal hypertension, with altered bowel perfusion increasing the translocation of gut bacteria and endotoxin, stimulating the release of vasoactive mediators, including TNFα, carbon monoxide, and nitric oxide (NO). NO is found in higher concentrations in the breath of HPS patients.2 Animal models display abnormal expression and activity of endothelin-type-B receptors, which further enhances the effects of NO.2 HPS is defined by finding IPVD’s in precapillary arterioles, often with the creation of direct arterial-venous vascular malformations, particularly in the lower lobes.1-3 These structures have been likened to telangiectasia, which are common in liver disease. Nonspecific clinical findings include progressive dyspnoea (common), digital clubbing and cutaneous spider naevi. HPS may present with paradoxical embolism, cerebral haemorrhage, or brain abscess.1-3 The hallmark clinical finding in HPS, although not universal, is orthodeoxia (a fall in PaO2 > 3mmHg when transferred from supine to upright), associated with platypnoea (dyspnoea which improves in recumbency).2 These findings relate to postural changes in pulmonary perfusion. Diagnostic investigations Contrast enhanced 2-D echocardiography using agitated saline shows the appearance of bubbles in the left atrium within 3-6 cardiac cycles of IV injection. Earlier appearance indicates 76 intracardiac R-L shunt, which is an important differential. A 99mTc microaggregated albumin scan is more specific. Normal pulmonary capillaries (15µm diameter) traps labelled albumin (>20µm diameter) in the lungs.1,2 Uptake in brain indicates transpulmonary passage, and the ratio can be used to quantify severity. Pulmonary angiography is not routinely done in HPS, unless the patient is poorly responsive to oxygen, indicating large shunt.2 Angiography may identify localised arterio-venous malformations that are amenable to surgical excision or embolisation.1 Management Oxygen is the main therapy. Drugs including NO synthetase inhibitors, almitrine and somatostatin, have not shown any benefit.1-3 Trials are underway with antibiotics to reduce translocation of microorganisms, and methylene blue.1 Success has been reported with portal pressure reduction using transjugular porto-systemic shunting (TIPS), but it is not yet established as a standard therapy for HPS.1,2 In severe cases with refractory hypoxaemia the definitive treatment is orthotopic liver transplantation (OLT).1-3 Prognosis Once PaO2 is less than 50mmHg, one year survival is between 16-38%.3 Complete resolution of HPS after liver transplantation is not universal, but has been documented in 6282% of survivors.2 Portopulmonary hypertension (PPHTN) PPHTN is defined by elevated mean pulmonary arterial pressure (mPAP >25mmHg at rest) in the setting of portal hypertension, and normal left ventricular end diastolic pressure.1,4,5 Mild-moderate symptoms correlate well with histo-pathological findings of pulmonary vasoconstriction and endothelial and smooth muscle hypertrophy.5 Severe cases develop progressive plexogenic arteriopathy with in situ thrombosis and fibrosis, leading to right heart failure.4,5 These histological lesions are indistinguishable from those found in primary pulmonary hypertension. The incidence ranges from 0.7% in the presence of cirrhosis, to 16% of patients assessed for liver transplantation.1,4 Factors involved in the development of pulmonary arteriopathy are yet to be identified. Proposed mechanisms include imbalances in endothelin vs nitric oxide, and/or thromboxane vs prostacyclin levels, due to altered liver function. Plasma endothelin-1 levels are substantially higher in PPHTN patients than patients with cirrhosis and no PPHTN.4 Genetic mutations in tissue growth factor receptor families have also been implicated, but no conclusive evidence exists. PPHTN is more common in the subset of auto-immune diseases involving the liver.4 The commonest presenting symptom is progressive dyspnoea on exertion. Other nonspecific complaints include fatigue, palpitations, syncope, and chest pain.1,3,4,5 Signs of pulmonary hypertension with right heart failure may be present, such as loud P2 associated with a systolic murmur of tricuspid regurgitation, raised JVP, ascites, and peripheral oedema. It is important to exclude other causes of pulmonary hypertension, such as left heart failure, valvular heart disease, interstitial or obstructive lung disease, chronic thrombo-embolism, and sleep-related breathing disorders.4,5 The investigation of choice is transthoracic echocardiography, measuring pulmonary and intracardiac pressures.1,3,4,5 Once the diagnosis of PPHTN has been established the severity is determined by the clinical symptoms, and values derived for cardiac index, pulmonary vascular resistance (PVR), and right atrial pressure (RAP).1 (see table).Right heart catheterisation is required for definitive diagnosis.5 77 Normal Mild Moderate NYHA class I/II II/III mPAP (mmHg) 15-24 25-34 35-44 Cardiac index (L/min/m2) 2.5-4.0 >2.5 >2.5 PVR (dynes/s/cm5) <240 240-500 500-800 RAP (mmHg) 0-5 0-5 5-8 Prognosis Favourable ?????? Specific treatment req’d No ?????? Reversible after OLT Yes ?????? Diagnostic criteria for determining mild, moderate, or severe PPHTN.1 Severe III/IV >45 <2.0 >800 >8 Poor Yes No Management Patients with mild disease are monitored using bi-annual 2-D echocardiography.4 More severe cases warrant medical treatment, either with palliation, or as a bridging therapy to transplantation. Medications Drugs used in primary pulmonary hypertension may not be suitable. B-blockers and nitrates increase the risk of variceal bleeding.4 Anticoagulation is controversial.1 Sildenafil and calcium-channel blockers have not been studied in PPHTN. Prostacyclin is recommended for its antiproliferative effects which can reverse the remodelling of the pulmonary vasculature.4 Data obtained from open-label trials show improvement in symptomatic end-points (eg exercise capacity), but there are no data showing survival benefits.1,4,5,6 Intravenous epoprostenol administration has significant risks. New inhaled, subcutaneous, or oral equivalents may be safe but have not been studied.6 Endothelin receptor-1 antagonists have theoretical benefits, but also have known hepatotoxic side effects. Experience with bosentan is restricted to specialised centres.1,4,6 Liver transplantation Recent outcome studies indicate patients with mild-moderate PPHTN (mPAP < 40mmHg) are at no additional risk from liver transplantation (OLT) than other patients with advanced liver disease.4 Severe PPHTN is a contraindication for OLT because of high intraoperative mortality (38-42%), and poor quality post-operative survival.1,3,4,5 World-wide experience with heart-lung-liver transplant is limited.4 Prognosis In severe PPHTN median survival is 6 months after diagnosis.1 References 1. Hoeper, MM, Krowka, MJ, Strassburg, CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet, 2004;363:1461-1468. 2. Yen, KT, Krowka, MJ, et al. Liver and lung: hepatopulmonary syndrome: recognising the clinical features and selecting the right studies. J Crit Illness. 2002;17:309-315. 3. Naeije, R Hepatopulmonary syndrome and portopulmonary hypertension. Swiss Med Wkly 2003:133:163-169. 4. Budhiraja, R, Hassoun, PM. Portopulmonary hypertension: A tale of two circulations. Chest 2003;123:562-576. 5. Krowka, MJ. Portopulmonary hypertension: understanding pulmonary hypertension in the setting of liver disease. Eur Respir J 1998;1:1153-1166. 78 6. Benza, RL, Medical treatment options / advances in portopulmonary hypertension: how the spectrum is expanding. Advances in Pulmonary Hypertension 2004;3:16-22. 79 DISCUSS THE MANAGEMENT OF A PATIENT WHO HAS AN ASYSTOLIC CARDIAC ARREST Dr. M. Ibrahim. Intensive Care Unit, The Austin Hospital, Victoria A. Primary ABCD Survey Initial Management 1. Diagnose (check responsiveness, absent carotid pulse, respiration) 2. Call for assistance (Emergency medical response) 3. Place patient on firm surface 4. Call for Defibrillator 5. Allocate responsibilties 6. Proceed to BLS Basic Life Support (BLS) 1. Airway: open airway (Head tilt, Jaw thrust, open mouth, clear airway) 2. Breathing: provide PPV (give 2 breaths) 100% 02 via Bag & mask or mouth to mask 3. Circulation: Give chest compressions (80-100/min) 4. Defibrillator: Attach Defibrillator paddles/ leads (To confmn asystole + if any doubt it could be fine VF -7 shock as per ACLS * Note: It is very important to identify and/or treat VF if any suspicion as prognosis is much better than asystole B. Secondary ABCD survey Advanced Cardiac Life Support (Asvstole) 1. Airway: Place airway device (Intubate) 2. Breathing: Confirm airway device by exam + confmnation device (!!) Breathing: Secure airway device Breathing: Confirm effective oxygenation and ventilation 3. Circulation: Confirm true asystole/ identify rhythm Circulation: Obtain IV access Circulation: Administer drugs: 1. Adrenaline Img IV push (Or 3mg via ETT) Repeat every 3 minutes OR Consider Vasopressin 40U IV (single dose) If no response use Adrenaline as above 2. Atropine Img IV (Or 3mg via ETT) Repeat every 3 min (up to 0.04 mg/kg) 3. Recheck rhythm and treat accordingly 4. Differential Diagnosis: Search and treat identifiable causes (5H/5T) Hypoxia/Hyperinflation Toxins/ Tablets (OD, illicit drugs) Hypovolaemia Tamponade, cardiac Hydrogen ion (Acidosis) Tension pneumothorax Hyperkalaemia/Hypokalaemia Thrombosis, coronary Hypothermia/Hyperthermia Thrombosis, pulmonary 80 Indications for: Potassium (K) → Hypokalaemia Calcium (Ca) → Hypocalcaemia, Hyperkalaemia, Massive transfusion, Ca antagonist OD Bicarbonate (HC03) → TCA overdose, Hyperkalaemia, Preexisting acidosis Magnesium (Mg) → Polymorphic VT, Hypokalaemia, Hypomagnesaemia C. When to stop Depends on reversible factors, comorbidities (generally 20-25 mins acceptable) D. Prognosis Generally poor for asystole patients (1-2% walk out of hospital) References 1. International Guidelines 2000 for CPR and ECC : a consensus on science. Circulation. 102( Suppl) 2. Wenzel V, et al. A comparison of Vasopressin and Epinehrine for out-of-hospital. cardiopulmonary resuscitation NEJM 2004; 350(2): 105-113 3. Oh's Intensive Care Manual, 5th Edition 4. Irwin and Rippe's Intensive Care Medicine, 5th Edition. 81 DISCUSS THE CAUSES AND MANAGEMENT OF PARALYTIC ILEUS Dr. G. Kwan. Intensive Care Unit, Queen Elizabeth Hospital, Hong Kong Definition of ileus A partial or complete non-mechanical blockage of the small and/or large intestine with temporary arrest of intestinal peristalsis It is common for a patient to acquire an ileus during a stay in ICU. The presence of ileus can lead to significant morbidity and possibly mortality. A rapid and efficient search for the cause of the ileus is critical to reduce this morbidity and to restore enteral nutrition promptly. Intra-abdominal causes of Ileus Infective disorders Peritonitis Diverticulitis Cholecystitis Appendicitis Tubo-ovarian abscess Inflammatory disorders Pancreatitis Perforated viscus Toxic Megocolon Intraperitoneal bleeding Peritionitis Ischaemic disorders Local arterial insufficiency Local venous insufficiency Mesenteric arteritis Strangulated disorders Retroperitoneal disorders Nephrolithiasis Pyelonephritis Hemorrhage Extra-abdominal causes of Ileus Drug induced Anticholinergic medication Opioids Chemotherapy e.g. vinblastine, vincristine Ganglionic blocking agents Metabolic disturbances Electrolytes disturbances e.g. hypokalaemia Sepsis Uremia Diabetic ketoacidosis Sickle cell anaemia with painful crisis Hypothyroidism 82 Reflex inhibition Myocardial infarction Pneumonia Pulmonary embolus Burns Fractures of the pelvis, ribs or spine Management • Review Patient medical and surgical history • Review drug history • Initial steps should entail establishing the presence of obstruction or ileus • Evaluate and correct for electrolyte disturbances – measuring serum sodium, potassium, chloride and bicarbonate levels) • Searching for evidence of infection and inflammatory disorders – white cell count with differential • Other laboratory abnormalities including serum amylase, ALP, CPK, AST, ALT and LDH, anion gap metabolic acidosis • Abdominal radiographs (supine and upright views) to help localise the abnormality and to exclude free intraperitoneal air, look for intestinal gas and fluid level and evidence of mechanical obstruction • Chest radiographs can indicate the presence of associated pulmonary disease as an extraabdominal cause of ileus • CT should be considered to look for possible cause of ileus • Initiation of nasogastric suction with low intermittent suctioning as bowel distension can result in nausea, vomiting, and increased risk of aspiration • Intravenous fluid for fluid supplement • Avoid use of opioids and other antimotility agents • Normalising glucose levels if hyperglycaemia is present • The therapy for ileus should be directed toward the treatment of the underlying causes • Gastric prokinetic agents can be considered if obstruction has been ruled out. Examples: Nesostigmine, Cisapride, Erythromycin, metaclopramide • Start Enteral feeding as presence of food in small bowel stimulates peristalsis • Surgical decompression e.g. rectal tube or endoscopic decompression if grossly distended large bowels with risk of perforation References 1. Ileus and mechanical obstruction. In : Kumur D, Wingate D: An illustrated guide to gastrointestinal motility. New York: Churchill Livingstone, 1993, pp 547-582. 2. Ileus and obstruction. In : Haubrich WS, Schaffner F, Berk JE: Bockus Gastroenterology. Philadelphia: WB Saunders, 1995, pp 1235-1248. 3. Approach to the patient with ileus and obstruction. In : Yamada T, Aplers DH, Owyang C et al: Gastroenterology. Philadelphia: JB Lippincott, 1995, pp 796-812. 4. Bauer AJ, Schwarz NT, Moore BA, Turler A, Kalff JC. Ileus in Critical illness: mechanisms and management. Curr Opin Crit Care 1998;8:152-157. 5. Corke C. Gastric emptying in the critically ill patient. Critical Care and Resuscitation 1999;1:39-44. 83 DISCUSS THE CAUSES, CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WITH D-LACTIC ACIDOSIS Dr. T. Fraser. Intensive Care Unit, The Geelong Hospital, Victoria D-lactic acidosis is a rare disorder. It was first described by vets in cattle! L-lactate is produced by mammalian cells. Under normal circumstances, the primary product of glycolysis, pyruvate, is metabolised in the Kreb’s cycle to produce energy, carbon dioxide and water. Under anaerobic conditions NAD+ is exhausted, pyruvate is transformed to lactate, and NAD+ regenerated. L-lactate is also the primary product of cellular energy metabolism in some tissues (eg red blood cells), which is returned to the liver to be converted back to glucose, in a process referred to as the Cori cycle. D-lactate is a stereoisomer of L-lactate, formed primarily by some gram positive anaerobic bacteria. D-lactate is only formed by mammalian cells in trivial amounts. Causes Gut pathology a) Short gut syndromes - Due to incomplete carbohydrate absorbtion so that it is metabolised by colonic flora. D-lactate is then absorbed - Described in small bowel resection, jejunoileal bypass and gastric bypass surgery b) Blind loops c) Bacterial overgrowth - Lactobacillus acidophilus - Strep bovis and others d) Intestinal ischaemia and other bowel catastrophes - Increasingly recognised - Levels rise within 5 minutes in rat models of intestinal infarction - Levels appear to rise further with reperfusion - Early evidence in human studies Other Has been linked with: - Thiamine deficiency syndromes - Treatment with medium chain triglycerides - Impaired metabolism Precipitants - Antibiotic therapy - Increased carbohydrate intake - Lactobacillus therapy Development of D-lactate is often delayed many years, and occurs in response to a precipitant. This is likely to be due to progressive selection of resistant organisms and increasing colonisation. Patients who develop D-lactic acidosis often have higher baseline Dlactic acid levels, reflecting this. Clinical Features Patient is unwell Marked CNS symptoms 84 - Confusion - Ataxia, dysarthria, visual disturbance - Headache Marked anion gap metabolic acidosis - No apparent cause - Serum lactate is normal (not measured with currently available assays) Clinical features attributable to cause Management Confirm diagnosis - D-lactate assays are available, but turn around time compromises utility • D-lactate dehydrogenase test available from SIGMA • Not difficult, just not widely available - Anion gap metabolic acidosis - Stool cultures • Useful to identify resistant organisms - Exclude other causes Treatment - Symptoms are usually short lived if stimulus removed - Supportive • Maintain oxygenation and perfusion along standard lines - Identify and manage the cause • Withdraw causative antibiotics (may be enough on its own) • Carbohydrate restriction • Antibiotics (oral vancomycin, metronidazole, ciprofloxacin or clindamycin have been suggested) • Surgical correction as indicated Conclusions Rare syndrome Be aware in the clinical context May be of interest in dead gut Vets are smarter than doctors References 1. Coronado BE, Opal SM, Yoburn DC: Antibiotic-induced d-lactic acidosis. Ann Intern Med 122:839–842 2. Mordes J, Rossini A. Lactic Acidosis. In ed: Irwin RS, Rippe JM Intensive Care Medicine. 