Transfusion Medicine - State of the Art October 26, 2013 1-5 PM When/how/why should we transfuse newborn? Benefits/hazards? Robert D. Christensen, MD Disclosure Statement ●Neither I nor any member of my immediate family has a financial relationship or interest (currently or within the past 12 months) with any entity producing, marketing, re-selling, or distributing health care goods or services that I will discuss in this presentation. ● I do not intend to discuss an unapproved/investigative use of a commercial product/device. Bring me the chart! RISKS BENEFITS 1. Managing NICU RBC transfusions in a multihospital system: how are we doing? Outline 2. What about the association between early RBC transfusion and severe IVH? 3. Serum bilirubin levels before vs. after transfusion: is hyperbilirubinemia a transfusion risk for certain neonates? ? 1. Managing NICU RBC transfusions in a multihospital system: how are we doing? Outline 2. What about the association between early RBC transfusion and severe IVH? 3. Serum bilirubin levels before vs. after transfusion: is hyperbilirubinemia a transfusion risk for certain neonates? ? Intermountain Healthcare Quality Improvement: Transfusions ● 2004 - Transfusion guidelines ● 2007 - Evaluated compliance, audited every NICU transfusion given in 2006. ● 2008 - Devised methods to improve guidelinecompliance and set a system-wide goal to increase from 60% to 90%. ● 2010 - Analyzed benefits/risks of the new program to improve compliance. ● 2011 - Analyzed transfusion practice one year after new program ceased. Transfusion Guidelines Calhoun DA, Christensen RD et al. Consistent Approaches to Procedures and practices in neonatal hematology Clin Perinatol 2000;27: 733-53. RBC ●Transfuse if Hct ≤35% if intubated and ≥40% O2 ●Transfuse if Hct ≤28% if intubated on <40% O2 or unexplained lethargy, poor wt gain, tachycardia, apnea. ●Transfuse if Hct ≤20% any neonate PLATELETS ●Transfuse if PL ≤100,000 and bleeding, pre or post op, ECMO ●Transfuse if PL ≤50,000 if “unstable” ●Transfuse if PL ≤25,000 any neonate Transfusion Guidelines Calhoun DA, Christensen RD et al. Consistent Approaches to Procedures and practices in neonatal hematology Clin Perinatol 2000;27: 733-53. RBC ●Transfuse if Hct ≤35% if intubated and ≥40% O2 ●Transfuse if Hct ≤28% if intubated on <40% O2 or unexplained lethargy, poor wt gain, tachycardia, apnea. ●Transfuse if Hct ≤20% any neonate Adopted as NICU Transfusion Guidelines at Intermountain PLATELETS Healthcare inpre2004 ●Transfuse if PL ≤100,000 and bleeding, or post op, ECMO ●Transfuse if PL ≤50,000 if “unstable” ●Transfuse if PL ≤25,000 any neonate How well are we complying with our transfusion guidelines? How Well Do We Comply with Our In 2007, Reviewed every NICU transfusions given during 2006 July 2008 Adherence to NICU transfusion guidelines: data from a multihospital healthcare system. Baer VL, Lambert DK, Schmutz N, Henry E, Stoddard RA, Miner C, Wiedmeier SE, Burnett J, Eggert LD, Christensen RD RESULTS: 2008 ● Overall 60% of RBC transfusion were compliant with the guidelines. ● Most violations were RBC transfusions given “late”. “...the greatest exposure to liability in the practice of medicine occurs when physicians fail to follow their own rules (practice guidelines).” Perry Mason, 1959 2008 – A program to make it easier for busy clinicians to comply with the transfusion guidelines 2009 – Jan 1, program instituted in all NICUs Transfusion Compliance Program 1.Electronic physician order entry for transfusions. 2.Training in all hospitals with a NICU. 3.Guidelines displayed on the screen at the time transfusion orders are entered. 4.Monthly report cards to each NICU director and nurse manager of their previous month’s compliance figures. 