transfusion thresholds: how low can we go?transfusion-related acute lung injury (trali) • acute...

Transfusion Thresholds:

How Low Can We Go?

Jeffrey L. Carson, M.D.Richard C. Reynolds Professor of Medicine

Chief, Division of General Internal MedicineRutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey, USAThursday, October 31, 13

Thursday, October 31, 13

Presentation Outline• Framework for transfusion decision

• Side effects of blood

• Effect of anemia on mortality and morbidity

• Effect of blood transfusion on mortality and morbidity

• Clinical trials

• FOCUS

• Observational data

• SummaryThursday, October 31, 13

Case 1

• 68 year old male with COPD is admitted to hospital with increasing dyspnea. He is hypoxic and has large infiltrate on chest xray. The patient is transferred to MICU, intubated and treated with antibiotics.

• Over the next 3 days Hgb falls from 11 to 8.5 g/dL. He appears to be euvolemic and BP is stable.

• Transfuse?Thursday, October 31, 13

What Hemoglobin Concentration Transfuse?11 g/dL

10 g/dL

9 g/dL

8 g/dL

7 g/dL

6 g/dL


Case 2

• 80 year old women 2 days postop for hip fracture repair

• PMH- hypertension, DM, history of MI three years ago

• Symptoms- tired and weak

• Exam ok

• Hgb 8.5 g/dL



10 g/dL

9 g/dL

8 g/dL

7 g/dL

6 g/dL


Case 3

• 66 year old male presents with chest pain to ER and ECG shows anterior wall MI

• Patient taken to cardiac catherization lab and stent inserted in LAD

• Admission Hgb 12.1. Following day Hgb 9.2

• Large hematoma in groin. Vitals normal

• Transfuse?


Case 3 continued

• Next day Hgb 8.1 g/dL

• Vitals normal. No chest pain or dyspnea

• Transfuse?



10 g/dL

9 g/dL

8 g/dL

7 g/dL

6 g/dL


Transfuse vs No Transfuse

Benefit Risks

Functional Recovery

Morbidity

Mortality

Risks from Anemia

Blood Side Effects


Side Effects of Allogeneic Transfusion


1 in 100 million

1 in 10 million

1 in 10

1 in 100

1 in 1000

1 in 10,000

1 in 100,000

1 in 1 million

1 in 1

Adverse effects of transfusion Modified from Dzik WH 2003


1 in 100 million

1 in 10 million

1 in 10

1 in 100

1 in 1000

1 in 10,000

1 in 100,000

1 in 1 million

1 in 1

HIV

HBV

HCV

FeverFatal Hemolysis



1 in 100 million

1 in 10 million

1 in 10

1 in 100

1 in 1000

1 in 10,000

1 in 100,000

1 in 1 million

1 in 1

HIV

TACO

HBV

HCV

Fever

Life threatening reaction

TRALI

Fatal Hemolysis



Transfusion-Related Acute Lung Injury (TRALI)

• Acute lung injury with bilateral infiltrates

• Absence circulatory overload

• Within 6 hours (usually 2 hours) of receipt of plasma-containing blood or components

• Chills, fever, dyspnea, cyanosis, and hypotension or hypertension

• RBC’s, FFP, platelets, granulocytes


Transfusion Associated Circulatory Overload (TACO)

• Volume overload from transfusion

• Frequency reported varies; about 1:100

• Common, clinically important, but treatable in most cases


1 in 100 million

1 in 10 million

1 in 10

1 in 100

1 in 1000

1 in 10,000

1 in 100,000

1 in 1 million

1 in 1

HIV

TACO

HBV

HCV

Death from medical error

Fever

Life threatening reaction

Motor vehicle fatalities

TRALI

Fatal Hemolysis

Firearm homicide

Fall fatalities

Lightning fatalities

Airplane fatalities

Adverse effects of transfusion contrasted with other risks Modified from Dzik WH 2003


Summary-Side Effects

• Risks of blood from known problems is very low and comparable to everyday risks

• Risk of HIV and Hepatitis C about 1:2 million

• TRALI is important serious side effect but TACO much more common

• Human error (wrong unit of blood to wrong patient) preventable cause of serious adverse effects of blood


Risk of Anemia


Anemia in Animals

Group Event Hgb (g/dL)

Normal ST segment changes < 5

Lactate production < 3

Ventricular function < 3

Death < 3

CAD ST segment changes 7-10


Effect of Anemia and CVD on Surgical Mortality and Morbidity

• Retrospective cohort study of patients who refuse blood transfusion for religious reasons