5th Ed. Lippencott, Williams, Wilkins 2003. Chapter 107 3. Serum D(-)-lactate levels as an aid to diagnosing acute intestinal ischemia. Am J Surg. 1994 Jun;167(6):575-8 85 DISCUSS THE CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WHO HAS THE ‘RETINOIC ACID SYNDROME’ Dr. D. Moxon. Intensive Care Unit, Royal Perth Hospital, WA DEFINITION Complex of symptoms and signs reported among patients receiving All Trans Retinoic Acid (ATRA) For the treatment of Acute Pro-Myelocytic Leukaemia (APML) This is molecular genetic subtype of AML APML is curable in >70% of patients SYMPTOMS AND SIGNS Respiratory Distress 84% Fever 81% Pulmonary Infiltrates 52% Pleural/Pericardial Effusions Episodic Hypotension Renal Dysfunction 36% 18% 11 % EPIDEMIOLOGY Approximately 20% of patients on ATRA will develop RAS Median time to onset of symptoms is 7days from commencement of ATRA PATHOLOGY Lung biopsy shows interstitial infiltration with mature myeloid cells. These cells release mediators and cause local capillary leak TREATMENT Close cooperation with haematologist Supportive care (NIV, Pressors, RRT, Factors) Cessation of ATRA Prompt administration of steroids vs possibility of infective cause for fever and infiltrates References 1. Up to date. RPA FRACP Course handout "Haematology 1". 86 HOW WOULD YOU MANAGE A PATIENT WHO HAS AN ACUTE POSTOPERATIVE COLONIC PSEUDO-OBSTRUCTION? Dr W. Newman. Intensive Care Unit, Mackay Base Hospital, Queensland Colonic pseudo-obstruction, or Ogilvie’s syndrome, occurs especially after trauma and orthopaedic surgery, and as a complication of serious medical conditions, such as pneumonia. More common in men past middle-age. Electrolyte imbalance is often a contributory factor. It is clinically recognisable where nausea, vomiting, abdominal pain and bloating complicate the post-operative state. The abdomen is distended, tympanitic, and bowel sounds are usually present. Abdominal Xrays show dilated right hemi-colon, gas in the rectum, the small bowel may also be dilated. Peritoneal signs are a sign of ischaemia or impending perforation, with an attendant mortality rate of 40%.1 Mechanical obstruction and toxic megacolon need to be excluded, as the treatment differs. With obstruction, X-rays may show lack of gas in the rectum, air-fluid levels in the small bowel, but a water-soluble contrast enema is needed to exclude obstruction with certainty. Toxic megacolon is characterised by fever, tachycardia, bloody diarrhoea and typical endoscopic findings of pseudo-membranous colitis. (Clostridium difficile infection, especially after broad spectrum antibiotics). Xrays may show “thumb-printing” due to submucosal oedema. The condition, originally reported by Ogilvie in 1948, was thought to be due to sympathetic deprivation of the colon. However, interrupting parasympathetic fibers from S2 to S4 leaves the distal colon atonic and a similar situation arises. Furthermore, administration of neostigmine improves the condition due to stimulation of muscarinic receptors in the colon. MANAGEMENT - Treatment of the underlying disorder. - Nil by mouth. - Nasogastric tube drainage and intermittent suctioning. - Lactulose should not be given, due to it supplying substrate for fermentation and further gas formation. - Discontinuation of anticholinergic drugs and opiates. - Correction of electrolyte imbalances: potassium, magnesium, calcium and phosphate. - Rectal tube placement and gravity drainage. - Positioning. For example, the knee-chest prone position with elevation of the pelvis.2 - Daily abdominal X-ray. A caecal diameter greater than 12 cm is associated with an increased risk of perforation.3 THE ABOVE SHOULD LEAD TO A RESPONSE in most patients within three days.4 If there is still no resolution after these measures, pharmacological agents can be used. Erythromycin, which binds to motilin receptors in the proximal small bowel and colon, is an option.5 This treatment has not been evaluated in a randomised study. In a prospective, randomised, controlled, double-blinded trial; 2mg IV neostigmine caused resumption of normal colon function in 91 % of patients.6 Neostigmine treatment - Bronchospasm, bradycardia, signs of ischaemia, perforation, obstruction, pregnancy and renal failure are contra-indications. 87 - Atropine 1 mg, should be drawn up and ready for any severe side effects (Glycopyrrolate can be considered as an alternative to atropine as it diminishes the central cholinergic effects of neostigmine without reducing the increased colonic drive)7 ECG monitoring for 30 mins after injection. Abdominal X-ray before and after the injection With the patient supine, 2 mg of neostigmine are given IV over 3 mins. A response occurs within minutes. The patient should remain recumbent for 60 mins. If no response occurs, a second dose may be tried. If the condition persists, colonoscopic decompression is indicated. A sustained response is reported in 42% of patients. Advancement of the colonoscope to the hepatic flexure is considered sufficient. Placement of a decompression tube may be tried, but this is a difficult procedure and the mortality rate associated is 1 %.8 Surgical treatment is needed if the above measures fail. Tube caecostomy is the procedure of choice. References 1. Saunders MD, Kimmey MB. Colonic Pseudo-Obstruction: The Dilated Colon in the lCU. Seminars in Gastrointestinal Disease. 2003;14(1): 20-27 2. Eisen GM, Baron TH,Dominitz JA et al. Acute colonic pseudoobstruction.Gastrointestinal Endoscopy. 2002;56(6) 3. Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie's syndrome). Analysis of 400 cases. Dis Colon Rectum 1986;29:203-210 4. Sloyer AF, Panella VS, Demas BE, et al: Ogilvie's syndrome. Successful management without colonoscopy. Dig Dis Sci 1988;33:1391-1396 5. Armstrong DN,Ballantyne GH, Modlin 1M. Erythromycin for reflex ileus in Ogilvie's syndrome. Lancet 1991;337:378 6. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the Treatment of Acute Colonic Pseudo-Obstruction. NEJM 1999;341(3):137-141 7. Child CS. Prevention of neostigmine-induced colonic activity: a comparison of atropine and glycopyrronium. Anaesthesia 1984;38:1083-1085 8. Vantrappen G. Acute colonic pseudo-obstruction. Lancet 1993; 341:152-153. 88 DISCUSS THE MANAGEMENT OF A PATIENT WITH AF, HYPOTENSION AND HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY Dr. A. Holley. Intensive Care Unit, Royal Brisbane Hospital, Queensland Issues in this patient: Hypertrophic obstructive cardiomyopathy (HOCM) Hypotension Rapid atrial fibrillation Potential for ischaemia, degeneration to VF/VT and cardiac arrest Pathophysiology: Hypertrophic cardiomyopathy (HCM) is a common disease, affecting approximately 1: 500. It usually displays autosomal dominant inheritance. Approximately 25% of patients with HCM exhibit a dynamic subaortic pressure gradient, hypertrophic obstructive cardiomyopathy (HOCM) used to describe this group. The characteristic feature of HOCM is myocardial hypertrophy that is out of proportion to the haemodynamic load. Hypertrophy can affect any or all areas of the heart and is usually asymmetrical. The predominant form involves disproportionate hypertrophy of the interventricular septum, with a normal or mildly hypertrophied left ventricular free wall. The ventricular cavities are usually small. Diastolic dysfunction ensues, with impaired left ventricular relaxation and increased filling pressures. Outflow obstruction arises as a result of the combined effects of septal hypertrophy and systolic anterior motion of the mitral valve leaflets. As the ventricle contracts the subaortic flow velocity increases. The acceleration of blood through the narrowed outflow region causes a pressure drop that draws the anterior mitral valve leaflet towards the ventricular septum (‘Venturi effect’). The mitral valve apparatus then contacts against the hypertrophied septum in mid-systole, obstructing the passage of blood through the outflow region. The onset of atrial fibrillation in both obstructive and non-obstructive HCM may result in: • • • • Cardiac failure Cardiogenic shock Syncope Systemic emboli. Many patients with HCM, particularly those with diastolic dysfunction, are intolerant of rapid atrial fibrillation, the following contribute to haemodynamic collapse: • Rapid heart rate • Loss of atrial systole • Greater degree of outflow obstruction due to the reduction in ventricular filling. The importance of atrial systole is increased in HCM, which is often associated with a decrease in peak early filling and an increased atrial contribution to ventricular filling Rapid AF with a rapid ventricular response can quickly evolve into ventricular tachycardia and ventricular fibrillation AF in HCM significantly increases the risk for stroke (21 versus 2.6 % in those in sinus rhythm). 89 Approach to this patient. 1. Ensure an adequate airway 2. Provide high flow oxygen 3. Secure IV access 4. Confirm AF with 12 lead ECG 5. Take bloods for electrolytes (ensure no hypokalaemia, hypomagnesaemia, hypophosphotaemia, hypocalcaemia), FBC (exclude anaemia) and Troponin. 6. Elevate legs to increase preload. 7. If the patient was already in ICU, the administration of inotropes may be responsible and should be switched off (Inotropes increase the gradient across the aortic valve). 8. Increase preload with bolus of crystalloid fluid. 250 ml 0.9% NaCl titrated to effect. 9. Recommendations for treatment of AF in patients with HCM were published in 2001 by the American College of Cardiology/American Heart Association/European Society of Cardiology: Therapeutic options for AF include: • Rhythm control (DC cardioversion with antiarrhythmic drugs to prevent recurrence) • Rate control with a beta blocker or calcium channel blocker. • Rhythm control is warranted in patients who deteriorate haemodynamically when in AF. Depending on the extent of hypotension, associated symptomatology and ventricular rate e.g. chest pain, profound dyspnoea, confusion/deteriorating consciousness the patient should be electrically cardioverted. A ß-blocker should be added as soon as possible, and in the context of hypotension, a pressor agent should paradoxically be provided. If the arrhythmia is prolonged or associated with more mild symptoms, therapeutic options include suppression of the arrhythmia with: 1. Amiodarone (current agent of choice) 2. Sotalol 3. Disopyramide Since AF in patients with HCM carries a significant risk of thromboembolism, all such patients, even those with paroxysmal AF, should be anticoagulated. This includes patients treated with rhythm control. Patients may present with haemodynamic collapse secondary to acute severe LV outflow tract obstruction which may be recurrent. This syndrome may occur spontaneously, or be precipitated by events that increase obstruction. These include: • Withdrawal of a beta blocker or calcium blocker • Decreased preload due to dehydration, diuretics, or an acute reduction in blood volume as with hemorrhage • Decreased afterload due to administration of a vasodilator Considerations: Severe obstruction usually resolves rapidly with the institution of the following : • Increase preload by elevation of the legs and administering intravenous fluids. • Intravenous phenylephrine to increase blood pressure, at a rate of 100 to 180 µg/min. (When the blood pressure is stabilised, the rate may be reduced). • Intravenous administration of a beta blocker (propranolol 1 mg, or esmolol). • Temporary dual chamber pacing. 90 Strategies for possible subsequent management / prevention: In obstructive HCM, dual-chamber pacing or myectomy surgery is indicated in patients refractory to medical therapy 1). A dual-chamber pacemaker with a short atrioventricular delay reduces the magnitude of left-ventricular outflow tract obstruction and alleviates symptoms in patients with severely symptomatic obstructive hypertrophic cardiomyopathy. Mechanisms by which pacing might improve the LV outflow obstruction are unclear, but possibly involve changes in the ventricular contraction pattern. Selection of optimal atrioventricular delay appears critical to achieving a beneficial haemodynamic result. 2). Myomectomy ( Morrow procedure) thins the ventricular septum and widens the outflow tract, which results in abolition of the systolic anterior motion, with resultant relief of the outflow obstruction and the concomitant mitral regurgitation. (mortality <1-2%), although the risks are somewhat higher in older patients who also require coronary artery bypass grafting. Candidates for surgery represent only a very small subset of the overall HCM population (about 5%). 3). Catheter-based alcohol septal ablation.( mortality < 2-3%. References 1. Maron BJ. Hypertrophic cardiomyopathy. Lancet 1997;350:127-133. 2. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:13081320. 3. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy: clinical spectrum and treatment. Circulation 1995;92:1680-1692. 4. Nishimura RA, Holmes DR. Hypertrophic Obstructive Cardiomyopathy. N Engl J Med 2004;350:1320-1328. 91 DISCUSS ALL THE METHODS USED TO IMPROVE THE LIKELIHOOD OF A SUCCESSFUL CANULATION OF A CENTRAL VEIN Dr. B. Cheung. Intensive Care Unit, Ipswich Hospital, Queensland SITE SELECTION indication, operator experience / institution practice options include internal jugular vein, subclavian vein, femoral vein, external jugular vein, antecubital vein/ Peripherally inserted central venous catheter (left/ right sides, different approaches- e.g. anterior, central, posterior approach for IJV) ANATOMICAL LANDMARKS Use of external anatomical landmark guided techniques, cut down method infrequent Reported failure rate 7 -20% depend on experience 183 consecutive patients require IJ cannulation (most for endomyocardial Bx), ultrasound to determine position (Denys & Uretsky, 1991) 92% lateral, anterior to carotid 2.5% not visualised, ?thrombosed 1% >1 cm lateral to carotid 2% medial, overlying carotid 3% small (< 0.5cm, unresponsive to Valsalva) CAROTID ARTERY PALPATION Carotid artery palpation can result in reduction in IJ vessel diameter (Armstrong et al 1994) HEAD ROTATION 20 degree/ maximum rotation Boyd et al (1996) 140 patients increased successful catheterisation Contralateral head rotation may increase vessel overlay of IJ vein upon the carotid artery (Troianos C, et al 1996, Sulek et al 1996) Underlie the muscle belly ? Risk of kinking POSTURE Venous filling, reduce gas embolism Patient may not tolerate Trendelenburg position (15/ 25 degree) USE OF VALSALVA MANOEUVRE Venous filling, PEEP WHICH SIDE? Left sided sites higher risk than right-sided (Balckshear & Gravenstein 1993, Sulek et al 2000) KEY- combination of variables results in largest cross sectional area of central vein and least potential risk EVIDENCE- mixed results SEEKER NEEDLE Latto (1999) advocated seeker needle to increase success & safety 21G, 40 mm needle 92 Allow more accurate control of insertion depth ULTRASOUND 2 dimensional ultrasound guidelines better than auditory signal (external/ internal) & tactile perception using external anatomical landmarks in identifying IJV real time Supported by literature review & meta-analysis (Randolph et al 1996, Calvert 2003) limited evidence for subclavian & femoral veins NICE guidelines - for central venous catheterisation into IJV in children & adults using 2D ultrasound guidance - Elective & emergency situation - Appropriate training - Audio-guided doppler NOT recommended Advantages - Precise target vein location - Detect anatomical variations & thrombosis - Avoid arterial puncture & other complication potential cost effectiveness- less procedure time & less complication resource impact- high set up cost but low procedure cost implementation & audit issues ?compliance/ medical legal deskilling issue (NICE state operators maintain their ability to use landmark method & that the method continue to be taught alongside the 2D ultrasound guided technique) OTHERS SMART Needle vascular access needle, 18-20 G with continuous wave Doppler at its tip to differentiate artery from vein (Verghese et al 2000) ECG guidance- may be useful to confirm position Electromagnetic technology- may be useful to confirm position. References 1. Denys B & Uretsky B (1991) Anatomical variation of internal jugular vein location: Impact on central venous access CCM, 19: 1516-19. 