Transfusion Literature Summaries

OVERVIEW

The current paradigm of the transfusion trigger of Hb 70 g/L comes from the TRICC trial… 

• It challenged the unsubstantiated belief that high hemoglobin values are safe, effective, and necessary in the critically ill.
• It triggered a more discerning look at the physiology of oxygen transport in the context of haemoglobin availability
• It raised the question of whether transfusion has problems in its own right

HARM FROM BLOOD TRANSFUSION

Hébert PC, Wells G, Tweeddale M, Martin C, Marshall J, Pham B, Blajchman M, Schweitzer I, Pagliarello G. Does transfusion practice affect mortality in critically ill patients? Transfusion Requirements in Critical Care (TRICC) Investigators and the Canadian Critical Care Trials Group. Am J Respir Crit Care  Med. 1997 May;155(5):1618-23. PubMed PMID: 9154866.

• observational study
• n = 4470
• patients who died had lower Hbs and more frequent transfusions
• patients with cardiovascular disease ->trend to increased mortality in patients with a Hb < 95g/L + significantly decreased mortality with larger RBC transfusions

Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill: current clinical practice in the United States. Crit Care Med 2004; 32:39–52 PMID: 14707558

• Blood transfusion is an independent risk factor for:
  • morbidity and mortality
  • ICU admission
  • Hospital LOS
  • Increased cost

Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002 Sep 25;288(12):1499-507. PubMed PMID: 12243637.

• prospective cross sectional study, n = 3,534
• for matched patients in the propensity analysis, the 28-day mortality was 22.7% among patients with transfusions and 17.1% among those without (P =.02)
• i.e. transfusion independently associated with death

Vincent JL, Sakr Y, Sprung C, Harboe S, Damas P; Sepsis Occurrence in Acutely  Ill Patients (SOAP) Investigators. Are blood transfusions associated with greater mortality rates? Results of the Sepsis Occurrence in Acutely Ill Patients study.  Anesthesiology. 2008 Jan;108(1):31-9. PubMed PMID: 18156879.

• Sepsis Occurrence in Acutely Ill Patients study was a multicenter, observational study followed up to 60 days
• Of 3,147 patients, 1,040 (33.0%) received a blood transfusion
• Transfused patients were sicker and did worse, but blood transfusion was not significantly associated with death in multivariate analysis – in fact the opposite was found in propensity analysis of matched pairs.
• Despite having the same first author, the findings of the SOAP study (septic patients) were contradictory to those of the ABC study

TRANSFUSION TRIGGERS IN NON-BLEEDING PATIENTS

Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-17. Erratum in: N Engl J Med 1999 Apr 1;340(13):1056. PMID: 9971864.

Study design

• The patients included were >16 years old, critically ill, normovolaemic, non-bleeding, Hb <90 within 72 of ICU admission
•  MC RCT involving 25 centers over 3 years with n = 838
• The comparison groups had different Hb target ranges – these were restrictive (70-90g/L) vs liberal groups (100-120g/L), with the lower value as the transfusion threshold

Findings

• no difference in the the primary endpoint of mortality @ 30 days (18.7 percent vs. 23.3 percent, p = 0.11)
• increased complications in liberal strategy group (APO, ARDS)
• significant reduction in blood exposure in the more restrictive group
• significantly lower in-hospital mortality in the less sick (APACHE 20 OR LESS: 8.7 percent in the restrictive-strategy group and 16.1 percent in the liberal-strategy group, p = 0.03) and those aged <55y in the restrictive transfusion strategy group
• The mortality rate during hospitalization was significantly lower in the restrictive-strategy group (22.2 percent vs. 28.1 percent, p = 0.05).
• trend to decreased survival with a restrictive strategy for patients with cardiovascular disease (but was not powered to answer this) – a quarter of the patients had cardiovascular disease, with no ill effects.
• no differences in duration of MV or ventilator free days

Commentary and Criticisms

• It was underpowered for the primary outcome – so always going to find no difference! 1620 patients would have been ideal to satisfy the power analysis. No difference seen for ICU mortality or 60 day mortality
• only 13% of screened patients were randomised
• mean Hbs were actually higher, 85 and 107 respectively for the 2 groups
• Performed prior to the use of leukodepleted blood (introduced in Australia in 2008) – in Canada this had ARR 1%
• Selection bias – 26% of those refused had CVD, cf 20% of those in the trial – 29% in total were excluded
• Practice misalignment — Deans et (2010) re-analysed TRICC: pre-existing IHD did worse with restrictive, young and not so sick did worse with liberal strategy – overall may have cancelled each other out
• Exclusions – blood transfusion before ICU (? applicable to surgery patients), cardiac surgery, refused for some other reason
• all patients in the liberal group

Westbrook et al. Transfusion practice and guidelines in Australian and New Zealand intensive care units. Intensive care medicine 2010 36 (7) p1138 -1146

• Australian intensivists seem to believe TRICC based on their clinical practice

Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P, Joffe A, Biarent D, Meert K, Peters MJ; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung  Injury and Sepsis Investigators Network. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007 Apr 19;356(16):1609-19. PMID: 17442904.

• a Canadian paediatric study
• mirrored the findings of TRICC, but with MODS as the primary outcome

Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012 Apr 18;4:CD002042. Review. PubMed PMID: 22513904.