• Outcome-30-day mortality or morbidity

• CVD- patient with history of MI, angina, CHF, or PVD

• 1,958 patients age 18 or older

Carson JL, et al. Lancet 1996;348:1055-60


Preop Hgb and Mortality

Preop Hgb N % Dead 95% CI0-5.9 36 33.3 18.6-51.0

6.0-6.9 27 18.5 6.3-38.17.0-7.9 49 12.2 4.6-24.78.0-8.9 39 12.8 4.3-27.49.0-9.9 75 8.0 3.0-16.6

10.0-10.9 109 4.6 1.5-10.411.0-11.9 212 2.4 0.8-5.4

12+ 1411 1.3 0.8-2.0

Carson JL, et al. Lancet 1996;348:1055-60


Preop Hgb by Cardiovascular Disease Interaction P=0.03

1

5

10

14

18

6 7 8 9 10 11 12

Adj

uste

d O

dds

Rat

io

Preoperative Hemoglobin g/dL

CVD- No CVD-Yes


Postop Hgb Level and Mortality in Patients with Hgb < 8 g/dL

Postop Hgb N(300) % 30 day

Mortality

% 30 day Mortality Morbidity

1.1-2 7 100 1002.1-3 24 54.2 91.73.1-4 28 25 52.6

4.1-5 32 34.4 57.7

5.1-6 54 9.3 28.6

6.1-7 56 8.9 22

7.1-8 99 0 9.4

Carson JL, et al. Transfusion 2002Thursday, October 31, 13

Conclusions-Risk of Anemia

• Mortality and morbidity rises as preoperative and postoperative hemoglobin falls

• Animal and human data suggest that patients with CVD may be less tolerant of anemia than patients without CVD


Efficacy of Transfusion Clinical Trials


Exposure to Blood TransfusionCarson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews 2012

Updated


Volume 340 Number 6

·

409

The New England

Journal

of

Medicine

© Copyr ight, 1999, by the Massachusett s Medical Society

VOLUME 340

F

EBRUARY

11, 1999

NUMBER 6

A MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIALOF TRANSFUSION REQUIREMENTS IN CRITICAL CARE

P

AUL

C. H

ÉBERT

, M.D., G

EORGE

W

ELLS

, P

H

.D., M

ORRIS

A. B

LAJCHMAN

, M.D., J

OHN

M

ARSHALL

, M.D., C

LAUDIO

M

ARTIN

, M.D., G

IUSEPPE

P

AGLIARELLO

, M.D., M

ARTIN

T

WEEDDALE

, M.D., P

H

.D., I

RWIN

S

CHWEITZER

, M.S

C

., E

LIZABETH

Y

ETISIR

, M.S

C

.,

AND

THE

T

RANSFUSION

R

EQUIREMENTS

IN

C

RITICAL

C

ARE

I

NVESTIGATORS

FOR

THE

C

ANADIAN

C

RITICAL

C

ARE

T

RIALS

G

ROUP

*

A

BSTRACT

Background

To determine whether a restrictivestrategy of red-cell transfusion and a liberal strategyproduced equivalent results in critically ill patients,we compared the rates of death from all causes at 30days and the severity of organ dysfunction.

Methods

We enrolled 838 critically ill patients witheuvolemia after initial treatment who had hemoglobinconcentrations of less than 9.0 g per deciliter within72 hours after admission to the intensive care unitand randomly assigned 418 patients to a restrictivestrategy of transfusion, in which red cells were trans-fused if the hemoglobin concentration dropped below7.0 g per deciliter and hemoglobin concentrationswere maintained at 7.0 to 9.0 g per deciliter, and 420patients to a liberal strategy, in which transfusionswere given when the hemoglobin concentration fellbelow 10.0 g per deciliter and hemoglobin concentra-tions were maintained at 10.0 to 12.0 g per deciliter.

Results

Overall, 30-day mortality was similar inthe two groups (18.7 percent vs. 23.3 percent, P=0.11). However, the rates were significantly lowerwith the restrictive transfusion strategy among pa-tients who were less acutely ill — those with anAcute Physiology and Chronic Health Evaluation IIscore of «20 (8.7 percent in the restrictive-strategygroup and 16.1 percent in the liberal-strategy group,P=0.03) — and among patients who were less than55 years of age (5.7 percent and 13.0 percent, respec-tively; P=0.02), but not among patients with clinical-ly significant cardiac disease (20.5 percent and 22.9percent, respectively; P=0.69). The mortality rateduring hospitalization was significantly lower in therestrictive-strategy group (22.2 percent vs. 28.1 per-cent, P=0.05).

Conclusions

A restrictive strategy of red-celltransfusion is at least as effective as and possibly su-perior to a liberal transfusion strategy in critically illpatients, with the possible exception of patients withacute myocardial infarction and unstable angina.(N Engl J Med 1999;340:409-17.)