5. “Board Goal” to increase compliance to >90% of all transfusions. System 2009 Percent of transfusions given within 100% 80% 60% 40% 20% 0% Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Percent of transfusions given within guidelines. NICU A - 2009 100% 80% 60% 40% 20% 0% Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Percent of transfusions given within guidelines. NICU B- 2009 100% 80% 60% 40% 20% 0% Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Associated with the improved compliance were the following… • • • • Fewer transfusions administered More neonates receiving no transfusions Lower blood bank charges No observed harm (no change in LOS or mortality rate, and trends toward improvements in IVH, NEC, ROP, BPD) Percent of NICU patients receiving one or more Tx Percent of NICU admissions that received one or more transfusions 20 18 16 14 12 10 8 6 4 2 0 2007 PRBC 2008 Platelets 2009 FP A total of 3923 NICU transfusions were administered in 2009. This was down from an average of 4907 during the two previous years. A decrease in RBC transfusions of 554/year. A decrease in platelet transfusions of 174/year. A decrease in frozen plasma transfusions of 256/yr. Effect on Blood Bank Charges • • • • RBC: 554 @ $847/transfusion…………..$469,238/year Platelets: 174 @ $1,398/transfusion…….$243,252/year Frozen Plasma: 256 @ $264/transfusion…$67,584/year Reduction in transfusion service charges… ……………...$780,074/year No evidence that outcomes were adversely affected. Primary Children’s Hospital • Mortality unchanged at 6% • Length of stay consistent at a median of 8 days. • Non-significant decrease in BPD, ROP, IVH,NEC. Perinatal Centers • Mortality unchanged at 1% • Length of stay consistent at a median of 9 days. • Non-significant decrease in BPD, ROP, IVH, NEC. The system-wide transfusion compliance program finished December 31, 2009. No further report cards, monthly reminders, corporate emphasis. Computerized transfusion order entry remained. In the two subsequent years (2010 and 2011) the rate of compliance with guidelines continued to improve (99%) and the transfusion rate continued to decline, for each NICU and for the corporation. 2012 1. Managing NICU RBC transfusions in a multihospital system: how are we doing? 2. What about the association between early RBC transfusion and severe IVH? 3. Serum bilirubin levels before vs. after transfusion: is hyperbilirubinemia a transfusion risk for certain neonates? ? A robust statistical association between early RBC transfusion of ELBW neonates and the development of IVH. Dos Santos et al. Transfusion 2010 (Brazil) Baer et al. Transfusion 2011 (USA) Baer et al. Transfusion 2011 (USA) Clear: A robust statistical association exists in ELBW In ELBW neonates, neonates between early RBC transfusion and early RBC transfusion the subsequent development ofisIVH. associated with severe IVH Unclear: ●Why? Baer et al. Transfusion 2011 ●Cause and effect? Baer et al. Transfusion 2011 Dos Santos et al. Transfusion 2010 ●Co-morbidities? Two “new” ways to eliminate or reduce early RBC transfusion: 1. Stripping (milking) umbilical cord blood of small preterm infants before the cord is clamped and cut. 2. Drawing baseline NICU blood tests from fetal blood in the placenta, thus initially drawing no blood from the neonate. Why do we typically clamp/cut the umbilical cord immediately after birth? Why do we typically clamp/cut the umbilical cord immediately after birth? So where does this blood go? DELAYED CLAMPING Many obstetricians & neonatologists have been uncomfortable delaying cord clamping, in VLBW deliveries, because of the desire to quickly hand-off the small neonate to the NICU resuscitation team. Dec 2012 A more rapid alternative to delayed cord clamping was proposed in 2008 – umbilical cord “milking”. Placental End CORD MILKING Dr. Hosono, Dept. Pediatrics, Nihon University, Tokyo, Japan Baby End Umbilical cord “milking” reduces the need for red cell transfusions in VLBW neonates. Tokyo, 2008 Studies of Benefits of Cord Milking @ VLBW Delivery ● More normal blood pressure ● Less vasopressor use ● Fewer early transfusions ● Lower incidence of IVH Dec 2012 Blood tests upon NICU admission: