Controversies in Early Goal Directed Therapy in Sepsis
Severe sepsis and septic shock is one of the commonest diagnosis in the critically ill and, despite
advances in our understanding of its pathophysiology as well as newer antibiotics, these clinical
conditions still have poor prognosis. Sepsis and septic shock lead to multiple organ dysfunction
syndrome (MODS) which is the leading cause of death in this condition. It is thus highly desirable to
have management principles in place that can treat sepsis/septic shock and reduce morbidity and
mortality. Early Goal Directed Therapy (EGDT) in sepsis is one such management protocol that has
gained popularity over the last decade or so.
Some historical background:
Time honoured initial clinical management of the critically has involved initiation of oxygen therapy,
administration of fluids and sooner or later pharmacological support of cardiovascular system
(inotropes, vasoactive drugs). This line of initial management has been based on observations that
critically ill patients are almost always (but not invariably) hypovolaemic and exhibit signs of organ
hypoperfusion with or without actual hypotension; this hypoperfusion leads to organ dysfunction and
if left untreated, leads to MODS and increased morbidity and mortality. It thus appears logical to
resuscitate these patients with oxygen, fluids and cardiovascular support so that organ perfusion is
restored and MODS (and its consequences) avoided. This resuscitation strategy was placed on a
proper physiological footing by work of Shoemaker and colleagues 1, 2 , who in mid 1980s
demonstrated that resuscitation by administration of oxygen, fluids and pharmacological support of
cardiovascular system (mainly by inotropes like dobutamine) resulted in increased cardiac output,
improved oxygen de livery to the tissue (increasing tissue oxygen consumption) and reduced mortality
in complex surgical patients. Subsequently, Edwards et al3 showed that applying these ‘survivors’
parameters’ to patients in septic shock reduced mortality in that condition. Many subsequent studies
demonstrated that this ‘strategy of goal directed therapy GDT’ did reduce mortality, however almost
all studies inc luded only a small number of patients. Not long after, some randomised controlled
studies showed that this GDT and pushing oxygen transport to supra-normal values had little impact
on mortality and may actually increase it4 . Improvement in mortalityshown in earlier studiesmay well
have been timely attention to detail in resuscitation and fluid therapy and early antibiotic use
especially in sepsis/septic shock. Soon, pulmonary artery floatation catheters which had played a
major role in management of patients with GDT (as cardiac output and oxygen transport were easily
measured by these catheters) came under a ‘scientific’ cloud and, as their use was discouraged 5, 6 (for
wrong reasons in author’s opinion), GDT died an untimely death.
Early Goal Directed Therapy for Sepsis:
Our understanding and knowledge of pathophysiology of critical illness, especially sepsis increased in
the last decades of 20th century; unfortunately, this increased knowledge has not translate into
improved survival. EGT was ‘resuscitated’ by seminal work of Emmanuel Rivers and colleagues in
20017 showing that ‘earlyresuscitation’ in severe sepsis/septic shock improved mortality. This
protocolised therapy, aiming for certain resuscitation goals, was named ‘Early Goal Directed
Therapy’ (EGDT) for sepsis by these authors7 and briefly consists of:
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An initial fluid bolus (500 ml crystalloid or colloid) to achieve a central venous
pressure (CVP) ≥8mmHg-12mmHg.
Central line placement (with measurement of central venous oxygen saturation –
ScvO2 ).
Vasopressors (if mean arterial pressure, MAP of ≤65 mmHg) or vasodilators if MAP
≥ 90mmHg.




Use of inotropes (usually dobutamine) to achieve a venous oxygen saturation
(ScvO2 ) of >70 %.
Failure to achieve this, use of blood transfusion or red cells to a packed cell volume
(PCV) of 30%.
Lactate measurement and achieving lactate reduction.
Antibiotics.
All these are to be achieved in first 6 hours in the emergency department with subsequent admission
to a place of higher level of care viz. ICU. EGDT for sepsis was endorsed and recommended by
Surviving Sepsis Campaign (SSC) in their ‘6 hour resuscitation bundle’ (2004, 2008 and 2012)8 . With
the SSC endorsing EGDT for sepsis, this approach became the ‘norm’ by which many ICUs’
performance began to be judged! However, controversies about this approach were voiced almost
from the beginning and these voices have recently gained more impetuous with publication of recent 3
randomised controlled trials9,10,11 .