©1999, Massachusetts Medical Society.

From the Critical Care Program (P.C.H., G.P.) and the Clinical Epide-miology Unit (P.C.H, G.W., I.S., E.Y.), University of Ottawa, Ottawa; theDepartment of Pathology, McMaster University, Hamilton, Ont. (M.A.B.);the Critical Care Program, University of Toronto, Toronto (J.M.); the Crit-ical Care Program, University of Western Ontario, London (C.M.); andthe Critical Care Program, University of British Columbia, Vancouver(M.T.) — all in Canada. Address reprint requests to Dr. Hébert at the De-partment of Medicine, Ottawa General Hospital, 501 Smyth Rd., Box 205,Ottawa, ON K1H 8L6, Canada.

*Study investigators are listed in the Appendix.

ED-cell transfusions are a cornerstone ofcritical care practice,

1

but there are diver-gent views on the risks of anemia and thebenefits of transfusion in this setting. One

important concern is that anemia may not be welltolerated by critically ill patients.

2,3

Indeed, two re-cent studies suggested that anemia increases the riskof death after surgery in patients with cardiac disease

2

and in critically ill patients.

3

Red-cell transfusions areused to augment the delivery of oxygen in the hopeof avoiding the deleterious effects of oxygen debt.

4

This view prompted the routine use of transfusionin patients with hemoglobin concentrations that wereoften more than 10.0 g per deciliter in studies eval-uating resuscitation protocols.

5,6

Critically ill patients may, however, be at increasedrisk for the immunosuppressive

7,8

and microcircu-latory

9,10

complications of red-cell transfusions. In ad-dition, concern about the supply and safety of bloodhas also encouraged a conservative approach to trans-fusions. For these reasons, the optimal transfusionpractice for various types of critically ill patients withanemia has not been established.

To elucidate the potential risks of anemia and pos-sible benefits of transfusions in critically ill patients,we conducted a randomized, controlled, clinical trialto determine whether a restrictive approach to red-cell transfusion that maintains hemoglobin concen-trations between 7.0 and 9.0 g per deciliter is equiv-

RThursday, October 31, 13

Transfusion in Critical Care

• Clinical trial in consecutive ICU patients with Hgb < 9.0 g/dL and euvolemia

• Restrictive: blood given when Hgb < 7.0 g/dL and maintained between 7-9 g/dL

• Liberal: blood given when Hgb < 10 g/dL and maintained between 10-12 g/dL

• Primary outcome 30 day mortality

Hebert et al NEJM 1999Thursday, October 31, 13

Outcomes TRICC Trial

Outcome Restrictive N=418

Liberal N=420

Difference (95% CI)

30 day death

18.7% 23.3% 4.7% (0.8-10.2)


Overall Ischemic Heart Disease

Liberal

Restrictive

Restrictive

Liberal


Morbidity Outcomes in TRICC

RestrictiveN (%)

LiberalN (%) P Value

MI 3 (0.7) 12 (2.9) 0.02

Pulmonary Edema

22 (5.3) 45 (10.7) 0.01

ARDS 32 (7.7) 48 (11.4) 0.06


n engl j med 356;16 www.nejm.org april 19, 2007 1609

The new england journal of medicineestablished in 1812 april 19, 2007 vol. 356 no. 16

Transfusion Strategies for Patients in Pediatric Intensive Care Units

Jacques Lacroix, M.D., Paul C. Hébert, M.D., James S. Hutchison, M.D., Heather A. Hume, M.D., Marisa Tucci, M.D., Thierry Ducruet, M.Sc., France Gauvin, M.D., Jean-Paul Collet, M.D., Ph.D.,

Baruch J. Toledano, M.D., Pierre Robillard, M.D., Ari Joffe, M.D., Dominique Biarent, M.D., Kathleen Meert, M.D., and Mark J. Peters, M.D., for the TRIPICU Investigators,* the Canadian Critical Care

Trials Group, and the Pediatric Acute Lung Injury and Sepsis Investigators Network

A BS TR AC T

From Université de Montréal (J.L., H.A.H., M.T., T.D., F.G., B.J.T.) and McGill Univer-sity (P.R.) — both in Montreal; University of Ottawa, Ottawa (P.C.H.); University of Toronto, Toronto ( J.S.H.); University of British Columbia, Vancouver (J.-P.C.); and University of Alberta, Edmonton (A.J.) — all in Canada; Université Libre de Bruxelles, Brussels (D.B.); Wayne State University, Detroit (K.M.); and the Institute of Child Health, London (M.J.P.). Address reprint requests to Dr. Lacroix at the Sainte-Justine Hospital, Rm. 3431, 3175 Côte Sainte-Cath-erine, Montreal, QC H3T 1C5, Canada, or at [email protected].

