Transfusion Limbo How Low Will You Go? Safely. Nina A. Guzzetta, M.D. Children s Healthcare of Atlanta Emory University School of Medicine

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1 Transfusion Limbo How Low Will You Go? Safely Nina A. Guzzetta, M.D. Children s Healthcare of Atlanta Emory University School of Medicine

2 Objectives Benefits and risks of RBC administration in pediatric patients Indications regarding the use of red blood cells (RBCs) in the perioperative period Review recent scientific evidence for transfusion targets and triggers

3 Transfusion Triggers 3 y.o kgs. s/p complete repair of Truncus Arteriosus (12 mm pulmonary homograft). RVOTO = 95 mm Hg.? GI bleed. Scheduled for EGD. Hgb = 4.7; Hct = y.o kgs. ASA I s/p repair of idiopathic scoliosis. Stable in PACU. Hgb = 7.3; Hct = wk. 3.4 kgs. s/p Norwood/Sano undergoing a Laparoscopic Nissen Fundoplication. Intubated: sat = 80% on RA; BE -3; LA = 2.2; Hgb = 11.6; Hct = 34.8

4 Transfusion Trends Transfusion 2010;50:584

5 Transfusion-Dependency Ratio Transfusion 2010;50:584

6 Transfusion Costs Transfusion 2010;50:753

7 Audit of Red Blood Cell Transfusion Keung et al. Paediatr Anaesth 2009;19: % of all RBC units released from the hospital blood bank were for perioperative transfusion 87% liver transplantation 79% cardiac surgery on CPB 55% cardiac surgery off CPB 61% cranioplasty

8 Benefits Oxygen-carrying capacity Tissue oxygenation Hemostasis

9 Benefit: Oxygen-Carrying Capacity Oxygen Delivery = CO x CaO 2 (Hgb x 1.36 x O 2 sat) What is the critical hemoglobin value for oxygen delivery?

10 Critical Hemoglobin Level Weiskopf et al. Anesthesiology 2002;96: healthy adult volunteers: 28 ± 4 yrs Induced an acute isovolemic hemodilution Assess tests of cognitive function pre- and posthemodilution

11 Critical Hemoglobin Level Pre Post Hgb (g/dl) 12.7 ± ± 0.3* HR (bpm) 67.7 ± ± 10.7* MAP (mmhg) 82.8 ± ± 8.7* BD (meq/l) 0.4 ± ± 1.6* Hgb = 5.7 g/dl reduced accuracy, slowed reaction time and degraded memory

12 Critical Hemoglobin Level Neonates, infants and young children do not compensate well for anemia: Higher baseline oxygen requirement Limited ability to increase cardiac output Neonates have fetal hemoglobin

13 Critical Hemoglobin Level Fontana et al. Anesth Analg 1995;80: healthy children undergoing idiopathic scoliosis correction: 12.5 ± 1.5 yrs No cardiac disease; anesthestized and ventilated with 100% O 2 Acute isovolemic hemodilution

14 Critical Hemoglobin Level Pre Post Hgb (g/dl) 10.0 ± ± 0.8* CI (l/min/m 2 ) 3.4 ± ± 1.1* HR (bpm) 79.1 ± ± 13.2 SVR (dynes/cm/sec) 1130 ± ± 297* SvO 2 (%) 90.8 ± ± 7.8* Lactate (mmol/l) 1.3 ± ± 0.5 Oxygen extraction ratio (%) 17.3 ± % ± 5.9*

15 Critical Hemoglobin Level Healthy 28 y.o., critical Hgb = 5.7 g/dl Healthy anesthesized children on 100% O 2, critical Hgb = 3.0 g/dl Critically ill children perhaps with marginal cardiac reserve and, perhaps, a low O2 sat, critical Hgb =?