2. Latto I (1999) Avoid internal jugular vein transfixation. Anaesthesia; 54: 400-1 3. Armstrong P, Sutherland R & Scott D (1994) The effect of position and different manoeuvers on internal jugular vein diameter. Acta Anaesthesiologica Scandinavica; 38: 229-31 4. Troianos CA, Kuwik RJ, Pasqual JR, Lim AJ, Odasso DP (1996) Internal jugular vein and carotid artery anastomotic relationship as determined by ultrasonography. Anesthesiology; 85: 43-8. 5. Bell D & McLeod SR (1999) Correspondence to ultrasound guided central vein cannulation. Anaesthesia; 54: 809-22. 6. Boyd R, Saxe A & Phillips E (1996) Effect of patient position upon success in placing central venous catheters. Am J Surg; 172(4): 380-2. 7. Sulek C, Gravenstein N, Blackshear R, Weiss L (1996) Head rotation during internal jugular vein cannulation and the risk of carotid artery puncture. Anesthesia & Analgesia; 82(1): 125-8. 8. Balckshear R & Gravenstein N (1993) Left sided sites for central venous catheterisation associated with higher risk than right-sided sites. Anesthesiogy; 79:A1073 93 9. Sulek C, Blas M & Lobato E (2000) A randomised study of left versus right internal jugular vein cannulation in adults. J Clin Anesth; 12(2): 142-5 10. Randolph A, Cook D, Gonzales C & Pribble C (1996) Ultrasound guidance for placement of central venous catheters: a meta-analysis of the literature. CCM; 24(12): 2053-8. 11. Calvert N, McWilliams R, Davidson A, Paisley S, Beverley C & Thomas T (2003) Ultrasonic locating devices for central venous cannulation: meta-analysis. BMJ; 2003(327): 361-7 12. Verghese S, McGill W, Patel R, Sell J, Midgley F & Ruttimann U (2000) Comparison of three techniques for internal jugular vein cannulation in infants. Paedatric Anaesthesia, 10: 505-11. SUMMARY DISCUSS ALL THE METHODS USED TO IMPROVE LIKELIHOOD OF A SUCCESSFUL CANNULATION FOR A CENTRAL VEIN SITE SELECTION - indication - options ANATOMICAL LANDMARKS Reported failure rate 7 -20% depend on experience CAROTID ARTERY PALPATION HEAD ROTATION POSTURE USE OF VALSALVA MANOEUVRE WHICH SIDE SEEKER NEEDLE - Latto (1999) advocated seeker needle to increase success & safety ULTRASOUND - 2 dimensional ultrasound guidelines better than auditory signal (external/ internal) & tactile perception using external anatomical landmarks in identifying IJV - real time - Supported by literature review & meta-analysis (Randolph et al 1996, Calvert 2003) - limited evidence for subclavian & femoral veins - NICE guidelines: for central venous catheterisation into IJV in children & adults using 2D ultrasound guidance Elective & emergency situation Appropriate training Audio-guided doppler NOT recommended - other issues OTHERS 94 DISCUSS THE CLINICAL FEATURES AND THE MANAGEMENT OF A PATIENT WITH A TIA Dr. H. Ramaswamykanive. Intensive Care Unit, Concord Hospital, New South Wales Transient ischaemic attack: Defined as transient neurologic deficits due to ischaemia in a particular angioanatomic territory, lasting for minutes to hours followed by complete restoration of function. Such attacks may anticipate oncoming thrombotic strokes. Epidemiology: Approximate incidence of TIA over the age of 65 years is 300,000 per year in USA. Patients who have one or more TIAs have 10-fold increase in risk of subsequent stroke. The combined risk for an adverse event (Stroke, CHF, AMI, Unstable angina, Ventricular arrhythmia, Death, or Recurrent TIA) was 25.1% within 90 days of TIA, about ½ of which occur in first 2 days and long term risk is about 4% per year after TIA. Pathophysiology: A critical level of blood flow is needed to maintain neuronal function and to prevent ischaemic damage. Normal cerebral bloodflow lies between 40 to 60 mls /100 gm/min. Less than 20 mls/100gm/min normal neuronal function fails and neurologic symptoms begin. At less than 8 mL/100g/min irreversible damage ensues. There is demonstrable temporary arrest in blood flow in the affected territory. The vascular occlusion is either by thromboembolic process secondary to atherosclerosis or cardioembolic source. TIAs also can occur in association with hypercoaguble states, arterial dissection, arteritis and cocaine. TIAs occurred before the development of atherothrombotic strokes in 25% - 50% of cases, 11% - 30% of cardioembolic strokes and in 11% - 14% of lacunar infarcts. The blood flow to the brain is classified into anterior and posterior circulation. TIAs from anterior circulation may be embolic or thrombotic and from posterior circulation more likely to be thrombotic. Clinical features: Carotid TIAs take the form of mono ocular blindness (amaurosis fugax), hemiparesis, hemisensory syndromes, aphasia, dyscalculia and confusion. Vertebrobasilar branch attacks consists of blindness, hemianopia, diplopia, vertigo, dysarthria, dysphagia, facial weakness or numbness, hemiplegia or quadriplegia and sensory syndromes in various combinations. Differential diagnoses of TIA include Migrainous accompaniments, Labrynthine vertigo, Cerebral seizures, Syncope, Transient global amnesia, Transient monoocular blindness of undetermined origin, Paraesthesia in women, Carpal tunnel syndrome, Cervical disc disease, Ulnar or median nerve compression at elbow, Hypoglycemia, Hyperventilation, Somatic symptoms associated with depression, Anxiety or hysteria, Transient symptoms of multiple sclerosis, Cervical traction. Evaluation of TIA This is based on symptomatology and pretest probability for each investigation. Current recommendations include a full blood count, blood chemistry, coagulation profile, ESR, ECG. Imaging studies include Noncontrast CT scan of brain, CT angiography; Duplex Ultrasonography, MRI and MR angiography is useful in evaluating infarct location and cerebral blood flow. Other investigations include Vasculitic screening, Cardiac ECHO and Holter Monitoring. 95 Management of TIA. The primary goal of TIA is the prevention of ischaemic stroke. Risk factor modification is essential in the management of stroke. Modifiable risk factors include hypertension, atrial fibrillation, diabetes, hypercholesterolaemia, obesity, cigarette smoking, excessive alcohol use, physical inactivity and stress. Nonmodifiable risk factors are age, sex, race/ethnicity, family history and genetics. By definition symptoms of TIA can persist up to 24 hours. But we know from the placebo group of the NINDS study that it is unlikely, patients with a persistent neurologic deficit longer than 90 minutes will resolve spontaneously and hence there is little justification for treating TIA any differently from stroke. Sensitive MRI sequences (diffusion weighted images) reveal evidence of brain infarction in 2/3rd of patients presenting with TIA and stroke in general. Anticoagulants, antiplatelet agents, antihypertensive agents and lipid lowering agents are fundamental to TIA/ Stroke management. 1. Anticoagulation is recommended after imaging brain in patients with TIA or in patients with atrial fibrillation, hypertension, poor left ventriclular function, rheumatic mitral valve disease, prosthetic heart valves, prior history of stroke or TIA, a history of systemic embolism, age greater than 75 years (the older you are, the more you need warfarin), considered to be at higher risk for stroke. 2. Antiplatelet agents used are Aspirin, Ticlopidine, and Clopidogrel and Extended release dipyridamole plus aspirin. Aspirin prevents only 1 in 6 strokes; ticlopidine not used much because of poor side effect profile, clopidogrel best option in patients with multiple risk factors. Extended release dipyridamole plus aspirin provides 23% better risk reductions than lower doses of aspirin. 3. Antihypertensive agents. Hypertension control is considered the crown jewel of stroke prevention. Patients with TIA have pressure dependent flow problem and therefore avoid acute lowering of blood pressure unless it hypertensive urgency. Studies have shown lowering blood pressure results in dramatic reduction in stroke risk. ACE inhibitors may have secondary stroke prevention effect above and beyond blood pressure lowering effect. 4. Lipid lowering agents (HMG Co A reductase inhibitors) have antithrombotic, antioxidant and anti atherosclerotic activity. Therefore approved for use in high normal, normal and even in those with low lipid levels. 5. Surgical therapy is robust for men, patients with hemispheric symptoms without diabetes and for persons with significant ulcerative atherosclerotic plaques as demonstrated by angiography, provided the surgeon has <6% perioperative complication rate. Studies have shown carotid endarterectomy decreases the risk of ipsilateral stroke or death from 26% to 9% in high grade (70% - 99%) stenosis. Benefit is less in women, patients with moderate grade (50%- 69%) stenosis and patients with retinal TIAs. 6. Angioplasty and stenting as alternative to carotid endarterectomy is being evaluated and is considered as investigational. References 1. Cerebrovascular Cases, John N Fink and Louis R Caplan. Med Clin North Amer 2003;87:755–770. 2. Atrial fibrillation/ Hypertension. Audio-Digest Internal Medicine 50(23) December 7, 2003. 96 3. 4. 5. 6. 7. Secondary stoke prevention. Audio-Digest Internal Medicine 50(01) January 7, 2003. Transient ischemic attack: an emergency medicine approach, Keith Thomas Borg and Arthur Martin Pancioli. Emergency Medicine Clinics Of North America 20(2002) 597– 608. Diagnosis and Treatment of Ischemic Stroke, Mark J Alberts, Am J Med.1999; 106: 211221. Principles and practice of neurology, Companion Handbook, Raymond D Adams and Maurice Victor. 5th edition 1994. Neurological and Neurosurgical Intensive care, Allan H Ropper 3rd editon.1993. 97 DISCUSS YOUR MANAGEMENT OF A PATIENT WITH CHEST TRAUMA WHO IS MECHANICALLY VENTILATED AND WHO DEVELOPS A BRONCHO-PLEURAL FISTULA Dr. M. Sanap. Intensive Care Unit, Flinders Medical Centre, South Australia Introduction Bronchopleural fistula ( BPF) is defined as a communication between the bronchial tree and pleural space. Clinically seen as a persistent air leak 24 hours after pneumothorax. Aetiology of BPF in chest trauma: - direct trauma - iatrogenic: puncture, laceration, barotraumas - spontaneous alveolar rupture due to underlying lung pathology - necrotising infection - acute lung injury Consequences: - persistent pneumothorax - inadequate ventilation - VQ mismatching - infection of pleural space - inability to maintain PEEP - inappropriate cycling of ventilator Problems with a BPF: - Failure of lung re-expansion - Loss of delivered tidal volume - Inability to apply PEEP - Inappropriate cycling of ventilator - Inability to maintain alveolar ventilation with resultant hypoxia and hypercapnia - Problems of weaning - Attributable mortality Main factors which perpetuate BPF are: - high airway pressures that increase leak during inspiration - increased mean intrathoracic pressures throughout the respiratory cycle (PEEP, inspiratory pause, high I:E) that increase leak throughout the breath - high negative suction All these factors tend to be present in patients with ARDS because they are necessary to support gas exchange and lung inflation. How to identify - Failure to reinflate lung despite chest tube drainage ( even with large lumen ICD) or continued air leak after evacuation of the PTX in the setting of chest trauma. - A persistent BPF results in air leak which can be detected by the continuous bubbling of air through the water seal of the suction system. 98 Management of BPF: A. CONSERVATIVE: 1. Large size chest tube (multiple if necessary) - Use drainage system with adequate capabilities - Large chest drains allow sufficient gas flow. 2. Application of positive intrapleural pressure: - Equivalent to PEEP via chest tube. - Synchronised closure of chest tube during inspiration has been tried in an attempt to decrease leak. - Increased risk of tension pneumothorax and very close observation is essential. 3. Drainage system: - Use drainage system with adequate capabilities - Ensure drainage system is capable of dealing with flow rates. 4. Ventilation: a. Conventional ventilation: - Aim is to reduce flow through fistula to promote healing and to decrease wasted ventilation while still maintaining adequate ventilation and oxygenation. - Use lowest possible tidal volumes, ventilatory rates, PEEP and inspiratory time. Encourage spontaneous breathing. IMV may have an advantage over assist control. - Goal is to maintain adequate ventilation and oxygenation while reducing the fistula flow and allow the repair to occur, lowest effective VT , fewest mechanical breaths per minute, lowest level of PEEP – reduce airway pressure, shortest inspiratory time, use greatest number of spontaneous breaths per minute, intermittent mandatory ventilation better than control ventilation, permissive hypercapnia and accept a lower arterial oxygenation. b. High frequency jet ventilation (HFJV) :- May be useful in severe BPF, particularly when there is a tracheal or bronchial fistula in the presence of normal lung parenchyma - However, better at controlling pO2 and pCO2 than conventional modes - Remains controversial in terms of benefit c .Independent Lung Ventilation:- Limited experience - It can be used for unilateral BPF - Patient intubated with double lumen tube - Needs 2 ventilators (synchronous or asynchronous) - Conventional ventilation of unaffected lung, affected lung either ventilated with lower pressures and volumes or with CPAP alone - Guided by volume of air leak, haemodynamic and gas exchange stability - Short term solution, bridge to surgical intervention. 5. Fibreoptic bronchoscopy and direct application of sealant (cyanoacrylate, fibrin agents, absorbable gelatin sponges e.g. Gelfoam): 99 Bronchoscopy may be useful to identify sites of proximal leak and can be used to localise distal leaks with the use of a balloon catheter passed down the suction channel and into more distal airways. Reduction of air leak on inflation of balloon indicates that catheter is in the correct area. An occluding material can then be injected. For distal fistulae a PA catheter has been used. Experience with this technique is extremely limited. It cannot be used for proximal leaks. B. INVASIVE: - Mobilisation of intercostal or pectoralis muscle - Thoracoplasty - Bronchial stump stapling - Pleural abrasion and decortication. Prognosis Mortality higher when: BPF develops late in the illness of a mechanically ventilated patient not related to chest trauma volume of leak greater (leaks of 500 ml or more associated with 100% mortality in one study) . References 1. Rajan Jain, S.S. Baijal , R.V. Phadke Endobronchial Closure of a Bronchopleural Cutaneous Fistula Using Angiography Catheter American Jornal of Roentogenology AJR 2000, 175: 1646 – 1648 2. Junaid H Khan, MD, et al Management Strategies for Complex Bronchopleural Fistula Asian Cardiovasc Thorac Ann 2000;8:78-84 3. Carvalho P, Thompson WH, Riggs R, Carvalho C, Charan NBManagement of bronchopleural fistula with a variable-resistance valve and a single ventilator. Chest. 1997 May;111(5):1452-4 4. Baumann MH, Sahn SA. Medical management and therapy of bronchopleural fistulas in the mechanically ventilated patient.Chest. 1990 Mar;97(3):721-8. Review 5. Sjostrand UH, Smith RB, Hoff BH, Bunegin L, Wilson E.Conventional and highfrequency ventilation in dogs with bronchopleural fistula. Crit Care Med. 1985 Mar;13(3):191-3 6. Ost D, Corbridge T. Independent lung ventilation.Clin Chest Med. 1996 Sep;17(3):591601. Review 7. Gas flow through a bronchopleural fistula. Measuring the effects of high-frequency jet ventilation and chest-tube suction.Chest. 1988 Jan;93 (1):210-3 8. M Litmanovitch, GM Joynt, PJ Cooper and P Kraus Persistent bronchopleural fistula in a patient with adult respiratory distress syndrome. Treatment with pressure-controlled ventilation Chest, Vol 104, 1901-1902 9. Ventilatory management of life-threatening bronchopleural fistulae. A summary. Crit Care Med. 1981 Jan;9(1):54-8 10. Prolonged high-frequency jet ventilation in a patient with bronchopleural fistula. An alternative mode of ventilation.Intensive Care Med. 1986;12(3):161-3 11. Unilateral high frequency jet ventilation. Reduction of leak in bronchopleural fistula.Intensive Care Med. 1984;10(1):39-41 13. Management of bronchopleural fistula with a variable-resistance valve and a single ventilator.Chest. 1997 May;111(5):1452-4. 14. EL York, DB Lewall, M Hirji, ET Gelfand and DL Modry Endoscopic diagnosis and treatment of postoperative bronchopleural fistula Chest, Vol 97, 1390-1392, 100 15. AG Fleisher, KG Evans, B Nelems and RJ Finley Closure of bronchopleural fistulas using Albumin-Glutaraldehyde tissue adhesiveAnn. Thorac. Surg., January 1, 2004; 77(1): 326 328. 16. K. Takaoka, S. Inoue, and S. Ohira Central Bronchopleural Fistulas Closed by Bronchoscopic Injection of Absolute Ethanol* Chest, July 1, 2002; 122(1): 374 - 378. 