*Investigators and site investigators of the Transfusion Requirements in the Pediat-ric Intensive Care Unit (TRIPICU) Study are listed in the Appendix.

N Engl J Med 2007;356:1609-19.Copyright © 2007 Massachusetts Medical Society.

BackgroundThe optimal hemoglobin threshold for erythrocyte transfusions in critically ill chil-dren is unknown. We hypothesized that a restrictive transfusion strategy of using packed red cells that were leukocyte-reduced before storage would be as safe as a lib-eral transfusion strategy, as judged by the outcome of multiple-organ dysfunction.

MethodsIn this noninferiority trial, we enrolled 637 stable, critically ill children who had he-moglobin concentrations below 9.5 g per deciliter within 7 days after admission to an intensive care unit. We randomly assigned 320 patients to a hemoglobin threshold of 7 g per deciliter for red-cell transfusion (restrictive-strategy group) and 317 patients to a threshold of 9.5 g per deciliter (liberal-strategy group).

ResultsHemoglobin concentrations were maintained at a mean (±SD) level that was 2.1±0.2 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group (lowest average levels, 8.7±0.4 and 10.8±0.5 g per deciliter, respectively; P<0.001). Pa-tients in the restrictive-strategy group received 44% fewer transfusions; 174 patients (54%) in that group did not receive any transfusions, as compared with 7 patients (2%) in the liberal-strategy group (P<0.001). New or progressive multiple-organ dysfunction syndrome (the primary outcome) developed in 38 patients in the restrictive-strategy group, as compared with 39 in the liberal-strategy group (12% in both groups) (ab-solute risk reduction with the restrictive strategy, 0.4%; 95% confidence interval, –4.6 to 5.4). There were 14 deaths in each group within 28 days after randomization. No significant differences were found in other outcomes, including adverse events.

ConclusionsIn stable, critically ill children a hemoglobin threshold of 7 g per deciliter for red-cell transfusion can decrease transfusion requirements without increasing adverse out-comes. (Controlled-trials.com number, ISRCTN37246456.)

Copyright © 2007 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by JEFFREY L. CARSON MD on October 6, 2007 .


Transfusion Requirements in the Pediatric Intensive Care Unit

TRIPICU

• Critically ill children 3 days to 14 years

• Hgb of 9.5 g/dL or less

• 7 g/dL vs 9.5 g/dL thresholds compared

• Primary outcome: new or progressive multiple-organ dysfunction syndrome

Lacroix et al. N Engl J Med 2007


CARING FOR THECRITICALLY ILL PATIENT

Transfusion RequirementsAfter Cardiac SurgeryThe TRACS Randomized Controlled TrialLudhmila A. Hajjar, MD, PhDJean-Louis Vincent, MD, PhDFilomena R. B. G. Galas, MD, PhDRosana E. Nakamura, MDCarolina M. P. Silva, MDMarilia H. Santos, MD, PhDJulia Fukushima, MScRoberto Kalil Filho, MD, PhDDenise B. Sierra, MDNeuza H. Lopes, MD, PhDThais Mauad, MD, PhDAretusa C. Roquim, MDMarcia R. Sundin, MDWanderson C. Leao, MDJuliano P. Almeida, MDPablo M. Pomerantzeff, MD, PhDLuis O. Dallan, MD, PhDFabio B. Jatene, MD, PhDNoedir A. G. Stolf, MD, PhDJose O. C. Auler Jr, MD, PhD

CARDIAC SURGERY IS ASSOCIATEDwith a high rate of allogeneicbloodtransfusion,varyingfrom40%to90%inmost reports.1-3

Therationale forperioperative redbloodcell (RBC)transfusionisbasedontheob-servation that anemia is an independentriskfactor formorbidityandmortalityaf-tercardiacoperations.4,5 However, trans-fusions have been associated with highrates of morbidity and mortality in criti-cally ill patients,6 and some recent stud-ieshaveshownworseoutcomes, includ-ing increased occurrence of renal failureand infection, as well as respiratory, car-

diac, and neurologic complications, intransfusedcomparedwithnontransfusedpatients after cardiac surgery.7,8

There is a lack of evidence regardingoptimalbloodtransfusionpractice inpa-tients undergoing cardiac surgery.9 On

See also pp 1568 and 1610.