16 Benefit: Tissue Oxygenation Does increasing oxygen-carrying capacity increase tissue oxygenation? Sepsis: malfunction of mitochondrial oxygen utilization The Storage Lesion

17 The Storage Lesion Storage of RBCs lead to time-dependent changes in both quantity and quality: ATP decreases with storage time changes in membrane lipid content, RBC shape and rigidity 2,3-DPG decreases with storage time increases hemoglobin affinity for oxygen Stored RBCs may not deliver sufficient oxygen to hypoxic tissue!

18 The Storage Lesion Karam et al. Crit Care 2010 Prospective PICU 29 centers Transfusion with units stored 14 days was associated with increased MODS and prolonged ICU stay Manlhiot et al. Ann Thorac Surg 2012 Retrospective pediatric cardiac surgery Transfusion with units 14 days was associated with numerous adverse outcomes

19 The Storage Lesion AS (additive solution) = 42 days CPDA (citrate-dextrose-phosphate-adenine) = 35 days 14 days old for all pediatric cardiac surgeries

20 Benefit: Tissue Oxygenation Autoregulation of tissue blood flow Hemoglobin is the sensor that couples decreasing oxygen tension to increasing tissue blood flow

21 Benefits: Hemostasis Rheological effects of RBCs promote plateletendothelial interaction RBCs promote platelet activation

22 Risks Hemolytic Transfusion Reaction 6.7% TRALI 3.9% Anti-D Event 10.8% Acute Transfusion Reaction 18.5% Transfusion- Transmitted Infection 1.0% Clinical errors 71% Inappropriate Blood Component Transfused 56.5% Lab errors 29% Serious Hazards of Transfusion Annual Report 2009.

23 Risks Rate of transfusion-related complications is higher in children than in adults Slonim et al. Transfusion 2008;48:73 Complication rate: 10.7 per 1000 units transfused in children 2.5 per 1000 units transfused in adults

24 Infectious Risks Hepatitis B virus 1:350,000 Hepatitis C virus 1:1,800,000 HIV type 1 and 2 1:2,300,000 HTLV type I and II 1:2,000,000 Mis-transfusion 1:14,000-1:38,000 Anesth Analg 2009;108:759-69

25 Nonimmune-Mediated Risks Volume overload Massive transfusion: Metabolic - hyperkalemia, hypocalcemia, hypothermia, dilution and pulmonary microembolization Necrotizing enterocollitis Miscellaneous: Transfusion hemosiderosis, plasticizers

26 Immune-Mediated Risks Alloimmunization Hemolytic transfusion reactions Febrile nonhemolytic transfusion reactions Allergic transfusion reactions Transfusion-related acute lung injury (TRALI) Transfusion-associated graft vs. host disease (TA-GVHD) Transfusion-related immunomodulation (TRIM)

27 Transfusion Triggers STS/SCA Practice guidelines. Ann Thorac Surg 2007;83:S27-86: Transfusion trigger = Hgb level at which rbc transfusion is administered Transfuse: Hgb < 6 g/dl Hgb < 7 g/dl for postoperative patients Hgb < 10 g/dl if critical end-organ ischemia

28 Transfusion Triggers Transfusion Guidelines for Neonates and Older Children. British J Haematology 2004 Hgb > 10 g/dl if chronic oxygen dependency Hgb > 12 g/dl if neonate receiving ICU care

29 Transfusion Triggers Guidelines on Neonatal Transfusion. British J Haematology 2013;160: Ventilated: age < 1 week - Hgb = 12 g/dl age > 1 week - Hgb = 11 g/dl On O 2 or ncpap: age < 1 week - Hgb = 10 g/dl age > 1 week - Hgb = 9 g/dl Off O 2 : age > 1 week - Hgb = 7.5 g/dl

30 Transfusion Triggers Critical Heart Disease in Infants and Children. Nichols DG, Cameron DE, Greely WJ et al. (Eds) The Science and Practice of Pediatric Cardiology. Garson AJ, Bricker JT, Fisher DJ et al. (Eds) In children with cyanotic congenital heart disease: Hgb = g/dl