17. P. H. Hollaus, F. Lax, B. B. El-Nashef, H. H. Hauck, P. Lucciarini Natural History of Bronchopleural Fistula After Pneumonectomy: A Review of 96 Cases Ann. Thorac. Surg., May 1, 1997; 63(5): 1391 - 1396 18. Shah AM, Singhal P, Chhajed PN, Athavale A, Krishnan R, Shah AC Bronchoscopic closure of bronchopleural fistula using gelfoam. J Assoc Physicians India. 2004 Jun;52:508-9 19. Dale K. Mueller, MD; Patrick E. Whitten, MD; William P. Tillis, MD; Linda M. Bond, MA and James R. Munns, MD Delayed Closure of Persistent Postpneumonectomy Bronchopleural Fistula* Chest. 2002;121:1703-1704.) 20. Transposition of modified latissimus dorsi musculocutaneous flap in the treatment of persistent bronchopleural fistula after posterolateral incision. J Thorac Cardiovasc Surg. 2004 Feb;52(2):84-7. 21. Closure of bronchopleural fistula after pneumonectomy with a pedicled intercostal muscle flap. Eur J Cardiothorac Surg. 1999 Aug;16(2):181-6. 101 A PATIENT HAS BEEN REFERRED TO YOU FOLLOWING A NEPHRECTOMY FOR A HYPERNEPHROMA PERFORMED 7 DAYS AGO FOR MANAGEMENT OF PYREXIA, OLIGURIA AND NOW HYPERKALEMIA. HE HAS BEEN CONFUSED DURING THE PAST THREE DAYS WITH EPISODES OF HYPOGLYCAEMIA AND THE NUMEROUS GLUCOSE INFUSIONS HAS CAUSED HIM TO DEVELOP HYPONATREMIA. HOW WOULD YOU MANAGE HIM? Dr. P. Dubey, Intensive Care Unit, The Mater Hospital, Queensland Management in Ward: Are there any emergencies to deal with? 1. How severe is the hyperkalemia? 2. How severe is the hyponatremia and does it need to be treated with hypertonic saline? 3. Is this an Adrenal crisis? The combination of pyrexia, hyperkalemia, hyponatremia and hypoglycaemia is strongly indicative of adrenal insufficiency.1 A combination of Hyponatremia and Hyperkalemia (Na: K ration <25:1)) is very strongly suggestive of Addison’s disease.2 Best would be to do an arterial blood gas analysis, this would confirm the most current levels of Na, K, Cl, Glucose, rule out hypoxia as a cause of confusion and confirm the existence of metabolic acidosis - another indicator of Adrenal crisis.2 Blood tests as UEC,LFTs, Ca++,Mg++, Glucose, Cortisol and ACTH with blood cultures can be sent and, already available levels of Ser Na. K+ and Ca++ can be compared for rapidity of decline in these values from preoperative state. Clinically assess intra-vascular volume status with HR, JVP and postural hypotension, if possible. Volume replacement with Normal saline is most important as this would correct the hyponatremia as well, and this should, at least, initially, cover for the electrolyte deficit from a mineral corticoid deficiency. Intravenous 0.9% saline, 1-2 Litres over 2-4 hours is given initially and thereafter on the basis of cardiovascular status.3 The volume deficit in acute adrenal crisis is seldom greater than 10% of TBW6 and a 1000 mL can be given in the first 30mins. A random cortisol sample can be drawn (if not already done-although not an absolute necessasity) and the patient given Hydrocortisone 100 mg IV bolus or Dexamethasone 10 mg can be given IV and a basal cortisol level requested followed by a short synacthen test (later in ICU). While the volume resuscitation is ongoing and the patient haemodynamically stable, he can be transferred to ICU but treatment should not be delayed pending transfer to ICU. Hyponatremia usually responds to saline resuscitation and care should be taken in treating hyponatremia with Hypertonic saline because of increased risk of Osmotic demyelination in a catabolic patient.4 Hyperkalemia of Adrenal insufficiency is usually close to 5.5 mol/L unless a significant degree of volume depletion is present.5 The hyperkalemia usually does not require specific therapy but, in this particular case the diagnosis is as yet unconfirmed and, if the electrolyte disorder is an urgency then, I would be inclined to treat is as an emergency, especially if, ECG changes of hyperkalemia are also present. Much less K+ loss is needed to decrease plasma K+ from 7.0 to 6.0 than is required to decrease it from 6.0 to 5.0. Hence, creating a small K+ loss can be very important if there is severe degree of hyperkalemia.5 102 50 mL of 50% dextrose can be given to correct for hypoglycaemia or 5% Dextrose be given with Normal Saline. Further fluid loading can be managed with assessment of volume status with serial CVP and arterial line for BP monitoring in ICU. Management in the ICU: The bolus dose is followed by Hydrocortisone 100mg IV 6-hourly. Once the synacthen test is complete, the steroid can be switched over to Hydrocortisone as it has mineralocorticoid activity as well. Mineralocorticoid replacement is usually not required initially, as saline resuscitation is enough to correct the electrolyte deficits and, Hydrocortisone 50mg has the activity of 0.1mg of Fludrocortisone.7 hence a total of 400mg of hydrocortisone/day would have the equivalent activity of nearly 1mg of Fludrocortisone. Blood cultures should then be sent and Broad-spectrum antibiotic started as diagnosis of sepsis would be difficult in presence of adrenal crisis and sepsis itself can lead to relative adrenal insufficiency. These antibiotics can later be stopped if blood cultures are negative and the steroids stopped if the synacthen test is normal and an alternative cause is found for this presentation. An Imaging of KUB is required to rule out obstruction of the remaining kidney, ureters. A CXR to check position of CVL placement may show a pathologic process as Consolidation and help identifying the source of sepsis. In critically ill patients with septic shock , a cut off level of 18 - 25 µg/dL of basal random cortisol can be used to identify patients who may benefit from low dose hydrocortisone replacement(200-300mg/day). A look into patient’s notes to check if adrenals were removed as well and chemotherapy, if any, that patient had involved use of steroids or the patient had been on long-term steroids in the year before surgery. If Etomidate was used perioperatively. Paraneoplastic syndromes associated with hypernephroma…hypercalcemia is commonest and hypoglycaemia has also been found but symptoms of Paraneoplastic syndrome usually subside after nephrectomy and their recurrence is a sign of tumour recurrence or incomplete removal. When the results of synacthen test and ACTH levels are available and an Adrenal insufficiency is confirmed, the IV steroids can be replaced with oral Steroids with or without mineralocorticoid replacement (Secondary adrenal insufficiency). If the patient fails to respond (confusion) to this treatment despite near normalisation of electrolyte parameters then further imaging of Brain and an EEG may be required to rule out metastatic disease to Brain or a non convulsive status epilepticus as a cause of neurological deterioration and, the electrolyte abnormalities, a result of intial management (aggressive treatment with 5% Dextrose) and inadequate intravascular repletion causing pre-renal failure, metabolic acidosis and hyperkalemia. (Just in case this missed Occam’s razor !) References 1. Oelkers W. Adrenal Insufficiency. NEJM 1996;vol 335,No 16: 1206-1212 2. Oh’s Intensive care manual, 5th Ed, p 577 3. Worthley LIG. Disorder of Adrenal function. In The Australian Short course in Intensive care –2003 Handbook. Editor Worthley LIG, 2003 4. Gerlach H. Adrenal Insufficiency. In Textbook of Critical care. Edited by Fink et al.Elsevier Saunders;2005 :1491-1503 5. Halperin M. Disorders of Plasma Potassium concentration. In Textbook of Critical care. Edited by Fink et al.Elsevier Saunders;2005 :1097-1111 103 6. 7. Vedig A. Adrenocortical Failure. In The Australian Short course in Intensive care – 1998 Handbook. Editor Worthley LIG, 1998 Adrenal insufficiencyWiebke Arlt; Bruno AllolioThe Lancet; May 31, 2003; 361, 9372; Academic Research Library. Pg. 1881 104 DISCUSS HOW YOU WOULD MANAGE A PATIENT WHO HAS DEVELOPED BLINDNESS WITH SERUM SODIUM OF 122 MMOLS/L AND MEASURED OSMOLALITY OF 290 MOSM/KG 1 HOUR FOLLOWING A TURP Dr. S. Vergese. Intensive Care Unit, Flinders Medical Centre, South Australia Transurethral resection of the prostate or a bladder tumour is often associated with the use of as much as 20 to 30 litres of nonconductive flushing solutions containing glycine, sorbitol or manitol. Variable quantities of this fluid enter the circulation via two routes: slowly via fluid that has leaked into the retroperitoneal space through the perforated prostatic capsule; and rapidly via direct entry into the large prostatic veins. The TURP syndrome consists of hypoosmolar hyponatremia, cardiovascular disturbances (e.g. hypertension, hypotension, bradycardia), an altered state of consciousness (e.g. agitation, confusion, nausea, vomiting, myoclonic and grand mal seizures) and (when glycine solutions are used) transient visual disturbances of blurred vision, blindness and fixed dilated pupils, associated with transurethral resection of the prostate.1,2 It may occur within 15 minutes or be delayed for up to 24 hours, postoperatively, and is caused by an excess absorption of the irrigating fluid which contains 1.5% glycine with an osmolality of 200 mosmol/kg (although hyponatremia syndromes have also been described when irrigating solutions containing 3% mannitol or 3% sorbitol have been used, both of which have an osmolality of 165 mosm/kg).3 The addition of ethanol 1% to these solutions has allowed fluid absorption to be monitored by expired ethanol tests.4 Symptomatology usually occurs when > 1 litre of 1.5% glycine or > 2 - 3 litres of 3% mannitol or sorbitol are absorbed.5 The excess absorption of irrigating fluid causes an increase in total body water (which is often associated with only a small decrease in plasma osmolality), hyponatremia (as glycine, sorbitol or mannitol reduces the sodium component of ECF osmolality), and an increase in the osmolar gap.6-8 When glycine is used, other features include hyperglycinaemia (up to 20 mmol/l - normal plasma glycine levels range from 0.15 to 0.3 mmol/l), hyperserinemia (as serine is a major metabolite of glycine), hyperammonaemia (following deamination of glycine and serine), metabolic acidosis and hypocalcaemia (due to the toxic effects of the glycine metabolites, glyoxylic acid and oxalate).9 Because glycine is an inhibitory neurotransmitter (by blocking chloride channels).10 and as it passes freely into the intracellular compartment, when glycine solutions are used, hyperglycinaemia may be more important in the pathophysiology of this disorder than a reduction in body fluid osmolality and cerebral oedema,11 as cerebral oedema is often minimal in this condition.12 Treatment is largely supportive with the management of any reduction in plasma osmolality being based on the measured plasma osmolality and not plasma sodium levels. If the measured osmolality is > 260 mosmol/kg and mild neurological abnormalities exist, if the patient is haemodynamically stable with normal renal function, close observation and reassurance (e.g. the visual disturbances are reversible and will last for less than 24 hours) are usually all that is needed. If the patient is hypotensive and bradycardic with severe and unresolving neurological abnormalities, haemodialysis may be warranted.13 Hypertonic saline is only used if the measured osmolality is < 260 mosmol/kg and severe non-visual neurological abnormalities exist. 105 References 1. Arieff AI, Ayus JC. Endometrial ablation complicated by fatal hyponatremic encephalopathy. JAMA 1993;270:1230-1232. 2. Istre O, Bjoennes J, Naess R, Hornbaek K, Forman. Postoperative cerebral oedema after transcervical endometrial resection and uterine irrigation with 1.5% glycine. Lancet 1994;344:1187-1189. 3. Gravenstein D. Transurethral resection of the prostate (TURP) syndrome: a review of the pathophysiology and management. Anesth Analg 1997;84:438-446. 4. Hahn RG. Ethanol monitoring of irrigating fluid absorption (review). Eur J Anaesth 1996;13:102-115. 5. Hahn RG. Irrigating fluids in endoscopic surgery. Br J Urol 1997;79:669-680. 6. Wang JM, Creel DJ, Wong KC. Transurethral resection of the prostate, serum glycine levels, and ocular evoked potentials. Anesthesiology 1989;70:36-41. 7. Hahn RG. Fluid and electrolyte dynamics during development of the TURP syndrome. Br J Urol 1990;66:79-84. 8. Ghanem AN, Ward JP. Osmotic and metabolic sequelae of volumetric overload in relation to the TURP syndrome. Br J Urol 1990;66:71-76. 9. L I G Worthley. Osmolar Disorders. Critical Care and Resuscitation 1999; 1: 45 -54. 10. Schneider SP, Fytte RE. Involvement of GABA and glycine in recurrent inhibition of spinal motor neurons. J Neurophysiol 1992;66:397-406. 11. Jensen V. The TURP syndrome. Can J Anaesth 1991;38:90-97. 12. Silver SM, Kozlowski SA, Baer JE, Rogers SJ, Sterns RH. Glycine-induced hyponatremia in the rat: a model of post-prostatectomy syndrome. Kidney Int 1995;47:262-268. 13. Agarwal R, Emmett M. The post-transurethral resection of prostate syndrome: therapeutic proposals. Am J Kid Dis 1994;24:108-111. 106 DISCUSS THE IDEAL PROPERTIES OF A PREDICTIVE SCORING SYSTEM FOR SEVERITY OF ILLNESS IN THE INTENSIVE CARE UNIT Dr S. Senthuran. Intensive Care Unit, Royal Brisbane Hospital, Queensland Accuracy High discrimination: This refers to how well the model can tell apart those who will live from those who will die. If the scoring system predicts 90% mortality, discrimination is perfect if observed mortality is 90%. Highly calibrated: The scoring system performs over a wide range of predicted mortalities – i.e it is accurate at predicted mortalities of 90%, 50% and 20%. Discrimination can be assessed using the receive operating characteristic (ROC) curve which plots sensitivity on the Y axis against (1-specificity) on the X axis. The co-ordinates for the curve are obtained by measuring the sensitivity & specificity at different decision thresholds i.e what is considered acceptable uncertainty (e.g 90%, 95% or 99% certain of correct prediction). Almost ideal system ROC curve sensitivity System no better than chance Area under the curve is proportional to the discriminatory power. 1- specificity (i.e false positive rate) Reliability There should be inter and intra observer agreement in data collection process and in how the score is used. The greater the subjectivity the (e.g choosing a primary diagnosis) the poorer the reliability of the system. Intra observer reliability estimates the random error in any measured score and can be measured by scoring on two occasions to see the fluctuations from session to session. Inter observer reliability can be measured by the intraclass correlation coefficients for continuous variables or the Kappa statistic for categorical data. Content Validity The model should be comprehensive: i.e should include quantifiable and difficult to quantify (e.g elective vs emergency admission, co-morbidities etc) factors in giving a predictive score for severity of illness. However as the number of variables in the model increase, the reliability and ease of administration decrease, necessitating a balance between content validity and reliability be struck. 107 Methodological rigour Scoring system should be derived from a large cohort of patients from several intensive care units to make it generally applicable and avoid bias. The variables used should be routinely collected and independent of ICU interventions so that any treatment effect is avoided. Rules for data collection must be rigorously adhered to especially with regard to missing data and classification of medical diagnosis. The scoring system should be validated using a different population than from which it was derived. References 1. Ridley S. Severity of illness scoring systems and performance appraisal (Review). Anaesthesia 1998;53:1185-94. 