Author Affiliations: Surgical Intensive Care Unit andDepartment of Anesthesiology, Heart Institute (InCor),Hospital das Clinicas da Faculdade de Medicina daUniversidadedeSaoPaulo, SaoPaulo,Brazil (DrsHajjar,Galas,Nakamura, Silva, Santos,Kalil Filho, Sierra, Lopes,Mauad,Roquim,Sundin, Leao,Almeida,Pomerantzeff,Dallan, Jatene, Stolf, andAuler andMsFukushima); andDepartmentof IntensiveCare, ErasmeHospital,Univer-

site Libre de Bruxelles, Brussels, Belgium (Dr Vincent).Corresponding Author: Jean-Louis Vincent, MD, PhD,Department of Intensive Care, Erasme University Hos-pital, Route de Lennik 808, B-1070 Brussels, Belgium([email protected]).Caring for the Critically Ill Patient Section Editor: DerekC. Angus, MD, MPH, Contributing Editor, JAMA([email protected]).

Context Perioperative red blood cell transfusion is commonly used to address ane-mia, an independent risk factor for morbidity and mortality after cardiac operations;however, evidence regarding optimal blood transfusion practice in patients undergo-ing cardiac surgery is lacking.

Objective To define whether a restrictive perioperative red blood cell transfusionstrategy is as safe as a liberal strategy in patients undergoing elective cardiac surgery.

Design, Setting, and Patients The Transfusion Requirements After Cardiac Sur-gery (TRACS) study, a prospective, randomized, controlled clinical noninferiority trialconducted between February 2009 and February 2010 in an intensive care unit at auniversity hospital cardiac surgery referral center in Brazil. Consecutive adult patients(n=502) who underwent cardiac surgery with cardiopulmonary bypass were eligible;analysis was by intention-to-treat.

Intervention Patients were randomly assigned to a liberal strategy of blood trans-fusion (to maintain a hematocrit !30%) or to a restrictive strategy (hematocrit !24%).

Main Outcome Measure Composite end point of 30-day all-cause mortality andsevere morbidity (cardiogenic shock, acute respiratory distress syndrome, or acute re-nal injury requiring dialysis or hemofiltration) occurring during the hospital stay. Thenoninferiority margin was predefined at !8% (ie, 8% minimal clinically important in-crease in occurrence of the composite end point).

Results Hemoglobinconcentrationsweremaintainedatameanof10.5g/dL (95%con-fidence interval [CI], 10.4-10.6) in the liberal-strategy group and 9.1 g/dL (95% CI, 9.0-9.2) in the restrictive-strategy group (P" .001). A total of 198 of 253 patients (78%) inthe liberal-strategy group and 118 of 249 (47%) in the restrictive-strategy group receiveda blood transfusion (P" .001). Occurrence of the primary end point was similar betweengroups (10% liberal vs 11% restrictive; between-group difference, 1% [95% CI, !6% to4%]; P=.85). Independent of transfusion strategy, the number of transfused red bloodcell units was an independent risk factor for clinical complications or death at 30 days (haz-ard ratio for each additional unit transfused, 1.2 [95% CI, 1.1-1.4]; P=.002).

Conclusion Among patients undergoing cardiac surgery, the use of a restrictive peri-operative transfusion strategy compared with a more liberal strategy resulted in noninfe-rior rates of the combined outcome of 30-day all-cause mortality and severe morbidity.

Trial Registration clinicaltrials.gov Identifier: NCT01021631JAMA. 2010;304(14):1559-1567 www.jama.com

©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, October 13, 2010—Vol 304, No. 14 1559

Downloaded From: http://jama.jamanetwork.com/ by a University of Medicine & Dentistry of NJ User on 06/02/2013


Original Article Liberal or Restrictive Transfusion in High-Risk

Patients after Hip SurgeryJeffrey L. Carson, M.D., Michael L. Terrin, M.D., M.P.H., Helaine Noveck, M.P.H., David

W. Sanders, M.D., Bernard R. Chaitman, M.D., George G. Rhoads, M.D., M.P.H., George Nemo, Ph.D., Karen Dragert, R.N., Lauren Beaupre, P.T., Ph.D., Kevin Hildebrand, M.D.,

William Macaulay, M.D., Courtland Lewis, M.D., Donald Richard Cook, B.M.Sc., M.D., Gwendolyn Dobbin, C.C.R.P., Khwaja J. Zakriya, M.D., Fred S. Apple, Ph.D., Rebecca A.