31 RBC Transfusion in Pediatrics Critically ill children Preterm infants Children undergoing cardiac surgery: Cardiac surgery in general Hct during DHCA/Low-Flow bypass Single ventricle population

32 Critically Ill Children Kneyber et al. Int Care Med 2007;33: Retrospective, single-center observational study 295 consecutive pts. (0 18 yrs.): 67 transfused; 228 not transfused Primary outcome: PICU mortality Secondary outcomes: ventilator days, vasoactive infusions, PICU length of stay

33 Primary outcome: Critically Ill Children RBC transfusion was independently associated with a higher PICU mortality (16.4% vs. 2.6%; p < ) Mortality related to the no. of transfusions (p = 0.002) and not to pre-transfusion Hgb level (p = 0.10) Secondary outcomes: Not transfused Transfused Ventilator days 3.2 ± ± 1.8* Vasoactive infusion (days) 2.8 ± ± 1.8* PICU stay (days) 3.2 ± ± 1.8* Int Care Med 2007;33:1414

34 Critically Ill Children Lacroix et al. N Engl J Med 2007;356: Prospective, multiple-center trial Critically ill children within 7 days after admission to an ICU Randomized to a restrictive versus liberal transfusion strategy: Restrictive: Hgb < 7.0 g/dl Liberal: Hgb < 9.5 g/dl Primary outcome: New or worsening MODS

35 Demographics: Critically Ill Children N Engl J Med 2007;356

36 Critically Ill Children Results: Restrictive (n = 320) Liberal (n = 317) Pts. receiving RBCs (%) 46 98* No. of units/pt. 0.9 ± ± 2.2* Hgb before first transfusion 6.7 ± ± 0.1* Hgb after first transfusion 9.4 ± ± 1.1* Average Hgb in ICU 8.7 ± ± 0.5* Total no. of transfusions * New/progressive MODS (%) day mortality N Engl J Med 2007;356:1609

37 Conclusions: Critically Ill Children In stable, critically ill children a Hgb threshold of 7 g/dl for RBC transfusion can decrease transfusion requirements without increasing new or progressive MODS.

38 Preterm Infants Bell et al. Pediatrics 2005;115: Prospective, single-center trial Preterm infants with a birth weight = grams Restrictive group: ventilated: Hct < 34%, nasal CPAP or O 2 : Hct < 28%, room air: Hct < 22% Liberal group: ventilated: Hct < 46%, nasal CPAP or O 2 : Hct < 38%, room air: Hct < 30%

39 Demographics: Preterm Infants Restrictive (n = 49) Liberal (n = 51) Birth weight (gms) 958 ± ± 193 Gestational age (wks) 27.7 ± ± 2.1 Multiple births (no.) Initial Hct % 49 ± 8 50 ± 8 Pediatrics 2005;115:1685

40 Preterm Infants Results: Restrictive (n = 49) Liberal (n = 51) Pts. receiving RBCs (no.) Transfusions/pt. 2.7 ± ± 4.1* Donor exposures (no.) 1.8 ± ± 2.5* Age at first transfusion (days) 8 3* Survival to discharge (%) IVH grade 4/leukomalacia (%) 12 0* >1 apnea episode/day (%) 43 20* Pediatrics 2005;115:1685

41 Conclusions: Preterm Infants The finding of more frequent major neurologic events in the restrictive transfusion group suggests that the practice of restrictive transfusion may be harmful to preterm infants.