108 DISCUSS YOUR MANAGEMENT OF A MECHANICALLY VENTILATED POSTOPERATIVE CORONARY ARTERY BYPASS PATIENT WHO HAS JUST DEVELOPED AF AND WHO IS HYPOTENSIVE Dr. D. Gardiner. Intensive Care Unit, Princess Alexandria Hospital, Queensland Consequences of AF: haemodynamic instability, discomfort, ↑ bleeding requiring re-operation, prolongs ICU and hospital stay (↑cost), ↑ stroke – 3x risk, risk generally commencing after 48hrs 1. Cardioversion a. Electrical - essential for severe haemodynamic compromise i. Direct Current Cardioversion - start 200J monophasic • Only 13.5% will remain in sinus at 48hrs, potentially harmful b. Chemical – indicated for less severe haemodynamic compromise i. Amiodarone • Drug of choice in setting of hypotension or left ventricular depression • 5mg/kg load followed by up to 15mg/kg over 24 hrs • Probably no better at cardioversion than other agents • Provides effective rate control even if fails to cardiovert • Cardiovascularly stable (not always) with low pro-arrhythmic risk ii. Other options: Sotolol (oral Class III anti-arrhythmic with β-antagonist activity) or Ibuletide (not available in Australia, new Class III agent -role expanding) 2. Supportive a. Mean arterial pressure and cardiac output - start or increase inotropes b. Rate Control – indicated in haemodynamically stable patient as spontaneous cardioversion frequent or as 2nd line to failed cardioversion i. β-blockers ii. Other options: Calcium Channel Blockers or Digoxin (less useful in the post cardiac patient where high catecholamine stimulation) 3. Prevent Recurrence - Most research has been in primary prophylaxis only not recurrence a. Reduce precipitants i. Electrolyte disturbances: Hypokalaemia (aim 4.5mmol/L), Hypomagnesaemia (prophylactic Mg has been shown to ↓ incidence AF) ii. Sympathetic activity – analgesia, reassurance, catecholamine infusions iii. Respiratory compromise or SIRS b. Specific strategies i. Restart or commence β-blocker • Major role in prevention of AF post-cardiac surgery • Pre or intra-operative initiation superior to post-operative ii. Amiodarone (effectively prevents post-operative AF in many trials) • Often used in addition to β-blockers • Care if: resting HR <50 bpm, 2nd or 3rd degree AV block, CCF, prolonged administration → organ toxicity iii. Sotalol - 80mg oral bd, REDUCE trial suggested inferior to amiodarone for prevention and some ↓ in stroke volume 109 iv. Atrial Pacing - pacing the atria just above the atria’s intrinsic rate Consider anti-coagulation – if AF persists for >48 hrs a. 90% of patients will not require a 6 week elective cardioversion Options: Warfarin (target INR 2-3), can be started immediately post-CABG without major ↑ bleeding risk; Heparin may increase bleeding risk post-CABG – not recommended; Aspirin (325mg/day) in low risk patients may be an acceptable alternative to warfarin. 4. References 1. Cresswell L.L. & Damiano, R.J. Postoperative atrial fibrillation: An old problem crying for new solutions. J Thorac Cardiovasc Surg 2001;121:638-41. 2. Falk, R.H. Medical Progress: Atrial Fibrillation N Engl J Med 2001;344:1067-78. 3. Knotzer, H. et al. Postbypass arrhythmias: pathophysiology, prevention, and therapy. Curr Opin Crit Care 2004;10:330-5. 4. Maisel, W.H. Atrial Fibrillation after cardiac surgery. Ann Intern Med 2001;135: 106173. 5. Mooss, A.N. et al. Electrophysiology: Amiodarone versus sotalol for the treatment of atrial fibrillation after open heart surgery: The Reduction in Postoperative Cardiovascular Arrhythmic Events (REDUCE) trial. Am J Heart 2004;148:641-8. 6. White, C.M. et al. Intravenous Plus Oral Amiodarone, Atrial Septal Pacing, or Both Strategies to Prevent Post-Cardiothoracic Surgery Atrial Fibrillation: The Atrial Fibrillation Suppression Trial II (AFIST II). Circulation 2003;108(SII):200-6. 110 DISCUSS THE INDICATIONS FOR AND COMPLICATIONS OF INTRAVENOUS SODIUM BICARBONATE Dr. R. Ramadoss. Department of Critical Care Medicine, Flinders Medical Centre, SA Blood gas analysis is one of the commonest investigation done in Emergency department and Intensive Care Unit. Metabolic acidosis is a common problem in patients admitted in Intensive Care Unit. Though it remains uncertain, whether or not there is true cause- effect relationship between acidosis and adverse clinical outcomes. Acidosis is a powerful marker of poor prognosis in critically ill patients.1 The condition responsible for severe acidemia determines the patient’s status and prognosis.2 Intravenous Sodium Bicarbonate (Sodabicarb, NaHCO3) is the mainstay of alkali therapy. [Carbicarb has sodabicarb; THAM has not been documented to be clinically more efficacious than bicarbonate2]. PHYSIOLOGIC BACKGROUND Severe academia (blood pH < 7.1) suppresses myocardial contractility, predisposes to cardiac arrhythmias, causes venoconstriction and can decrease peripheral vascular resistance and blood pressure, reduce hepatic blood flow and impair oxygen delivery3. It also promotes respiratory muscle fatigue and insulin resistance. Acidemia progressively attenuates the effects of catecholamines on the heart and vasculature. With administration of sodabicarb and improving pH towards the physiological level, the vicious cycle of detoriation can be arrested. While maintaining the metabolic milieu the physician buys time thus allowing general and cause specific measures can be taken4 as well as endogenous reparatory processes to take effect. INDICATIONS FOR SODIUM BICARBONATE THERAPY: Normal Anion Gap (AG) Metabolic Acidosis: Normal AG metabolic acidosis are due to renal tubular acidosis or gastrointestinal bicarbonate loss.5 It also occurs as a complication of aggressive volume resuscitation with solution that do not contain bicarbonate (Dilutional acidosis).2 Bicarbonate therapy is usually administered if the plasma bicarbonate level is 18 mmol/ L or less. Increased Anion Gap (AG) Metabolic Acidosis: Three common conditions which produces increased AG acidosis are Lactic acidosis, Diabetic Ketoacidosis (DKA) and during CardioPulmonary Resuscitation (CPR). In all these situations bicarb therapy is controversial. This is discussed later. Poisonings: 1. Aspirin intoxication. Sodium bicarbonate must be administered to raise blood pH to about 7.45 – 7.50. The resultant alkalinisation of the urine promotes the excretion of salicylate. 2. Methanol and Ethylene Glycol intoxication. They can produce severe high AG acidosis. Large amount of alkali are often required to combat the severe acidemia 2. 3. Tricyclic antidepressants poisoning. 111 Sodium bicarbonate therapy increase the binding of the drug with protein and reduce the amount of circulating free drug5. Hyperkalemia: Life threatening arrhythmia due to hyperkalemia is a strong indication of sodabicarb therapy. Infact sodabicarb therapy in VF/VT, PEA or Asystole due to hyperkalemia is the only class I indication as per ACLS protocol 7. How much Sodium Bicarbonate? The administration of sodabicarb carries some risk, it should be given judiciously in amounts that will return blood pH to a safer level of about 7.20 2, and not to create overshoot alkalosis. To achieve this goal, plasma bicarbonate must be increased to 8 to 10 mmol / L How to Administer? Except in hyperkalemia and extreme acidemia sodabicarb should be administered as infusion (over few minutes to few hrs). Rapid administration can cause a fall in Blood pressure, fall in PaO2 and transient rise in intracranial pressure 6, hence should be avoided. COMPLICATIONS OF SODIUM BICARBONATE THERAPY: Is low pH bad? The experience with permissive hypercapnia for patients with ARDS or status asthmaticus in which hypercapnia and acidemia are tolerated has changed the perspective of acidemia. Is sodium bicarbonate therapy without problem? The most obvious side effects of sodium bicarbonate therapy are hyperosmolality and hypernatremia 2, 6 . It can lead to extra cellular fluid overload especially in patients with heart failure or renal failure 2. Bicarbonate therapy during CPR: Laboratory and clinical data indicates 8 that Contrary to popular belief, it does not the ability to defibrillate or improve survival 9 . Can compromise coronary perfusion pressure. May inactivate simultaneously administered catecholamines. In the presence of reduced capacity to excrete CO2, sodabicarb increases the mixed venous pCO2. CO2 may paradoxically increase intra cellular acidosis. Hence routine use of bicarb is not advisable during CPR (except in hyperkalemia), it may be harmful (class III). In Diabetic Keto Acidosis (DKA): Bicarb therapy is controversial in DKA. It has several potentially deleterious effects including worsening of hypokalemia, worsening of intra cellular acidosis and production of paradoxical central nervous system acidosis 10 . Studies have demonstrated no difference in outcome.Jeffery.B et al 10 concludes that bicarbonate should not be administered during DKA for pH > 6.9; for pH < 6.9, the evidence is incomplete and does not suggest a beneficial effect. Patients with a substantial component of hyperchloremic acidosis, due to urinary loss of ketoacid anions (which cannot be used to regenerate bicarbonate) can benefit alkali therapy 2. 112 In Lactic Acidosis: In animals and humans bicarbonate infusion can augment the production of lactic acid, possibly due to a shift in the oxyhemoglobin, saturation relationship, enhanced anaerobic glycolysis mediated by pH sensitive rate limiting enzyme phosphofructokinase and changes in hepatic blood flow or lactate uptake.6 Even when bicarb administration elevates arterial pH (administration of sodabicarb of 1 mmol / kg for 1 to 2 mt showed to increase pH by 0.05 units) its effects on the CSF and intracellular spaces may not be concordant. Intracellular pH has been shown to fall with bicarbonate in RBCs, Muscle, Liver, Lymphocytes and Brain. Serum ionised calcium concentration is reduced by sodabicarb infusion. Because left ventricular contractility has been shown to vary directly with ionised calcium concentration, hence reduction in ionised calcium may cause ventricular depression 6. Most importantly does sodabicarb therapy correct haemodynamics, buy time for other interventions or improve outcome? In prospective trials11,12 sodabicarb did not improve haemodynamics or Catecholamine responsiveness. Bicarbonate was indistinguishable from saline with regard to heart rate, Blood pressure, Central Venous Pressure, Pulmonary Aretery Occlusion Pressure, Cardiac output, Oxygen delivery and Oxygen consumption. Current evidences do not encourage the use of sodabicarb in lactic acidosis. CONCLUSION: The indications for sodabicarb therapy are limited to normal AG metabolic acidosis, certain poisons and hyperkalemia.5 Refrences 1. J.A.Kellum. Metabolic acidosis in patients with sepsis. Epiphenomenon or part of the pathophysiology. Critical Care and Resuscitation 2004; 6: 197-203. 2. Adrogue H.J et al. Management of Life-threatening Acid-Base Disorders; NEJM 1998; 338: 26-34. 3. Kraut JA et al. Use of base in the treatment of severe acidemic states; AJKD 2001; 38: 703-27. 4. Bulent ceuhaci et al. Sodium bicarbonate controversy in lactic acidosis. Chest 2000; 118: 882-884. 5. J.McNamara, L.I.G. Worthley. Acid-Base Balance: Part II. Critical Care and Resuscitation 2001; 3: 188-201. 6. S.M.Forsythe, G.A. Schmidt. Sodium bicarbonate for treatment of lactic acidosis. Chest 2000; 117: 260-267. 7. Guidelines for Cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2000; 102(supp I): I 142 –157. 8. Guidelines for Cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2000; 102(supp I): I 129 –135. 9. Dybvik.T et al. Buffer therapy during out of hospital cardiopulmonary resuscitation. Resuscitation 1995; 29: 87-88. 10. J.B.Boord et al. Practical Management of Diabetes in critically ill patients. AJRCCM 2001; 164: 1763-1767. 11. Cooper D.J, Waleey KR et al. Bicarbonate does not improve haemodynamics in critically ill patients who have lactic acidosis; a prospective, controlled clinical study. Ann.Inter Med 1990; 112: 492-498. 113 12. Mathieu D, Nevierw r, et al. Effects of bicarbonate therapy on haemodynamics and tissue oxygenation in patients with lactic acidosis. a prospective, controlled clinical study. Criti Care Med 1991; 19: 1352-1356. 114 DISCUSS THE ANTIBIOTIC MANAGEMENT OF A PATIENT WITH MRSA AORTIC VALVE ENDOCARDITIS WITH VANCOMYCIN ALLERGY Dr. A. MacCormick. Intensive Care Unit, Royal Melbourne Hospital, Victoria Management of antibiotic therapy in the setting of vancomycin allergy includes: 1) Assessment of the allergy and its clinical relevance. If the reaction is minor or can be safely managed and sensitivity testing suggests that vancomycin is the best agent then treatment with vancomycin could be considered. Reactions include “red man” syndrome which can be managed by slow infusion and prophylactic antihistamines, “pain and spasm” syndrome which can also be avoided by slow injection and ototoxicity which may be avoided by keeping levels < 40µg/mL. Skin rashes and drug fever occur in 4-5% of patients and may be of varying severity. Anaphylaxis and, rarely, an induced neutropaenia would necessitate avoidance or cessation of vancomycin therapy. 2) Specific antibiotic alternatives: The clinical evidence for success of alternative antibiotics is limited but is beginning to accumulate – especially as vancomycin intermediate and vancomycin resistant strains of staph aureus are becoming more prevalent. Antibiotic choice must be guided by demonstration of in vitro sensitivity. a) Teicoplanin is a glycopeptide antibiotic with the same spectrum of activity as vancomycin but has a better side-effect profile and may be better tolerated. In clinical studies it is as, or less effective than vancomycin.1 An initially recommended dose of 6 mg/kg/d has been said to be too low. Teicoplanin trough serum concentrations provide the best predictor of treatment success. Trough serum levels > 25mg/L are associated with a 90% success rate.2 b) Trimethoprim-sulphamethoxazole has been compared with vancomycin for the treatment of Staph Aureus including cases of MRSA endocarditis. It was not as successful as vancomycin overall and was least successful in those with right-sided endocarditis and methicillin sensitive staph aureus. Thus it could be considered as an agent for MRSA endocarditis.3 c) Oral ciprofloxacin and rifampicin has been given for right-sided endocarditis in iv drug users and been found to be as effective as vancomycin.2 d) Quinupristin-dalfopristin is a combination of two naturally occurring compounds isolated from Streptomyces pristinaspiralis. It inhibits protein synthesis by binding to the 50S ribosome. Its spectrum of activity is similar to vancomycin. 99.9% of staph aureus were sensitive in one study. It is given iv every 8 hours in a dose of 7.5mg/kg.4 e) Linezolid is an oxazolidinone that belongs to a class of synthetic antimicrobial agents. It interferes with protein synthesis by inhibiting the initiation complex at the 30S ribosome. This is a unique action and no cross-resistance with other antimicrobials currently occurs. It is active against most gram-positive organisms including MRSA. It has 100% oral bioavailability. The recommended dose is 600mg BD. There are case reports of successful treatment of MRSA endocarditis.5,6,7,8 f) Daptomycin is a naturally occurring antibiotic that is a fermentation by-product of Streptomyces roseosporus. It binds to the cell membrane in a calcium dependant manner causing depolarisation and cell death. It is active against Streptococci, multi-drug resistant staph aureus and enterococcal species. It is administered once daily up to 6 115 mg/kg. It has been shown to be active against Glycopeptide Intermediate-Resistant Staph Aureus in a simulated model of endocarditis.9 A case study has described successful treatment of prosthetic aortic valve endocarditis.10 g) Other agents which have been shown to be effective in MRSA endocarditis experimental models are Lysostaphin11 and Ampicillin-Sulbactam.12 Considering availability of agents in Australia the best regimen practically, (provided in vitro susceptibility is proven) may be linezolid until the infection is clinically controlled (4-6 weeks) followed by an alternative regimen (usually rifampicin with fusidic acid) as described in a recent study of treatment of reduced vancomycin susceptibility staph aureus in Australia and New Zealand.13 Refrences 1. Wood MJ, “The comparative efficacy and safety of teicoplanin and vancomycin” J Antimicrob Chemother 1996 Feb; 37(2):209-222 2. Hoen B “Special issues in the management of infective endocarditis caused by Grampositive cocci” Infect Dis Clin N Am 16(2002):437-452 3. Markowitz et al “Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection.” Ann Intern Med 1992 Sep 1; 117(5):390-8 4. Lundstrom and Sobel “Antibiotics for gram-positive infections: vancomycin, quinupristindalfopristin, linezolid, and daptomycin” Infect Dis Clin N Am 18 (2004) 651-668 5. Leung et al “Treatment of vancomycin-intermediate Staphylococcus aureus endocarditis with linezolid” Scand J Infect Dis 2004; 36(6-7);483-5 6. Bassetti et al “Successful treatment of methicillin-resistant Staphylococcus aureus endocarditis with linezolid” Int J Antimicrob Agents 2004 Jul; 24(1): 83-4 7. Pistella et al “Successful treatment of disseminated cerebritis complicating methicillinresistant Staphylococcus aureus endocarditis unresponsive to vancomycin therapy with linezolid” Scan J Infect Dis 2004;36(3):222-5 8. Birmingham et al “Linezolid for the treatment of multi-drug resistant, gram-positive infections: experience from a compassionate-use program” Clin Infect Dis 2003;36:15968 9. Akins and Rybak “Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant staphylococcus aureus, vancomycin-resistant enterococcus faecium and methicillin-resistant staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations” Antmicr Agents and Chem Feb 2001 45(2):454-459 10. Mohan et al “Methicillin-resistant Staphylococcus aureus prosthetic aortic valve endocarditis with paravalvular abscess treated with daptomycin” Heart Lung 2005 JanFeb; 34(1):69-71 11. Patron et al “Lysostaphin treatment of experimental aortic valve endocarditis caused by a staphylococcus aureus isolate with reduced susceptibility to vancomycin” Antmicr Agents and Chem; July 1999 43(7):1754-1755 12. Backo et al “Treatment of Experimental Staphylococcal Endocarditis Due to a Strain with Reduced Susceptibility In Vitro to Vancomycin: Efficacy of Ampicillin-Sulbactam” Antmicr Agents and Chem; Oct 1999; 43(10):2565-2568 13. Howden et al “Treatment Outcomes for serious infections caused by Methicillin-Resistant Staphylococcus Aureus with Reduced Vancomycin Susceptibility” Clin Inf Dis 2004;38:521-8. 