Horney, B.A., Jay Magaziner, Ph.D., M.S.Hyg., for the FOCUS Investigators

N Engl J MedVolume 365(26):2453-2462

December 29, 2011


FOCUS Methods• RCT in hip fracture patients

• CVD or CVD risk factors

• Hemoglobin < 10 g/dL

• Liberal (10 g/dL) vs Restrictive (8 g/dL or symptoms) Transfusion

• Function, mortality, myocardial infarction, morbidity

• 2016 patients from 47 centers in US and Canada


TotalN=2016

LiberalN=1007

RestrictiveN=1009

Age (+SD) 81.6 (+8.9) 81.8 (+ 8.8) 81.5 (+9.0)

Female 75.7% 75.2% 76.3%

Any CVD 62.9% 63.3% 62.6%

Coronary artery disease

39.9% 39.9% 39.9%

CHF 17.4% 18.3% 16.6%

Peripheral vascular disease 10.9% 11.6% 10.1%

Stroke or TIA 23.5% 24.7% 22.2%

DM 25.2% 25.1% 25.4%

Clinical Characteristics


Hgb and TransfusionsLiberal

N=1007RestrictiveN=1009

Hgb Prior to Transfusion 9.2 (SD+0.5) 7.9 (SD+0.6)

Transfused Patients 974 (96.7%) 415 (41.0%)

Median Units Transfused

2.0 (interquartile

range, 1,2)

0 (interquartile

range, 0,1) Total Units Transfused

1866 units 652 units


Primary Outcome: Not Walking or Dead at 60 days

LiberalN=1007

RestrictiveN=1009

Risk Difference(95% CI)

Odds Ratio(95% CI)

60 days 351 (35.2%) 347 (34.7%) 0.5% (-3.7% to 4.7%)

1.01(0.84 to 1.22)

30 days 459 (46.1%) 481 (48.1%) -2.0% (-7.7 to 3.8)*

0.92 (0.73 to 1.16)*

*99% Confidence Intervals for secondary outcomes


Mortality

0%

2%

4%

6%

8%

10%

In-hospital 30 Day 60 Day

6.6%

4.3%

1.4%

7.6%

5.2%

2%

Liberal Restrictive

all p=NS


Post Randomization Cardiac Events

LiberalN=1005

RestrictiveN=1008

Absolute risk difference (99% CI)

Odds Ratio (99% CI)

Elevated troponin 62 (6.2%) 59 (5.9%) 0.3%

(-2.4% to 3.1%)1.06

(0.65 to 1.71)

MI 23 (2.3%) 38 (3.8%) -1.5%(-3.5 to 0.5)

0.60 (0.30-1.19)

In-hospital mortality 20 (2.0%) 14 (1.4%) 0.6%

(-0.9% to 2.1%)1.44

(0.58 to 3.56)MI, unstable angina or

Death43 (4.3%) 52 (5.2%) -0.9%

(-3.3 to1.6)0.82

(0.48 to 1.42)


!

Delirium SeverityGruber-Baldini J Am Geriatr Soc 61:1286–1295, 2013


Days from Randomization to Discharge

LiberalN=1007

RestrictiveN=1009

Mean + SDMean + SD

US - N=1220 3.67 + 3.38 3.97 + 3.89

Canada- N=791 12.03 + 9.31 12.70 + 9.48

p=NS


n engl j med 368;1 nejm.org january 3, 2013 11

The new england journal of medicineestablished in 1812 january 3, 2013 vol. 368 no. 1

Transfusion Strategies for Acute Upper Gastrointestinal Bleeding

Càndid Villanueva, M.D., Alan Colomo, M.D., Alba Bosch, M.D., Mar Concepción, M.D., Virginia Hernandez-Gea, M.D., Carles Aracil, M.D., Isabel Graupera, M.D., María Poca, M.D.,

Cristina Alvarez-Urturi, M.D., Jordi Gordillo, M.D., Carlos Guarner-Argente, M.D., Miquel Santaló, M.D., Eduardo Muñiz, M.D., and Carlos Guarner, M.D.

A BS TR AC T

From the Gastrointestinal Bleeding Unit, Department of Gastroenterology (C.V., A.C., M.C., V.H.-G., C.A., I.G., M.P., C.A.-U., J.G., C.G.-A., C.G.), Blood and Tissue Bank (A.B., E.M.), and the Semi-Critical Unit (M.S.), Hospital de Sant Pau, Autonomous University, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (C.V., A.C., I.G., C.G.) — all in Barcelona. Address reprint requests to Dr. Villa-nueva at Servei de Patologia Digestiva, Hospital de la Santa Creu i Sant Pau, Mas Casanovas, 90. 08025 Barcelona, Spain, or at [email protected].

N Engl J Med 2013;368:11-21.DOI: 10.1056/NEJMoa1211801Copyright © 2013 Massachusetts Medical Society.

BackgroundThe hemoglobin threshold for transfusion of red cells in patients with acute gastro-intestinal bleeding is controversial. We compared the efficacy and safety of a re-strictive transfusion strategy with those of a liberal transfusion strategy.

MethodsWe enrolled 921 patients with severe acute upper gastrointestinal bleeding and ran-domly assigned 461 of them to a restrictive strategy (transfusion when the hemo-globin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis.