What is the scientific basis of EGDT and what are the controversies that have arisen? Is there any
scientific substance in these controversies? Given the controversies should we now abandon EGDT or
continue to follow it? This brief review will try and address these issues in the following passages
with appropriate minimum detail for the sake of brevity.
1. There is very ‘thin’ scientific basis for EGDT for sepsis. EGDTfor sepsis become a
standard care and management of sepsis and septic shock globally, especially after
endorsement by SSC in their ‘6 hour sepsis bundle’. EGDT showed a significant mortality
reduction in the treatment group (33.3% versus 49.2%; p = 0.01). However, it was a single
centre, unblinded study with a small number of patients (n=288 of which 25 were excluded
from the final analysis). A Chinese study12 is referenced by SSC as evidence in support of
EGDT for sepsis. However, there is no English translation available and therefore its claims
cannot be verified. A meta-analysis published in 2013 identified 4 randomised control trials
(RCTs) and 18 observational studies on EGDT for sepsis 13 ; there was no difference in
mortality observed in RCT but with observational studies ‘a statistically significant ‘odds of
surviving with 6 hour bundle care’ as against control (odds ratio 0.58; 95% CI 0.51-0.67;
p<0.0001)’ was demonstrated. However, most of these before and after studies were
uncontrolled and/or retrospective studies. Many of these observational studies have been cited
by SSC as further supportive proof of EGDT for sepsis stating that ‘a large number of other
observational studies using this form of early resuscitation have shown significant survival
benefit compared to historical institutional controls’. Data and conclusions from
observational studies should be adopted with caution.
2. Targeted CVP is an arbitrary figure with no physiological basis. A target level of CVP of
≥ 8 mmHg but ≤ 12 mmHg lacks scientific validation. First of all, CVP does not reflect left
ventricular filling pressure, especially in sepsis14 . There is evidence that targeting CVP
without regard to patients’ clinical state can and does lead to fluid overload as the authors
themselves admitted; moreover fluid overload is directly linked to increased mortality15,16 .
3. What does a central venous oxygen saturation (ScvO2 ) of >70% indicate? ScvO2 of <70%
is suggested as evidence of organ hypoperfusion in Rivers et al7 study. In this context it is
‘equated’ with mixed venous oxygen saturation (SvO 2 ). There are differences in blood
contained in the superior vena cava (mostly coming from brain) and that found in the
pulmonary artery (from whereSvO2 is measured). Moreover, it has been shown that ScvO 2
cannot be used as a substitute for SvO2 in the critically ill17 and in cardiac surgery patients18 ;
especially in low cardiac output states, the very physiological abnormality low ScvO 2
attempting to diagnose. There is no certainty that increasing ScvO 2 will reduce lactate.
4. Transfusing blood for a PCV of <30 does not improve outcome in sever sepsis. Blood
transfusions for a haemoglobin of >70g/l (7g/dl) have been shown to be of little benefit and
may well cause harm10,19 nor do they reduce lactate of increase ScvO 2 21 .A recent randomised
trial in this regard has shown no mortality benefit is sepsis patients with blood transfusion10 .
5. Dobutamine infusion may not achieve increase in tissue perfusion and may be
harmful.Use of dobutamine to increase oxygen delivery (DO 2 ) and oxygen consumption
(VO2 ) is not necessarily without harm4,22 . Besides, ‘calculated’ increases inDO2 and VO2 need
measurement of cardiac output, something not done in Rivers et al study.
There are a whole lot of other minor but significant points that make EGDT for sepsis questionable. In
the original article by Rivers et al7 there is hardly any mention of oxygen as initial step in
management; it is mentioned only in passing. Ventilation, sedation (and paralysis) is mentioned as a
‘step’ in management if ScvO 2 cannot be improved with above measures. Ventilation is not without
risk and may well cause further hypotension with use of sedative agents). The EFDT pathway
mentions cardiac index, and VO2 , neither of which has been (or could be) measured in the trial!So
why have Rivers et al7 mentioned it? And the original protocol mentions antibiotics but last of all.
Experience and the literature have shown that if any strategy works in sepsis, it is early use of
antibiotics!
So, should we abandon EGDT for sepsis? The answers are not easy. Early resuscitation is important
in severe sepsis/septic shock; however, it needs to be tailored to each patient’s need. Antibiotics
certainly are life-saving in severe sepsis/septic shock. EGDT may also have been of educational value
in that the clinical community is much more aware of early treatment of sepsis. This may well be its
greatest contribution to the wellbeing of sepsis patients and their improved survival.