116 DO YOU USE SELECTIVE DECONTAMINATION OF THE GASTROINTESTINAL TRACT IN YOUR INTENSIVE CARE UNIT? IF SO WHY? IF NOT WHY NOT? Dr. G. Ding. Intensive Care Unit, The Canberra Hospital, ACT We do not use selective decontamination of the gastrointestinal tract in our ICU. The aim of selective decontamination of the digestive tract (SDD) is to reduce the incidence of nosocomial infections and ventilator associated pneumonia (VAP) in the critically ill ICU population. Hospital acquired pneumonia occurs in approximately 0.5 – 1% of all hospital admissions in the US and affects approximately 27% of critically ill patients. Mortality ranges from 20 to 70%. Cost of treatment US$5,800 to $20,000 per case. The nosocomial infections targeted by selective decontamination of the digestive tract are VAP caused by micro aspiration of organisms from the oropharynx, catheter sepsis and pancreatic colonisation (in cases of pancreatitis) from translocation of gut organisms to the blood stream. Decontamination is achieved by the application of topical paste to the aerodigestive tract, nasogastric antimicrobials and administration of a parenteral antibiotic(s). Targeted organisms are gram negative aerobic and fungal pathogens that may colonise the patient. Indigenous gut flora (anaerobes) are not targeted in an attempt to retain their protective effect. A suggested regimen includes: Topical paste 6 hourly to oropharynx of 2% tobramycin, 2% polymyxin E, and 2% amphotericin B. Plus 10 mL of solution with 100mg polymyxin E, 80mg Tobramycin, 500mg amphotericin B 6 hourly via NGT. Plus or minus 4 day parenteral treatment with cefotaxime. The topical and enteral antibiotics are non absorbable and therefore systemic toxicity is avoided. The argument for SDD. Reduction in VAP and other nosocomial infections. A meta-analyses by D’amico et al,1 showed a reduction in respiratory infections from 36% in control patients to 16% in patients treated with topical and systemic antibiotics and 28% in control patients to 18% in patients only treated topically. Implying treating 5 patients with topical and systemic prophylaxis or 9 patients with topical prophylaxis will prevent one infection. The mortality was reduced in the group treated with systemic and topical prophylaxis from 30% in controls to 24%. Mortality in the group treated only topically was 26%. Treatment/prophylaxis of 23 patients would be required to prevent one death with topical and systemic methods. No mortality benefit was seen in the topical group alone. 117 The meta-analyses by Nathens et al,2 only showed a reduction in mortality in surgical patients treated with systemic and topical prophylaxis. Medical patients appeared to derive no statistical benefit. Luiten et al,3 in a prospective randomised trial of SDD in acute pancreatitis, demonstrated a 50% reduction in the incidence of infected pancreatic necrosis (38% vs 18%). The benefits are therefore: 1 a reduction in mortality (possibly only in surgical/trauma patients) 2 reductions in infections 3 reductions in cost associated with nosocomial infections. Argument against SDD With regular use of antibiotics there is a selective pressure in the bacterial population towards resistance to the antimicrobials in use. Levy 4 formulated five underlying principles of antimicrobial resistance First: given sufficient time and drug use, antibiotic resistance will emerge. Second: antibiotic resistance is progressive, evolving from low levels through intermediate to high levels. Third: organisms that are resistant to one drug are likely to become resistant to other antibiotics. Fourth: once resistance appears, it is likely to decline slowly, if at all. Fifth: the use of antibiotics by any one person affects others in the extended as well as the immediate environment. These principles apply to all antibiotic administration, including the use of SDD; therefore, the clinical benefits of SDD must be balanced against the potential for the greater emergence of antibiotic-resistant infections as a result of its use. The use of antibiotics in SDD not only potentially increases the risk of resistance in microbes that are targeted but also in others. Hammond and Potgieter5 found a statistically significant increase in the occurrence rate of infections caused by Acinetobacter species in the year after beginning a trial of SDD in their ICUs compared to the year preceding the trial. Sanchez-Garcia6 found level of carriage of MRSA, coagulase-negative staphylococci, and enterococci was significantly higher in the SDD-treated patients Verwaest7 found significantly more bacteremias due to Gram-positive bacteria were observed among SDD-treated patients. Increased antimicrobial resistance was also detected among the SDD-treated patients, including tobramycin-resistant Enterobacteriaceae, ofloxacinresistant nonfermenters, ofloxacin-resistant Enterobacteriaceae, and MRSA. Cost of the intervention Components include the cost of antibiotics. Preparation of the paste from components? Topical preparations manufactured by drug companies or hospital pharmacists. Added nursing time placing the paste in the oropharynx and administering nasogastric and parenteral antimicrobials. Manipulation of the airway with risks of tube dislodgment and/or increased risk of micro aspiration. 118 Conclusions On the basis that the unit I work in has a majority of medical ICU patients and the future risk of significant antimicrobial resistance, measures other than SDD are used to reduce the risk of VAP and other nosocomial infections. Possible exceptions to this generality may occur in specific cases such as severe pancreatitis Refrences 1. D’Amico R, et al. Effectiveness of antibiotic prophylaxis in critically ill adult patients: systemic review of randomized trials. BMJ 1998;316:1275. 2. Nathens A, et al. Selective Decontamination of the Digestive Tract in Surgical Patients. A Systematic Review of the Evidence Arch Surg. 1999;134:170-176. 3. Luiten EJT, Hop WCJ, Lange JF, Bruining HA. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg. 1995;222:57-65. 4. Levy SB. Multidrug resistance: a sign of the times. N Engl J Med 1998;338,1376-1378. 5. Hammond JM, Potgieter PD. Long-term effects of selective decontamination on antimicrobial resistance. Crit Care Med 1995;23,637-645. 6. Sanchez-Garcia, M, Cambronero Galache, JA, Lopez Diaz, J, et al Effectiveness and cost of selective decontamination of the digestive tract in critically ill intubated patients: a randomized, double-blind, placebo-controlled, multicenter trial. Am J Respir Crit Care Med 1998;158,908-916. 7. Verwaest C, Verhaegen J, Ferdinande P, et al. Randomized, controlled trial of selective digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med 1997;25,63-71. 119 WHAT ARE THE INDICATIONS FOR AND COMPLICATIONS OF NACETYLCYSTEINE Dr. L. Min. Department of Critical Care Medicine, Flinders Medical Centre, SA Acetylcysteine (Parvolex), the acetylated variant of the amino acid L-cysteine, and is deacetylated in the liver to cysteine, or oxidised to other metabolites such as N-acetylcystein, It is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. It’s chemical formula is C5H9NO3S and a molecular weight is 163.2. Following intravenous administration, mean terminal half-life is 1.95 hours and 5.58 hours for reduced and total acetylcysteine. Indications Acetaminophen Overdose. NAC provide a glutathione substitute, directly conjugate with NAPQI, reduces acetaminophen-induced damage. Experimental evidence indicates the combination of NAC and cimetidine might have an additive effect in the treatment of acetaminophen overdose. Contrast-introduced nephropathy. In patients with chronic renal insufficiency, usage of acetylcysteine can prevent the rise in serum creatinine level post intravenous administrationof contrast. ARDS. As an antioxidant, used in the treatment of patients “at risk” for the development of acute respiratory distress syndrome. Sepsis. As free radical scavengers, may improve survival of sepsis patient Prevent liver injury. Continuous infusion of N-acetylcysteine reduces liver warm ischaemia reperfusion injury, and improved flow in the microcirculation and intracellular tissue oxygenation. Can be used in liver resection and liver transplantation. Preeclamptic prophylaxis. Preeclampsia is associated with an imbalance between oxidants and antioxidants, resulting in reduced effects of the endothelium-derived, relaxing-factor nitric oxide, NAC remove reactive oxygen species, resulting in an improvement of endothelial function. Type2 diabetes . Improves insulin sensitivity Sjogren’s syndrome. Therapeutic effect on ocular symptoms, halitosis and daytime thirsty. Respiratory. Oral NAC protect against inhalation of perfluoroisobutene. Oral NAC has been advocated as a mucolytic agent for use in chronic bronchitis, improvements in expectoration and decrease of cough severity. Research also indicates intravenous NAC can improve contractility and attenuate low-frequency human diaphragm fatigue. Myoclonus Epilepsy. Decreased in myoclonus and some normalisation of somatosensory evoked potentials. HIV. NAC supplementation might be a valuable component of an integrated protocol for HIV-seropositive individuals, particularly those with low GSH levels and CD4+ cell counts of more than 200X10(6)/l. It can inhance the antibody–dependent cellular cytotoxicity of neutrophils. It can protect hematopoietic progenitor cells from zidovudine (AZT) –induced toxicity. It may help to prevent the early stage HIV-infected patients to progress to AIDS. Influenza. NAC treatment decreased both the frequency and severity of influenza-like episodes, and length of time confined to bed. 120 Cancer. Prevent cardiotoxity of doxorubicin and reduce haemorrhagic cystitis due cyclophosphamide and ifosfamide. Heart Disease. NAC seems to positively impact homocysteine and possibly lipoprotein (a) levels, protect against ischemic and reperfusion damage, and enhance of the effectiveness of nitroglycerine(NGT). Heavy Metals. NAC is more effective than calcium EDTA or dimercaptosuccinic acid as an agent to increase the urinary excretion of chromium and boron. NAC is protective against mercury-induced damage to the liver and kidneys, promote the urinary elimination of methyl mercury. Other toxicology. Prevent hepatotoxicity due to CHCl3 or CCl4 or neuropsychiatric sequele of CO poisoning Cigarette Smoking. NAC inhibited cigarette–induced mucous cell hyperplasia and epithelial hypertrophy. Oral administration of NAC also counteracted the cigarette-induced decline in the proportion of alveolar lymphocytes and the decreased phagocytic capacity and ability to produce leukotriene B4 of alveolar macrophages in smokers. Kidney stones. Inhibit calcium stone formation Controindication and precautions Hypersensitivity or previous anaphylactic reaction to acetylcysteine or any component of the preparation. Be caution to be used in asthma or where there is a history of bronchospasm, May cause coughing and stidor. NAC infusion in doses used to treat paracetamol intoxication causes small to moderate derangements of the coagulation system, which affect both vitamin K dependent coagulant and anticoagulant proteins. Be caution to be used in patients with a past medical history of oesophageal varices and peptic ulceration (acetylcystein induced vomiting may increase the risk of haemorrhage) May cause a false positive reading for ketones on a urine test strip. Can chelate zinc and copper, long term use should take extra zinc and copper. Urticaria, rash (erythematous and maculopapular), cyanosis and injection site reaction. Tachycardia, chest pain, and extrasystoles. Cough congestion, runny nose. Might increase the incidence of teratogenicity when administered during pregnancy. In healthy individuals, doses as low as 1.2 g daily might act as a pro-oxidant and might lower GSH and increase the amount of oxidised GSH. Overdose Severe anaphylactoid reactions, Respiratory depression. Haemolysis, DIC, Renal failure, ARDS GI haemorrhage, Death. 121 DISCUSS THE INDICATIONS AND CONTRAINDICATIONS OF MORPHINE IN THE TREATMENT OF ACUTE PULMONARY OEDEMA Dr. M. Heaney. Intensive Care Unit, Royal Perth Hospital, Western Australia Acute cardiogenic pulmonary oedema is a common problem in the hospital setting with a reported in hospital mortality of 15 - 20%. Patients present with acute onset shortness of breath and are markedly distressed. Clinical findings include diaphoresis, clamminess, tachycardia, crepitations throughout both lung fields, left ventricular S3 and occasionally bronchospasm. Before the mid twentieth century treatment options for acute pulmonary oedema (APO) were limited, consisting simply of digitalis, opium and venesection. While morphine has been used for centuries to treat acute pulmonary oedema, it is only part of a therapeutic armamentarium including oxygen, furosemide, nitrates and newer therapies such as nesiritide and levosemindan. To understand the rationale for the use of morphine in acute pulmonary oedema it is essential to first understand the pathophysiology of this condition. Pathophysiology Acute pulmonary oedema occurs in the setting of an acutely decompensated left ventricle either as a result of an acute process- myocardial ischaemia/infarction or as a result of exacerbation of a pre-existing cardiac condition such as valvular disease, hypertensive heart disease, or cardiomyopathy. In patients with a chronic process neurohumeral mechanisms including the sympathetic, RAAS, and AVP are activated in attempts to compensate for the failing ventricle. Intense sympathetic activation leads to a compensatory tachycardia and increased vascular tone- in the venous system this helps to maintain preload, however in the arterial system this adaptive response results in increased after load which is deleterious to the failing ventricle. As the decompensating left ventricle fails, left ventricular end diastolic pressure increases which in turn increases pulmonary venous and capillary hydrostatic pressures. When this pressure is greater than 18mmHg (may be lower in patients with hypoalbuminaemia) a protein sparse plasma ultrafiltrate is forced across the alveolo- capillary membrane resulting in interstitial oedema (Kerley B lines and upper lobe diversion on CXR). Compensatory mechanisms for lymphatic drainage of fluid are rapidly overwhelmed ultimately leading to alveolar flooding (Bat wing appearance on CXR) The patient develops acute dyspnoea, coughs and expectorates pink frothy fluid- and literally feels they are drowning. This sensation of suffocation intensifies firght, increases heart rate and blood pressure, increases work of breathing and further impairs ventricular function; if this vicious cycle is not broken, death ensues rapidly. The therapeutic goals in treatment of APO are: 1. reduction of cardiac workload by reduction of preload and after load 2. Relief of pain and agitation 3. Improve cardiac contractility 4. Control excess retention of salt and water The ideal therapeutic agent shoud be titratable, rapidly acting and have minimal side effects As will be outlined below morphine certainly fulfils some of these goals but its side effect profile limits its usefulness. Advantages Morphine has been used in the treatment of APO for centuries and many authors uncritically encourage its continuing use. Its potent anxiolytic and sedative effects are 122 extremely advantageous in relieving the agitation associated with APO. By reducing systemic catecholamines and possibly vagotonic activity, morphine reduces heart rate, reduces blood pressure, reduces contractility and thus reduces myocardial oxygen consumption. Morphine also has potent effects on the vasculature via both central sympatholytic mechanisms and peripheral histaminergic mechanisms. Arterial vasodilatation reduces after load, which decreases myocardial workload. Pulmonary capillary pressure is reduced and cardiac output increases. Morphine is a potent venodilator of peripheral and splanchnic systems. This increased venous capacitance results in a reduced preload to the failing ventricle. Recent research has suggested that the vasodilator effects of morphine are solely due to histamine release with very little or no