ResultsA total of 225 patients assigned to the restrictive strategy (51%), as compared with 65 assigned to the liberal strategy (15%), did not receive transfusions (P<0.001). The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P = 0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P = 0.01), and adverse events oc-curred in 40% as compared with 48% (P = 0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child–Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child–Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P = 0.03) but not in those assigned to the restrictive strategy.

ConclusionsAs compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.)

The New England Journal of Medicine Downloaded from nejm.org by JEFFREY CARSON on January 2, 2013. For personal use only. No other uses without permission.

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Methods

• Adults with hematemesis or melena

• Selected exclusions:

• Massive exsanguinating bleeding

• Acute coronary syndrome or other cardiovascular disease

• Hemoglobin level > 12 g/dL


Transfusion Protocol and Outcomes

• Restrictive: 7 g/dL with target 7-9

• Liberal: 9 g/dl with target 9-11

• In both groups, patients received one unit immediately.

• Primary outcome: Death at 45 days

• Secondary outcomes: further bleeding defined as hematemeis, fresh melena with bp <100 or puls


Rate of Survival, According to Subgroup.

Villanueva C et al. N Engl J Med 2013;368:11-21

Rate of Survival, According to Subgroup.


Liberal versus restrictive transfusion thresholds forpatients with symptomatic coronary artery diseaseJeffrey L. Carson, MD, a Maria Mori Brooks, PhD, b J. Dawn Abbott, MD, c Bernard Chaitman, MD, d

Sheryl F. Kelsey, PhD, b Darrell J. Triulzi, MD, e Vankeepuram Srinivas, MD, f Mark A. Menegus, MD, f

Oscar C. Marroquin, MD, g Sunil V. Rao, MD, h Helaine Noveck, MPH, a Elizabeth Passano, MS, b

Regina M. Hardison, MS, b Thomas Smitherman, MD, g Tudor Vagaonescu, MD, i Neil J. Wimmer, MD, j andDavid O. Williams, MD j New Brunswick, NJ; Pittsburgh, PA; Providence, RI; Saint Louis, MO; New York, NY;Durham, NC; and Boston, MA

Background Prior trials suggest it is safe to defer transfusion at hemoglobin levels above 7 to 8 g/dL in most patients.Patients with acute coronary syndrome may benefit from higher hemoglobin levels.

Methods We performed a pilot trial in 110 patients with acute coronary syndrome or stable angina undergoing cardiaccatheterization and a hemoglobin b10 g/dL. Patients in the liberal transfusion strategy received one or more units of blood toraise the hemoglobin level !10 g/dL. Patients in the restrictive transfusion strategy were permitted to receive blood forsymptoms from anemia or for a hemoglobin b8 g/dL. The predefined primary outcome was the composite of death,myocardial infarction, or unscheduled revascularization 30 days post randomization.

Results Baseline characteristics were similar between groups except age (liberal, 67.3; restrictive, 74.3). The meannumber of units transfused was 1.6 in the liberal group and 0.6 in the restrictive group. The primary outcome occurred in 6patients (10.9%) in the liberal group and 14 (25.5%) in the restrictive group (risk difference = 15.0%; 95% confidence intervalof difference 0.7% to 29.3%; P = .054 and adjusted for age P = .076). Death at 30 days was less frequent in liberal group(n = 1, 1.8%) compared to restrictive group (n = 7, 13.0%; P = .032).

Conclusions The liberal transfusion strategy was associated with a trend for fewer major cardiac events and deaths than amore restrictive strategy. These results support the feasibility of and the need for a definitive trial. (Am Heart J 2013;0:1-8.e1.)

Recently, published guidelines recommended that clini-cians adopt a restrictive transfusion strategy inmost acutelyill patients.1,2 Patients with coronary artery diseasefrequently become anemic and receive transfusion becausethey have pre-existing anemia, undergo invasive pro-cedures, and receive multiple classes of anticoagulants.3

Moderate anemia may result in increased rates ofmyocardial ischemia and infarction in patients with pre-existing coronary lesions that limit myocardial oxygendelivery.4 Observational studies examining the associationbetween transfusion and outcomes document an associa-tion between transfusion and increased.5 These studies arelimited by confounding (more severely ill patients also getmore transfusions), making causal inferences impossible.6,7

However, there are no clinical trials to guide transfusiondecisions in patients with acute coronary syndrome. Theabsence of high quality evidence contributes to theongoing large variation in clinical practice8

Given this uncertainty, we undertook a multicenterpilot trial to evaluate the feasibility and outcomes of aliberal transfusion strategy compared to a restrictivetransfusion strategy in patients with symptomatic coro-nary artery disease including acute coronary syndromes.