Blood culture, CBC with differential count and platelets, state metabolic screen, other tests (blood type, Coombs, coagulation profile) Blood tests that can be drawn from a neonate on NICU admission Very low birth weight premature birth Very low birth weight premature birth Initial phlebotomy for laboratory tests Very low birth weight premature birth Initial phlebotomy for laboratory tests Transfusion of donor blood Another way to obtain fetal blood for all of the NICU admission laboratory tests Another way to obtain fetal blood for all of the NICU admission laboratory tests PROSPECTIVE STUDY: All baseline blood tests obtained from the umbilical vein in 100 VLBW neonates, matched with 100 drawn in the standard way (from the neonate). ● Feasible in actual practice (Ogden, Provo, St. George) ● 95% of attempts were successful ● Successfully drawn even at 23 weeks gestation Higher hemoglobin 24 hrs after birth (2.5±0.4 g/dL, p=0.000) Fewer RBC transfusions during the first three days (p=0.04). Fewer RBC transfusion during the first five days (p=0.000). Fewer RBC transfusions during the first week (p=0.000). Less use of vasopressors for hypotension (p<0.001) Lower prevalence of grade 3 and 4 IVH (p=0.05) 2013 After cord milking, an adequate volume of fetal blood remains in the VLBW placenta (97% of instances) for all needed blood tests. COMMITTEE OPINION The American College of Obstetricians and Gynecologists Committee on Obstetric Practice Dec 2012 December 2012: Delayed Clamping (or Cord milking) …50% reduction in RBC transfusion …50% reduction in IVH. Unresolved issue: Effect of the placental transfusion on whole blood viscosity in VLBW neonates. Blood Viscosity (THICKNESS) can be measured in the laboratory using an instrument called a “CONE AND PLATE VISCOMETER” The fourEvidence: with the highest viscosity measurements vs. the 16 others Best @ VLBW delivery, cord milking – ● Reduces early RBC transfusion ● Maintains more normal BP ● Reduces odds of IVH ● Does not cause hyperviscosity Ranked in order of highest to lowest peak viscosity Patient 1 Peak Visc (cP) Peak Hct (%) Gest age (w) Hypotonic Plethora Peak bili (mg/dL) Lowest gluc (mg/dL) Lowest pl count (109/L) 9.5 55.5 31 No No 9.8 39 322 Patient 2 7.7 59.7 31 No No 10.2 45 153 Patient 3 6.9 61.2 30 No Yes 8.2 51 207 Patient 4 6.5 59.4 31 No No 6.1 43 212 Four highest viscosity X±SD (%) 7.7±1.3 59.0±2.4 31±1 0/4 (0%) 1/4 (25%) 8.6±1.8 44±5 224±71 Patients 5-20 X±SD (%) 5.1±0.7 46.6±5.7 28±3 1/16 (6%) 2/16 (13%) 9.0±2.0 54±19 181±71 P value, highest three vs. remaining 0.001 0.001 0.074 1.000 0.508 0.672 0.310 0.297 2013 If the rate of early RBC transfusions of VLBW neonates is brought down, using a transfusionmanagement program, what will happen to the incidence of IVH? Hypothesis: If RBC transfusion is causally-linked with IVH in some cases, successful efforts to eliminate (or reduce) early RBC transfusions should diminish the incidence of IVH. Hypothesis: If RBC transfusion is causally-linked with IVH in some cases, successful efforts to eliminate (or reduce) early RBC transfusions should diminish the incidence of IVH. Hypothesis: If RBC transfusion is causally-linked with IVH in some cases, successful efforts to eliminate (or reduce) early RBC transfusions should diminish the incidence of IVH. Hypothesis: If RBC transfusion is causally-linked with IVH in some cases, successful efforts to eliminate (or reduce) early RBC transfusions should E=mc2 diminish the incidence of IVH. Baby Einstein NICU Transfusion Compliance/Management Program Percent of VLBW neonates with a RBC transfusion during their first week (n=2761) Percent of VLBW neonates with a RBC transfusion during their first week (n=2761) As the early RBC transfusion rate fell in half over this period, what happened to the severe IVH rate? Percent of VLBW neonates with a GRADE 3 or 4 IVH % with a grade 3 or 4 IVH -○- Percent of VLBW neonates with a GRADE 3 or 4 IVH % with a grade 3 or 4 IVH -○- As the