involvement of mu opiate receptors. Morphine administered intravenously has peak clinical effects within minutes and clinical duration of action of three to four hours. The dose (2 - 4mg every 5 - 10 min) can be titrated to clinical effect- as ascertained by the patient’s degree of anxiety and level of consciousness. Morphine administered cautiously does not cause respiratory failure or aggravate existing CO2 retention associated with APO. Morphine’s potent analgesic action is dually advantageous in the patient with chest pain and APO. Relief of pain reduces deleterious sympathetic effects. Disadvantages Morphine also has significant disadvantages in this setting. Rapid administration of morphine potentiates histamine release from the lungs resulting in pulmonary vasoconstriction and bronchospasm, further increasing the work of breathing. While administration of morphine results in advantageous preload reduction in volume overloaded patients with chronic heart failure, not all patients with APO are overloaded- and administration of morphine to these patients may result in severe hypotension. Morphine can cause excessive preload reduction – with resultant decreased cardiac output and hypotension; patients with less compliant hearts – particularly those with diastolic dysfunction, aortic stenosis and acute myocardial infarction are most susceptible. Most patients with APO have a compensatory tachycardia, but in those patients who do not, morphine’s vagotonic effects may result in symptomatic bradycardia. While the dose of morphine is titratable its clinical effects may be markedly prolonged in this predominantly elderly population resulting in decreased levels of consciousness and even obtundation. Several case series report excessive administration of morphine to elderly patients with APO requiring reversal with naloxone. Although naloxone will reverse morphine’s effects on conscious level it does not reverse morphine’s vasodilator effects and hypotension may be a persistent problem. Morphine is a potent respiratory depressant and while not contraindicated in patients with marginally elevated CO2 levels, which are presumed due to alveolar flooding, its effects in the patient subgroup with hypercarbia and respiratory acidosis- having more severe APO must be monitored vigilantly. As elderly patients with APO often have impaired renal function- the accumulation of morphine-6-gloucuronide with its prolonged half-life may cause further respiratory depression. Administration of morphine to patients with severe pulmonary oedema has been shown to result in increased need for intubation (OR 5.0) and increased requirement for admission to the intensive care unit (OR 3.1), however this data was collected retrospectively and may have been subject to observer bias. Morphine also increases antral tone and decreases gastrointestinal motility resulting in delayed gastric emptying, which may have implications in patients who require noninvasive ventilation or intubation for worsening symptoms. Morphine’s emetogenic side effects are also unwelcome in this setting of an agitated distressed patient who may require airway intervention/tight fitting mask. 123 Conclusion While the administration of morphine to patients with acute pulmonary oedema is a time honoured practice, in this age of evidence based medicine available data does not suggest that morphine reduces morbidity and mortality, in fact treatment with morphine may have deleterious effects on patient outcome with need for increased intubation and admission to the intensive care unit. A large prospective randomised trial is necessary to answer this question definitively. Refrences 1. Braunwald: Heart Disease: A Textbook of Cardiovascular Medicine 6th ed 2001 2. Jackson G, Gibbs CR, Davies MK, Lip GY.ABC of heart failure: Pathophysiology. BMJ 2000; 320: 167-170 3. Hakim TS, Grunstein MM, Michel RP. Opiate action on the pulmonary circulation. Pulm Pharmacol 1992;5:159-165 4. Vasko JS, Henney RP, Oldham HN et al. Mechanisms of action of morphine in the treatment of experimental pulmonary oedema. Am J Cardiol 1966; 18:876-883 5. Vismara LA, Leaman DM, Zelis R. The effects of morphine on venous tone in patients with acute pulmonary oedema. Circulation 1976;54:335-7 6. Mattu A. Cardiogenic pulmonary oedema. Current opinion in Cardiovascular, Pulmonary and Renal Investigational Drugs.2000; 2:9-16 7. Millane T, Jackson G, Gibbs CR, Lip GY. ABC of heart failure:Acute and chronic management strategies.BMJ 2000; 320:559-62 8. Sacchetti A, Ramoska E, Moakes ME, McDermott P, Moyer V. Effect of ED management on ICU use in acute pulmonary edema. Am. J. Emerg. Med. 1999; 17:571-4 9. Chambers JA, Baggoley CJ. Pulmonary oedema-prehospital treatment: Caution with morphine dosage. Med J. Aust. 1992;157:326-8 10. Hoffman JR, Reynolds S. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary oedema. Chest 1987;92:586-93. 124 DISCUSS THE CLINICAL PRESENTATION AND MANAGEMENT OF A PATIENT WHO HAS AN ACUTE BUDD-CHIARI SYNDROME Dr. J. Lewis. Intensive Care Unit, Royal Perth Hospital, Western Australia Definition Budd-Chiari Syndrome refers to hepatic venous drainage obstruction. It is usually associated with thrombosis in the hepatic veins that frequently extends into the IVC. Aetiology Most cases are secondary to an underlying condition however 20% are idiopathic. Underlying aetiologies are listed below:1,2,3,4 1. Myeloproliferative disorders ~50% Polycythaemia rubra vera Essential thrombocythaemia Agnogenic myeloid metaplasia 2. Malignancy Hepatocellular, adrenal, renal, pancreatic, gastric, lung, sarcoma of right atrium 3. Infections and benign lesions of the liver Hepatic cysts, abscesses 4. Hypercoagulable states OCP Pregnancy Factor V Leiden mutation Prothrombin gene mutation Anti-thrombin III deficieny Protein C, S deficiency Lupus anticoagulant Paroxsmal nocturnal haemoglobinuria 5. Membranous webs 6. Others Vasculitis… Clinical Presentation The clinical presentation maybe divided into history, examination and Investigation. Notes on each of these aspects are below.4,5 History Females > males (2:1) Any age (especially 20-40yo) Epigastric/ Right upper quadreant pain Abdominal distension Features of Liver dysfunction Features of underlying aetiology Maybe acute (20%), even fulminating, subacute (40%) or chronic (40%) Maybe asymptomatic (5%) Examination Tender hepatomegaly Ascites Signs of liver failure (jaundice, oedema, coagulopathy, encephalopathy) 125 Signs of portal Hypertension take time to develop Cirrhosis takes time to develop Investigations LFTs variable increases in transaminases, ALP, Bili May see synthetic dysfunction (coagulopathy, hypoalbuminaemia) Imaging US MRI angiography Venography (contrast CT, sulfur colloid scintigraphy, arteriography) Other liver biopsy other tests to guide supportive care Differential diagnosis Veno-occlusive disease Acute liver failure Chronic liver failure Portal hypertension Right heart failure Treatment The treatment maybe divided into medical, radiological and surgical. These are considered below. Medical Control of oedema/ascites Fluid and salt restrict Frusemide/spironolactone Stockings Paracentesis Consider thrombolysis6, 7 Consider if <3-4 weeks Systemic vs local administration Only case series level of evidence Seek and treat underlying condition ?anticoagulation ?aspirin /hydroxyurea if myeloproliferative disorder Routine supportive care Includes optimising nutrition and other supportive care for liver failure Radiological Angioplasty8 If focal stenosis that is accessible radiological (eg membranous web in IVC) Stenting9 Helps patency post angioplasty Avoid placement in sites that preclude liver transplantation (if possible future option) TIPS10 If above options not viable Surgical11 Portosystemic shunting Various shunts (portocaval, splenorenal, mesocaval, portoatrial) 126 Usually requie anticoagulation Thrombectomy usually not possible Liver transplantation If cirrhosis or advanced liver failure May cure underlying condition (eg Protein C or S deficiency or AT III deficiency) Refrences 1. Dilawari, JB, Bambery, P, Chawla, Y, et al. Hepatic outflow obstruction (Bubb Chiari syndrome): Experience with 177 patients and a review of the literature. Medicine 1994; 73:21 2. Powell-Jackson, PR, Melia, W, Canalese J, et al. Budd-Chiari syndrome: Clinical patterns and therapy. Q J Med 1982; 51:79 3. Maddrey, WC. Hepatic vein thrombosis (Budd-Chiari syndrome). Hepatology 1984; 4:445 4. Murad, SD, Valla, DC, De Groen, PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004; 39: 500 5. Hadengue, A, Poliquin, M, Vilgrain, V, et al. The changing scene of hepatic vein thrombosis: Recognition of asymptomatic cases. Gastroenterology 1994; 106: 1042 6. Raju, G, Felver, M, Olin, J, et al. Thrombolysis for acute Budd-Chiari syndrome: Case report and literature review. Am J Gastroenterol 1996; 91:1262 7. Sholar, PW, Bell, WR. Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal haemoglobinuria. Ann Intern Med 1985; 103:539 8. Sparano, J, Chang, J, Trasi, S, et al. Treatment of the Budd-Chiari syndrome with percutaneous transluminal angioplasty: Case report and review of the literature. Am J Med 1987; 82: 821 9. Witte, AM, Kool, LI, Veenendaal, R, et al. Hepatic vein stenting for Budd-Chiari syndrome. Am J Gastroenterology 1997; 92: 498 10. Mancuso, A, Fung, K, Mela, M, Tibballs, J. TIPS for acute and chronic Budd-Chiari syndrome: a single-centre experience. J Hepatol 2003; 38: 751 11. Orloff, MF, Daily, PO, OrloffSL, et al. A 27 year experience with surgical treatment of budd-Chiari syndrome. Ann Surg 2000; 232: 340. 127 DISCUSS THE DIAGNOSIS AND MANAGEMENT OF GOUT IN A CRITICALLY ILL PATIENT WITH ACUTE RENAL FAILURE Dr. T. Corcoran. Intensive Care Unit, Royal Perth Hospital, Western Australia The necessity to diagnose and treat gout may arise in one of three situations in the critically ill. Patients with documented gout may develop an acute attack during admission to the Intensive Care Unit; previously undiagnosed patients may develop gout during the course of their stay in ICU and patients may rarely be admitted to ICU with a complication of gout. The development of acute renal failure limits the treatment options in all three scenarios as most therapies are relatively contraindicated. This discussion will focus on the diagnostic and therapeutic issues in the previously undiagnosed patient developing gout in ICU. Gout (monosodium urate crystal deposition disease) is a metabolic disorder characterised by deposition of monosodium urate (MSU) crystals in tissues and the development of local inflammatory response. When plasma becomes saturated with MSU, crystals become deposited in tissues and joints provoking an intense neutrophil-mediated inflammatory response. Uric acid is the end product of purine nucleotide degradation in humans, being converted from xanthine to uric acid by the enzyme xanthine oxidase, the liver and intestine accounting for the majority of production owing to high content of the enzyme in these tissues. MSU is 75% excreted in the urine and 25% in the intestine. Alkalinisation of the urine promotes excretion and it is easily dialysed. All patients with gout are hyperuricemic although not necessarily at the time of presentation. The hyperuricemia may arise out of increased production or decreased excretion and there are primary and secondary classifications in both categories. The majority of patients who have idiopathic gout have decreased excretion of uric acid, although conditions with increased cellular turnover (increased uric acid production- myeloproliferative conditions) and certain drugs (decreased renal excretion – low dose aspirin and loop / thiazide diuretics) produce secondary gout. Idiopathic gout is associated with Type 2 Diabetes Mellitus, Hypertension, Truncal Obesity, Hypothyroidism, Hyperlipidaemia and Coronary Artery Disease but whether these are just epiphenomena remains to be determined.1;2 Renal failure has unpredictable effects upon uric acid levels and uremia may suppress the immune response to MSU crystals and therefore modify the presentation of the disease. Many of the factors associated with the precipitation of an acute attack are present at the time of admission to intensive care for many patients- surgery, trauma, dehydration, use of diueretics or aspirin, First attacks are almost invariably characterised by acute mono/pauciarticular arthritis,3 although patients with myeloproliferative disorders or those receiving cyclosporine for solid organ transplantation may develop polyarticular attacks.4 The affected joint is acutely inflamed, tender, with reduced range of movement and swelling and inflammation of overlying tissues. It must be distinguished from disorders with similar presentations such as septic arthritis, cellulitis and pseudogout, which may also co-exist. This may at times be difficult and the distinction from septic arthritis is not always clear, as acute gout may be associated with similar systemic manifestations such as pyrexia, neutrophil leucocytosis, elevated ESR and C-reactive protein levels. There are eleven clinical diagnostic criteria for gout but these are unhelpful in the critically ill patient.5 As mentioned serum uric acid levels may be normal or low during an acute attack and the performance of 24-hour urinary uric acid excretion is impractical and imprecise even in the non-emergent setting. The most useful diagnostic examination is to aspirate a sample of fluid from an affected joint. This should be sent for gram stain, microscopy, culture, cell count and examination for the presence of crystals under polarised light. In a severe attack the synovial fluid may be very cloudy owing to a high content of neutrophils (5,000 to 50,000 per µL) and the fluid may appear purulent if 128 there is a heavy MSU crystal load, again leading to confusion with a diagnosis of septic arthritis. As large a sample of joint fluid possible should be collected (if necessary using ultrasound guided sampling) and sent fresh to the laboratory for processing, - there it should be examined under polarised light for the presence of intra- and extracellular needle-shaped MSU crystals- they are yellow when aligned parallel to the axis of a red compensator, but they turn blue when aligned across the direction of polarisation – this is negative birefringence. Calcium pyrophosphate crystals which are found in pseudogout are of a different shape and show weak or no positive birefringence.6;7 If the diagnosis remains unclear but a high suspicion of gout exists then examination of synovial fluid from an uninvolved joint may yield positive results as the crystals will be detectable here also. Once the diagnosis has been reached and infection excluded the principle aim of treatment is symptomatic and to aid resolution of inflammation. Correction of uric acid concentrations, an important consideration in the non-critical illness setting are of less importance. In chronic gout serum urate concentrations are lowered by increasing renal excretion (using probenecid or sulphinpyrazone – uricosuric agents) or by decreasing production (using allopurinol- a xanthine oxidase inhibitor). None of these treatments are pertinent to the care of the critically ill patient with an acute attack. It should be remembered that gout is a self-limiting disease and a single acute attack in a critically ill patient is relatively innocuous. The most commonly used treatment for acute gout, colchicine is no longer popular. It works by inhibiting microtubule polymerisation and thus disrupting chemotaxis and phagocytosis in inflammatory cells, undesirable actions in the immunologically – threatened critically ill patient. It has an extensive adverse reaction profile including nephro-, hepatoto- and marrow toxicity. Nonsteroidal antiinflammatory drugs have become the drugs of first choice in the treatment of acute attacks of gout. These agents, such as indomethacin, acting through inhibition of prostaglandin synthesis via an action on the enzyme cyco-oxygenase, are effective anti-inflammatory agents and also have analgesic properties. However, they do have side effects which are particularly poorly tolerated in the critically ill; impaired platelet function, gastric mucosal erosions, altered intrarenal haemodynamics producing renal impairment and fluid retention. In particular because of their unpredictable effect in evolving or resolving acute renal failure in the critically ill patient, this class of drugs is not employed and therefore are not an option in this scenario. Recently, systemic or intra-articular steroids or corticotrophin have been employed with some success for the treatment of acute attacks in patients with monoarticular gout. They appear to provide rapid relief and a potent anti-inflammatory effect, and may be suitable for termination of an acute attack in a critically ill patient in whom other agents sre unsuitable- particularly given the neutral effect of these agents in relation to renal function. Relatively high doses need to be employed however (Methylprednisolone 100 - 150mg per day for three days for example) and mandates the absolute exclusion of an infective process as the use of glucocorticoids is associated with a) immunosuppression and b) masking of the signs of developing infection both of which are undesirable in the critically ill patient. The use of intraarticular glucocorticoids is particularly attractive if trying to avoid systemic effects but the same argument for ruling out infection applies. There may be a case to be made for no treatment at all for the following reasonsa). Use of definitive agents (which reduce serum urate concentrations) is not possible in the critically ill patient with acute renal failure. b). Agents which provide symptomatic anti-inflammatory relief are either not suitable in this class of patient or have a marginal risk-benefit ratio. Given the benign nature of an acute attack of gout, and the significant array of potentially hazardous side effects that treatment may entail, it may be that treatment is less important than accurate diagnosis in the critically ill patient. Once we can be sure that an acutely inflamed 129 joint is neither cellulitic nor septic then perhaps appropriate analgesia while awaiting the attack to recede may be a more prudent course to follow rather than risk incurring a costly drug adverse reaction Refrences 1. Rott KT, Agudelo CA. Gout. JAMA 2003; 289(21):2857-2860. 