• 19 trials involving a total of 6264
• Restrictive transfusion strategies reduced the risk of receiving a RBC transfusion by 39% (RR 0.61, 95% CI 0.52 to 0.72).
• The volume of RBCs transfused was reduced on average by 1.19 units (95% CI 0.53 to 1.85 units).
• However, heterogeneity between trials was statistically significant (P<0.00001; I(2)≥93%) for these outcomes
• no impact on the rate of adverse events compared to liberal transfusion strategies (i.e. mortality, cardiac events, myocardial infarction, stroke, pneumonia and thromboembolism).
• Restrictive transfusion strategies were associated with a statistically significant reduction in hospital mortality (RR 0.77, 95% CI 0.62-0.95) but not 30 day mortality (RR 0.85, 95% CI 0.70 to 1.03).
• did not reduce hospital or intensive care length of stay.
• No trials in ACS

Aronson D, Dann EJ, Bonstein L, Blich M, Kapeliovich M, Beyar R, Markiewicz W, Hammerman H. Impact of red blood cell transfusion on clinical outcomes in patients with acute myocardial infarction. Am J Cardiol. 2008 Jul 15;102(2):115-9. Epub 2008 May 9. PubMed PMID: 18602505.

• Prospective database, n = 2,358 of RBC transfusion in MI; cox-regression models for motality at 6 months
• 192 (8.1%) received RBC transfusion.
• Six-month mortality rates were higher in patients receiving transfusion (28.1% vs 11.7%, p <0.0001).
• protective effect of transfusion in patients with nadir hemoglobin < or=8 g/dL (adjusted HR 0.13, 95% CI 0.03 to 0.65, p = 0.013).
• transfusion was associated with increased mortality in patients with nadir hemoglobin >8 g/dL (adjusted HR 2.2, 95% CI 1.5 to 3.3; p <0.0001)

Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, Kalil Filho R, Sierra DB, Lopes NH, Mauad T, Roquim AC, Sundin MR, Leão WC, Almeida JP, Pomerantzeff PM, Dallan LO, Jatene FB, Stolf NA, Auler JO Jr. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010 Oct 13;304(14):1559-67. PubMed PMID: 20940381.

• post cardiac surgical patients
• RCT with n = 502
• HCT 30% vs HCT > 24%
• no difference in mortality and severe morbidity
• number of RBC’s transfused was an independent risk factor for clinical complications
•  but large separation between groups not achieved and high base line event rate

TRANSFUSION TRIGGERS IN BLEEDING PATIENTS

Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J, Guarner-Argente C, Santaló M, Muñiz E, Guarner C. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan 3;368(1):11-21. PMID: 23281973.

Study design

• non-blinded, parallel group SC RCT in Spain
• n = 921
• adult patients with hematemesis or melaena
• Restrictive strategy (Hb transfusion threshold <7 g/dL targeting post-transfusion 7-9 g/dL) versus liberal strategy (Hb transfusion threshold <9g/dL targeting post-transfusion 9-11 g/dL)

Outcomes

• primary outcome was mortality at 45 days: 5% vs. 9% (HR 0.55; 95% CI 0.33-0.92; P=0.02; NNT=25) in favour of restrictive approach
• other secondary outcomes:  further bleeding associated with hemodynamic instability or Hgb drop ≥2 within 6 hours, number of RBCs transfused, cardiac complications, transfusion reactions and mean LOS

Commentary and criticisms

• Patients with major haemorrhage or low rebleeding risk were excluded
• Patients had emergency upper GI endoscopy within a mean of 5 hours of admission — unrealistic in most clinical settings
• Subgroup analysis suggested benefit extends beyond those with portal hypertension
• the liberal arm may have benefited from hemostatic resuscitation rather than simply RBC transfusion which may cause dilutional coagulopathy

LEUCODEPLETION

Hébert PC, Fergusson D, Blajchman MA, Wells GA, Kmetic A, Coyle D, Heddle N, Germain M, Goldman M, Toye B, Schweitzer I, vanWalraven C, Devine D, Sher GD; Leukoreduction Study Investigators: Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood cell transfusions. JAMA 2003, 289:1941-1949.

• observational study suggesting a benefit from leukoreduction
• subsequently adopted in Australasia, despite an absence of high quality evidence (no RCTs)

References and Links

CCC Transfusion Series
Blood Products	Cryoprecipitate, Fresh Frozen Plasma (FFP), Platelets, Red Cells (RBCs) Concentrates: Prothrombinex, Factor VIIa, Fibrinogen Concentrate
Reversal	Rivaroxaban / Apixaban / Enoxaparin: Andexanet Alfa, Rivaroxaban and Bleeding Dabigatran: Idarucuzimab, Dabigatran and bleeding Heparin: Protamine Warfarin: Vitamin K / FFP / PTx, Warfarin Reversal, Warfarin Toxicity
Testing	Coagulation Studies, TEG / ROTEM (Thromboelastography), Platelet function assays
General Topics	Acute Coagulopathy of Trauma, Blood Bank, Blood conservation strategies, Blood Product Compatibilities, Blood transfusion risks, Disseminated Intravascular Coagulation, Massive blood loss, Massive transfusion protocol (MTP), Modifications to blood components,Procedures and Coagulopathy, Storage Lesions, TRALI, Transfusion Literature Summaries, Transfusion Reactions