References:
1. Shoemaker WC, Kram HB, Appel PL. Therapy of shock based on pathophysiology,
monitoring and outcome prediction. Crit Care Med 1990; 18:519-25.
2. Shoemaker WC, Appel PL, Kram HB et al. Haemodynamic and oxygen transport monitoring
to titrate therapy in septic shock. New Horiz 1993; 1:145-59.
3. Edwards JD, Brown GC, Nightingale P et al. Use of survivors’ cardiorespiratory values as
therapeutic goals in septic shock. Crit Care Med 1989; 17:1098-1103.
4. Hayes MA, Timmins MC, Yau E et al. Evaluation of systemic oxygen delivery in the
treatment of critically ill patients. N EngJ Med 1994; 300:1717-22.
5. Gore JM, Goldberg RJ, Spodick DH et al. A community-wise assessment of the use of
pulmonary artery catheters in patients with acute myocardial infarction. Chest 1987; 92:72127.
6. Shah MR, Hasselblad V, Stevenson LW et al. Impact of pulmonary artery catheter in
critically ill patients: meta-analysis of randomised clinical trials. J A M A 2005; 294:1664-70.
7. Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in treatment of severe sepsis
and septic shock. N Eng J Med 2001; 345:1368-77.
8. Dellinger RP, Levy MM, Rhodes A et al. Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock:2012. Crit Care Med 2013;
41:580-637.
9. The ProCESS Investigators. A randomised trial of protocol-based care of early septic shock.
N Eng J Med 2014; 370:1683-93.
10. Holst LB, Hasse N, Wetterslev J et al. A lower versus higher haemoglobin threshold for
transfusion in septic shock. N Eng J Med 2014; 371:1381-91.
11. The ARISE Investigators and the ANZICS Clinical Trials Group. Goal directed resuscitation
for patients with early septic shock. N Eng J Med 2014; 371:1496-1506.
12. Early goal-directed therapy collaborative group of Zhejiang Province: the effect of early goaldirected therapy on treatment of critical patients with severe sepsis/septic shock: a
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
.
multicentre, prospective randomised controlled study. Zhongguo Wei Zhong Bing Ji Jiu Yi
Xue 2010; 22:31-4. (In Chinese).
Chen C, Kollef MH. Conservative fluid balance in septic shock: an example of targeted
therapeutic minimization. Crit Care 2014; 18:481.
Marik PE, Cavallazzi E. Does the central venous pressure (CVP) predict fluid responsiveness:
an update meta-analysis and a plea for some common sense. Crit Care Med 2013; 41:177481.
Kelm DJ, Perrin JT, Cartin-Cebra R et al. Fluid overload in patients with severe sepsis and
septic shock treated with early goal-directed therapy is associated with increased acute need
for fluid-related medical interventions and hospita l death. Shock 2015; 43:68-73
Boyd JH, Forbes J, Nakada T et al. Fluid resuscitation in septic shock: a positive fluid balance
and elevated central venous pressure increases mortality. Crit Care Med 2011; 39:259-65.
Edwards DJ, Mayall RM. Importance of the sampling site for measurement of mixed venous
oxygen saturation in shock. Crit Care Med 1998; 26:1356-60.
Yazigi AI, Khoury EI, Jebara S et al. Comparisonof central venous to mixed venous oxygen
saturation in patients with low cardiac index and filling pressure after cardiac surgery. J
Cardithorc Vasc Anesth 2008; 22:77-83.
Hebert PC, Wells G, Blajchman MA et al. A multicentre randomised controlled clinical trial
of transfusion requirements in critical care. N Eng J Med 1999; 340:409-41.
Fuller BM, Gajera M, Schorr C et al. The impact of packed red blood cell transfusion on
clinical outcome in patients with septic shock treated with early goal directed therapy. Indian
J Crit Care Med 2010; 14:165-9.
Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with
sepsis. J A M A 1993; 269:3024-9.
Bouferrache K, Amiel JB, Chimot L et al. Initial resuscitation guided by Surviving Sepsis
Campaign recommendations and early echocardiographic assessment of haemodynamics in
intensive care unit septic patients: a pilot study. Crit Care Med 2012; 40:2821-7.