2. McGill NW. Gout and other crystal-associated arthropathies. Baillieres Best Pract Res Clin Rheumatol 2000; 14(3):445-460. 3. Wortmann RL. Gout and hyperuricemia. Curr Opin Rheumatol 2002; 14(3):281-286. 4. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000; 11(5):974-979. 5. Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977; 20(3):895-900. 6. Lumbreras B, Pascual E, Frasquet J, Gonzalez-Salinas J, Rodriguez E, Hernandez-Aguado I. Analysis for crystals in synovial fluid: training of the analysts results in high consistency. Ann Rheum Dis 2005; 64(4):612-615. 7. Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Ann Intern Med 1999; 131(10):756-759. 130 DISCUSS THE MANAGEMENT OF THE GUILLAIN BARRE SYNDROME Dr. D. Rigg. Intensive Care Unit, The Canberra Hospital, ACT Guillain – Barre Syndrome (GBS) is an acute idiopathic inflammatory demyelinating polyneuropathy characterised by generalised neuromuscular weakness and areflexia. The following points should be noted: Several forms are recognised with specific distinguishing features. Diagnosis is based on history, clinical features and CSF and neurophysiological testing. Mortality rate is 3- 5%, with 7-15% having permanent neurological sequelae If patients advance past the acute phase of illness most recover function spontaneously requiring only supportive treatment and clinical monitoring. Patients can now be treated with specific, effective, disease-modifying therapies – intravenous immunoglobulin (IVIg) OR plasma exchange (PE). Approximately 20-30% will require invasive mechanical ventilation in ICU. Additionally, autonomic dysfunction may necessitate ICU admission. Factors during the acute phase associated with poor prognosis include: age > 60 severe and rapidly progressive disease, mean nerve conduction amplitudes on distal stimulation <20% normal. Mechanical ventilation, for more than one month and pre-existing pulmonary disease are also associated with poor outcome. The key management issues at admission to hospital include: Initial disposition – Ward or ICU bed? In whom do we initiate specific therapy – when, what type (IVIg or PE), dose regimen, duration? Initial Disposition This decision depends on rate of onset, nature and severity of disease and respiratory function. Ambulatory patients with mild disease may go to a general ward provided they have frequent clinical review. Deterioration can occur rapidly and unpredictably. Assessment should include peripheral motor function, bulbar function, respiratory system and cough. Bedside spirometry looking at FVC, maximum inspiratory and expiratory pressures is useful in those at risk for respiratory failure. Non-ambulatory patients, those with rapid progression (<7 days), inability to raise head against gravity, bilateral facial weakness, significant autonomic dysfunction or obvious aspiration, atalectasis or respiratory failure require ICU admission. Specific Immunomodulatory Therapy The American Academy of Neurology (AAN) practice parameter on immunotherapy for GBS published in 2003 assessed the evidence for use of immunotherapy for GBS including plasma exchange (PE), immunoadsorption, intranenous immunoglobulin (IVIG), or steroids. General conclusions were: Treatment with PE or IVIg hastens recovery from GBS. The effects of plasma exchange and IVIg are equivalent. 131 Combining the two treatments is not beneficial. Steroid treatment given alone is not beneficial. Specific Recommendations: PE is recommended for nonambulant adult patients with GBS who seek treatment within 4 weeks of the onset of neuropathic symptoms. PE should also be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms; IVIg is recommended for nonambulant adult patients with GBS within 2 or possibly 4 weeks of the onset of neuropathic symptoms. The effects of PE and IVIg are equivalent; Corticosteroids are not recommended for the management of GBS; Sequential treatment with PE followed by IVIg, or immunoabsorption followed by IVIg is not recommended for patients with GBS; PE and IVIg are treatment options for children with severe GBS. Recent Cochrane reviews have reached similar conclusions. ICU MANAGEMENT OF GUILLAIN-BARRE SYNDROME Upon admission to Intensive Care, specific management issues include: 1. When to intubate and ventilate. Choice of drugs for induction and optimal timing for tracheostomy are important subsequent considerations. 2. Recognition and management of Autonomic Dysfunction. 3. Who gets immunomodulatory therapy (see above). 4. Monitoring, prevention and treatment of medical complications. 5. Nutritional support. 6. Supportive nursing care. 7. Analgesia, anxiolysis and psychological support for patient and family. Multidisciplinary rehabilitation involving physio, occupational and speech therapists. Monitoring and preventing of both short and long term complications is the cornerstone of good multidisciplinary ICU management. Mechanical Ventilation Certain clinical and diagnostic features are associated with severity of disease and increased risk of mechanical ventilation. Sharshar (2003) identified several features as independent predictors for invasive mechanical ventilation. These include: 1) time from onset to hospital admission of <7 days; 2) inability to lift elbows or head off bed; 3) inability to stand; 4) ineffective cough; and 5) increased liver enzymes. The 20/30/40 rule states that patients with FVC <20 mL per kg, maximal inspiratory pressure <30 cm H2O or maximal expiratory pressure < 40 cm H2O generally progress to mechanical ventilation (Lawn 2001). Ropper and Kehne suggest intubation if one of the following criteria are met: ventilatory failure with reduced expiratory VC of 12 to 15 mL per kg, oropharyngeal paresis with aspiration, falling VC over 4 to 6 hours, or clinical signs of respiratory fatigue at a VC of 15 mL per kg. In general, indications for intubation and mechanical ventilation include: Impending or worsening hypercapnoeic respiratory failure High risk of aspiration (bulbar involvement) Ineffective cough (i.e. inability to clear secretions) The presence of autonomic dysfunction may result in profound hypotension at induction due to inability to increase cardiac output in response to vasodilatation. 132 Suxamethonium may precipitate arrhythmia and should be avoided in those with significant autonomic dysfunction. While early tracheostomy is desirable, delaying this up to 10-14 days may result in up to 30% of patients avoiding the procedure. Autonomic Dysfunction 50% have autonomic dysfunction, although most are mild. Specifically: Arrhythmias are common including bradycardia, complete heart block, VT and cardiac arrest; Blood pressure variation Paralytic ileus and bladder dysfunction Excessive sweating BP may fluctuate with transient hypertensive episodes. Sympathetic overactivity may cause sudden diaphoresis, general vasoconstriction, and sinus tachycardia. Sympathetic underactivity may lead to postural hypotension and heightened sensitivity to dehydration and sedativehypnotic agents. Excessive parasympathetic activity may cause facial flushing with feelings of generalized warmth and bradycardia. Those in ICU require continuous ECG and BP monitoring. Occasionally transcutaneous pacing and invasive haemodynamic monitoring is required. Short acting drugs (eg nitroprusside / esmolol / noradrenaline / metaraminol ) and the judicious use of volume loading is used for BP control. General Medical, Nursing and Allied Health Management This revolves around the prevention of complications, similar to all long term ICU patients, including: Prophylaxis for thromboembolism - calf compressors, TED stockings, heparin - DVT/PE are common causes of morbidity and mortality in GBS. Monitoring and treatment of infective complications Bowel, bladder, pressure and eye care Nutritional support - enteral route is preferred. There may be gastric paresis, paralytic ileus and diarroea. Swallowing should be carefully assessed by speech pathologist during recovery phase. Chest physiotherapy is routine. Analgesia, anxiolysis and management of insomnia. They may have pain requiring opiate analgesia. There is evidence that tricyclics, carbamazepine and gabapentin may reduce opiate requirements. Early introduction of musculoskeletal rehabilitation including joint and tendon mobilisation, splinting and tilt table work. Early education and good communication help facilitate good psychological health during recovery and rehabilitation phases. Refrences 1. Hughes RA et al. Practice parameter: immunotherapy for Guillain-Barre syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2003 Sep 23;61(6):736-40 2. Hughes RA, van der Meche FG: Corticosteroids for treating Guillain-Barré syndrome. Cochrane Database Syst Rev (2):CD001446, 2000. 3. Hund EF, Borel CO, Cornblath DR, et al. Intensive management and treatment of Guillain-Barré syndrome. Crit Care Med 1993;21:433–446. 133 4. 5. 6. Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF. Anticipating mechanical ventilation in Guillain-Barré syndrome. Arch Neurol 2001;58:893-8 Ropper AH, Kehne SM: Guillain-Barré syndrome: management of respiratory failure. Neurology 35:1662, 1985 Sharshar T et al. Early predictors of mechanical ventilation in Guillain-Barre syndrome. Crit Care Med 2003 Jan 31(1):278-83 134 INDEX 2,3-diphosphoglycerate, 8, 9 ADP/ATP ratio and, 11 shock and, 11 stored red blood cells and, 11 Abciximab, 42 Activated partial thromboplastin time, 50 Addison’s disease, 102 Anaemia, 17 causes, 17 chronic inflammation, 24 chronic renal failure, 24 classification, 17 folate deficiency, 23 haemolysis causes, 25 haemolytic, 25 autoimmune, 27 clinical features, 28 investigations, 28 treatment, 28 iron deficiency, 18 macrocytic, 21 megaloblastic, 21 causes, 23 clinical features, 23 investigations, 23 treatment, 24 microcytic, 18 nonmegaloblastic, 21 normocytic, 24 pernicious, 23 secondary, 24 sickle cell, 2 Antithrombin III, 47 Arteriopathies, 25 Aspirin action, 39 dosage, 40 indications, 39 side-effects, 40 Atrial fibrillation, 109 Broncho-pleural fistula management, 98 Budd-Chiari Syndrome, 125 Cardiac arrest asystolic, 80 Cardiomyopathy hypertrophic, 89 Central venous cannulation, 92 Clopidogrel action, 40 dosage, 41 indications, 41 side-effects, 41 Coagulation, 42 activation, 42 blood products, 49 disorders, 51 causes, 51 extrinsic pathway, 43 factors, 44 inhibition, 47 inhibitors, 48 intrinsic pathway, 42 tests, 50 Cold antibody, 28 Coronary artery bypass, 109 Cross-linked fibrin derivatives, 51 Cryoprecipitate, 49 Cyanocobalamin, 21 Dazoxiben action, 40 Desmopressin, 38 Dipyridamole, 40 action, 40 Direct Coombs test, 28 Disseminated intravascular coagulation, 54 causes, 55 clinical features, 56 investigations, 56 treatment, 56 B12 deficiency, 22 Bleeding time, 38 Bohr effect, 9 Embden-Myerhof pathway, 9 Epsilon-aminocaproic acid, 38 Erythroid cell, 1 135 Erythropoietin molecular weight, 1 physiology, 1 Euglobulin clot lysis time, 51 A, 1 A2, 1 binding of nitric oxide, 12 biosynthesis, 1 disorders of, 1 fetal, 9 function, 8 molecular weight, 1 normal values, 17 oxygen affinity, 8 Haemolysis extravascular, 27 intravascular, 25 clinical features, 26 investigations, 27 Haemolytic crisis, 2 Haemolytic uraemic syndrome, 26 Haemopexin, 27 Haemophilia A, 53 Haemophilia B, 54 Haemostasis, 35 Haptoglobin, 27 Heparin cofactor II, 47 Hepatopulmonary syndrome, 76 Hydroxocobalamin, 21 Hypersplenism, 29 Hypoadrenalism, 102 Hyponatraemia, 105 Factor IX complex, 49 Factor V, 46 Factor VIIa recombinant, 49 Factor VIII, 46, 47 recombinant, 49 replacement, 49 Factor X activation, 43 Factor XI, 47 Factor XII, 47 Factor XIII deficiency, 54 FDPs, 51 Fibrin formation, 44 Fibrin degradation products, 51 Fibrinogen, 44 Fibrinogen assay, 51 Fibrinolytic inhibitors, 38 Folate deficiency, 22 Folic acid physiology, 21 Folic acid and B12 interactions, 21 Fresh frozen plasma, 49 Indirect Coombs, 28 Intestinal pseudo-obstruction acute postoperative, 87 Intrinsic factor antibody, 24 Iron deficiency causes, 19 clinical features, 19 investigations, 19 treatment, 20 normal serum levels, 18 normal tissue levels, 18 Iron binding proteins, 19 Glycoprotein IIb/IIIa inhibitors, 41 Gout treatment in acute renal failure, 128 Granulocyte, 1 Guillain-Barre syndrome management of, 131 Haem biosynthesis, 2 disorders of, 2 Haemochromatosis, 20 causes, 20 clinical features, 20 investigations, 20 treatment, 20 Haemoglobin Koilonychia, 19 Lactic acidosis D-lactate, 84 Lymphocyte, 1 136 Megakaryocytes, 35 Methaemoglobinaemia, 5 causes, 7 clinical features, 7 investigations, 7 treatment, 8 Methicillin resistant Staphylococcus aureus, 115 Monocyte, 1 defect drugs aspirin, 39 hepatic failure, 39 renal failure, 39 function, 35 intravenous, 38 lifespan, 35 Platypnoea, 70 Polycythaemia, 29 causes, 29 rubra vera causes, 30 clinical features, 30 investigations, 30 treatment, 30 secondary, 31 causes, 31 treatment, 31 Porphyria congenital erythropoietic, 3 cutanea tarda, 3, 20 Porphyrias, 2 clinical features, 3 erythropoietic, 2 hepatic, 2 inducing drugs, 5 investigations, 5 neurological lesions, 3 safe drugs, 5 skin lesions, 3 treatment, 5 Porphyrin, 2 Portopulmonary hypertension, 76 Proerythroblast, 1 Pronormoblast, 1 Protein C pathway, 47 Prothrombin time, 50 Protoporphyria, 2 Pulmonary oedema acute, 122 treatment with morphine, 122 Purpura nonthrombocytopenic, 35 N-acetylcysteine complications of, 120 Normoblast, 1 Orthodeoxia, 70 Oxygen-haemoglobin dissociation curve, 10 acute myocardial infarction and, 11 anaemia and, 11 chronic change, 12 chronic lung disease and, 11 cirrhosis and, 11 clinical effects of, 11 congenital heart disease and, 11 critically ill patients and, 11 hypophosphataemia and, 11 in disease, 11 low cardiac output and, 11 massive transfusion and, 11 normal, 10 shift to the left, 12 shift to the right, 12 shock and, 11 thyrotoxicosis and, 11 P50, 10 alterations of, 10 definition, 10 normal value, 10 Paralytic ileus, 82 Platelet activation, 36 adhesion, 36 aggregation, 36 disorders, 37 release, 36 Platelet factor 3, 35 Platelet factor 4, 35 Platelets, 1 Rapoport-Luebering shuttle, 9 Red blood cell enzyme defects, 29 137 half-life, 1 morphology, 1 production, 1 Reticulocyte circulation time, 1 life cycle, 1 Retinoic acid syndrome, 86 clinical features, 37 investigations, 37 nonimmune, 38 treatment, 38 THromboelastography, 51 Thrombophilia, 48 Thrombopoietin, 35 Thrombotic thrombocytopenic purpura, 25 TIA clinical features and management, 95 Ticlopidine action, 40 Tirofiban, 42 Transcobalamin I, 21 Transcobalamin II, 21 Transfusion siderosis, 20 TURP Syndrome, 105 Scoring system, 107 Sedation in ICU, 67 Selective decontamination of the gastrointestinal tract, 117 Severity of illness score, 107 Sodium bicarbonate complications of, 111 Subacute combined degeneration, 22 Subclavian vein thrombosis, 72 Sulphaemoglobinaemia, 8 causes, 8 clinical features, 8 treatment, 8 Vancomycin allergy, 115 Vitamin B12, 21 absorption, 21 intrinsic factor, 21 K factors, 45 von Willebrand factor, 36 von Willibrand factor, 46 von Willibrand’s disease, 54 Thalassaemia, 2 alpha, 2 beta, 2 Thrombin formation, 44 Thrombin time, 50 Thrombocytopenia, 37 causes, 37 Warm antibody, 27 XDPs, 51 138
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