42 Cardiac Surgery Children after cardiac surgery Hct during DHCA/Low-Flow bypass Single ventricle population

43 Cardiac Surgery Willems et al. Crit Care Med 2010;38: Children after cardiac surgery, within 7 days of ICU admission were randomized to receive a transfusion: Restrictive - Hgb < 7.0 g/dl Liberal - Hgb < 9.5 g/dl Exclude: age < 28 days, remained cyanotic postop Primary outcome: New or worsening MODS

44 Cardiac Surgery Crit Care Med 2010;38:649

45 Results: Cardiac Surgery Restrictive n = 63 Liberal n = 62 Pts transfused (%) * Total no. transfusions 13 83* New/Progressive MODS (%) Age, days (%) Age, > 365 days (%) 13 0* Infections (%) day mortality (%) Crit Care Med 2010;38:649

46 Conclusion: Cardiac Surgery In this subgroup analysis of cardiac surgery patients, a restrictive red-cell transfusion strategy was not associated with any significant difference in new or progressive MODS, but this evidence is not definitive.

47 Hematocrit and DHCA Duebener et al. Circulation 2001;104:I Assess the effects of Hct on cerebral microcirculation during DHCA 3 groups of piglets underwent 1 hour of DHCA: Hct = 10%; Hct = 20%, Hct = 30% Assess functional capillary density

48 Hematocrit and DHCA Circulation 2001;104:I-260

49 Hct and Low-Flow CPB Jonas et al. J Thorac Cardiovasc Surg 2003;126: Prospective, randomized, single-center trial Infants undergoing low-flow CPB Primary peri-operative endpoint: CI at 24 hours Primary long-term endpoint: PDI and MDI at 1 year

50 Demographics: Hct and Low-Flow CPB Low Hct (n = 73) High Hct (n = 74) Age (days) Birth weight (kg) Total CPB time (min) Low-flow time (min) Hct at onset of lowflow 21.5 ± ± 3.2* J Thorac Cardiovasc Surg 2003;126:1765

51 Hct and Low-Flow CPB Results - Low Hct group: Lower CI at 24 hours postop and over the first 24-hours postop Higher serum lactate levels 60 minutes post- CPB At 1 year of age, worse PDI (p = 0.008) At 1 year of age, worse MDI J Thorac Cardiovasc Surg 2003;126:1765

52 Hct and Low-Flow CPB Conclusions: Cerebral microcirculation is better maintained at a higher Hct = 30% than at a lower Hct = 20% during DHCA or low-flow CPB.

53 Bidirectional Glenn and Fontan Cholette et al. Pediatr Crit Care Med 2011;12:39-45 Prospective, randomized, single-center trial Upon ICU admission 60 patients were randomized for 48 hours postop to receive a transfusion: Restrictive - Hgb < 9.0 g/dl Liberal - Hgb < 13.0 g/dl Primary outcome: lactate

54 Bidirectional Glenn and Fontan Pediatr Crit Care Med 2011;12:39

55 Bidirectional Glenn and Fontan Restrictive Group (n = 30) Liberal Group (n = 30) Mean Hgb (g/dl) 11.1 ± ± 0.5* No. RBC transfusions 0.43 ± ± 1.2* Peak lactate (mmol/l) 3.1 ± ± 1.3 Mean lactate (mmol/l) 1.4 ± ± 0.4 SaO 2 (%) 83 ± ± 5.2 SvO 2 (%) 57 ± ± 6.6* rso 2 (%) 64 ± ± 8.3* Mechanical ventilation (hrs) 23 (5 625) 20 (4 216) PICU stay (days) 6.6 ± ± 3.3 Hospital stay (days) 11 (4-78) 9.5 (5-62) Survival to discharge (%) 30 (100%) 29 (96%) Pediatr Crit Care Med 2011;12:39-45

56 Bidirectional Glenn and Fontan Conclusions: Children with single-ventricle physiology do not benefit from a liberal transfusion strategy after cavopulmonary connection. A restrictive RBC transfusion strategy decreases the number of transfusions, donor exposures and potential risks in these children.

57 Questions Regarding Transfusion Future Research: Prospective, randomized controlled trials Neonates versus older infants and children Preterm versus term neonates Children with congenital heart disease Cyanotic versus noncyanotic Palliated versus repaired defects