early RBC transfusion rate fell in half, the severe IVH rate, in parallel, fell in half. Percent of VLBW neonates with a GRADE 3 or 4 IVH % with a RBC transfusion in 1st week -●- % with a grade 3 or 4 IVH -○- As the early RBC transfusion rate fell in half, the severe IVH rate had a parallel fall. 2013 Do we want to consider doing this in our hospital? VLBW Deliveries ● Cord milking ● Drawing no blood initially from the neonate What are the proposed mechanisms explaining transfusionassociated IVH? Mechanism for TA-IVH? 1. Banked RBC lose elasticity as well as nitric oxide synthase 2. Stiff transfused RBC get “stuck” temporarily in capillary beds 3. Lack of pericytes in cerebral capillaries <28 weeks render the capillaries more likely to rupture during down-stream occlusion. Capillaries in the germinal matrix of the VLBW brain are particularly susceptible to rupture, because they lack supporting cells (pericytes). RBC traverse the smallest capillary beds one at a time, in line. RBC traverse the smallest capillary beds one at a time, in line. RBC pass through capillary spaces smaller than themselves. This can only occur because; 1) RBC deform, 2) RBC release nitric oxide thereby dilating the capillaries. Banked RBC (even after a few days) develop a “storage lesion” that involves; 1) less deformability and 2) depletion of nitric oxide synthase. Transfused RBC (poor deformability and lacking nitric oxide synthase) can clog capillaries. Transfused RBC (poor deformability and lacking nitric oxide synthase) can clog capillaries. Transfused RBC with poor deformability Transfused RBC (poor deformability and lacking nitric oxide synthase) can clog capillaries. Transfused RBC with poor deformability If transfused RBC clog capillary flow, pressure can increase upstream leading to capillary rupture. 1. Managing NICU RBC transfusions in a multihospital system: how are we doing? 2. What about the association between early RBC transfusion and severe IVH? 3. Serum bilirubin levels before vs. after transfusion: is hyperbilirubinemia a transfusion risk for certain neonates? ? Are RBC transfusions a risk factor for hyperbilirubinemia? ● Bilirubin load from hemolysis of effete donor RBC or cells lysed during the transfusion process? ● Type specific vs. “universal donor” blood? ● What are the odds that a RBC transfusion will result in a ≥10 mg/dL increase in TSB? METHODS and RESULTS 454 RBC transfusions where a TSB was obtained in the 8 hour period before and also in the 48 hour period after transfusion. ● Phototherapy on before/during the transfusion – TBS increased by 1 mg/dL ● No phototherapy on before/during the transfusion – TSB increased by 3 mg/dL (p<0.0001) ●No phototherapy on before/during the transfusion – 80% had phototherapy begun within 1 day after the transfusion. (p<0.0001) METHODS and RESULTS ● Type specific blood gave a smaller increase in TSB than did “universal donor” blood (p<0.0001) but the clinical significance was nil (0.3 mg/dL difference). ● 7% of transfusions were followed by a >5mg/dL rise in TSB ● 1% of transfusions were followed by a >10 mg/dL rise in TSB (with no other clear explanation, i.e. Coombs -). Are RBC transfusions a risk factor for hyperbilirubinemia? ● Not a major risk factor (3 mg/dL) ● Type specific and “universal donor” blood equivalent in this regard. ● 7% of transfusions associated with a >5mg/dL rise in TSB, 1% with a >10 mg/dL rise. ● Worth considering this as a risk factor among selected neonates already at risk for extreme hyperbilirubinemia. 1. Managing NICU RBC transfusions in a multihospital system: how are we doing? RECAP 2. What about the association between early RBC transfusion and severe IVH? 3. Serum bilirubin levels before vs. after transfusion: is hyperbilirubinemia a transfusion risk for certain neonates? ? When/how/why should we transfuse newborn? Benefits/hazards? Thanks for your kind attention ! Robert D. Christensen, MD
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