MethodsStudy populationWe enrolled patients from 8 US hospitals from March 15, 2010

to May 8, 2012 who were: (1) greater than 18 years of age; (2)

From the aDivision of General Internal Medicine, University of Medicine and Dentistry of NewJersey, Robert Wood Johnson Medical School, New Brunswick, NJ, bDepartment ofEpidemiology, University of Pittsburgh, Pittsburgh, PA, cDivision of Cardiology, Rhode IslandHospital, Alpert Medical School, Brown University, Providence, RI, dDepartment of Medicine,Saint Louis University, Saint Louis, MO, eInstitute for Transfusion Medicine, University ofPittsburgh School of Medicine, Pittsburgh, PA, fDivision of Cardiology, Albert Einstein Collegeof Medicine, New York, NY, gDivision of Cardiology, University of Pittsburgh School ofMedicine, Pittsburgh, PA, hDuke Clinical Research Institute, Duke University, Durham, NC,iDivision of Cardiology, University of Medicine and Dentistry of New Jersey, Robert WoodJohnson Medical School, New Brunswick, NJ, and jCardiovascular Division, Brigham andWomen's Hospital, Harvard Medical School, Boston, MA.T. Bruce Ferguson, Jr, MD, served as guest editor for this article.RCT reg #NCT01167582.Submitted November 27, 2012; accepted March 5, 2013.Reprint requests: Jeffrey L. Carson, MD, Division of General Internal Medicine, RobertWood Johnson Medical School, New Brunswick, NJ.E-mail: [email protected]/$ - see front matter© 2013, Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.ahj.2013.03.001

Funded by National Heart, Lung, Blood InstituteAmerican Heart Journal 2013


MINT Methods

• RCT; pilot study in 110 patients

• ACS (STEMI, NSTEMI, Unstable angina) and Stable coronary artery disease patient undergoing cardiac catherization during the index hospitalization

• Hemoglobin < 10 g/dL

• Liberal (10 g/dL) vs Restrictive (8 g/dL or symptoms)

• Feasibility and clinical outcomesThursday, October 31, 13

Clinical Endpoints at 30 Days

AN=55

BN=54


Death/MI/Revascularization 6 (10.9%) 14 (25.9%)

15.0%(0.7 to 29.3)*

Death 1 (1.8%) 7 (13.0%) 11.2%**(1.5 to 20.8)

MI 5 (9.1%) 7 (13.0%) 13.0%(-7.9 to15.6)

Revascularization 0 (0.0%) 2 (3.7%) 3.7%(-1.3 to 8.7)

*p=0.054, adjusted for age p=0.076 **p=0.032


Clinical Endpoints at 30 Days

LiberalN=55

RestrictiveN=54


Death/MI/Revascularization 6 (10.9%) 14 (25.9%)

15.0%(0.7 to 29.3)*

Death 1 (1.8%) 7 (13.0%) 11.2%**(1.5 to 20.8)

MI 5 (9.1%) 7 (13.0%) 13.0%(-7.9 to15.6)

Revascularization 0 (0.0%) 2 (3.7%) 3.7%(-1.3 to 8.7)

*p=0.054, adjusted for age p=0.076 **p=0.032


p=0.032


Transfusion thresholds and other strategies for guidingallogeneic red blood cell transfusion (Review)

Carson JL, Carless PA, Hebert PC

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 4

http://www.thecochranelibrary.com

Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


CLINICIAN’S CORNERJAMA CLINICAL EVIDENCE SYNOPSIS

Outcomes Using Lower vs HigherHemoglobin Thresholdsfor Red Blood Cell Transfusion

Jeffrey L. Carson, MDPaul A. Carless, MMedSc (Clin Epid)Paul C. Hebert, MD, MSc

TH E O P T I M A L H E M O G L O B I N/hematocrit criterion for transfu-sion remains controversial in sev-

eral clinical settings.1 New evidence maybest guide clinical practice. This up-dated Cochrane evidence includes 9 ad-ditional studies summarizing a total of19 randomized controlled clinical trialsinvolving more than 6000 patients thatcompared clinical outcomes betweenstrategies using a higher vs lower he-moglobin/hematocrit threshold for redblood cell transfusion.2

SUMMARY OF FINDINGSThe hemoglobin transfusion thresholdused in the study groups testing lowerthresholdsfortransfusionvariedfrom7.0to 10.0 g/dL. In the comparison groups,

hemoglobin levelsweremostcommonlymaintained at 9.0 to 13.3 g/dL.

A lower hemoglobin threshold fortransfusion was associated with re-duced red blood cell transfusion (meandifference,!1.19 units per patient; 95%CI, !1.85 to !0.53). The hemoglo-bin concentration of patients random-ized to the lower hemoglobin thresh-old for transfusion was significantly lessat the end of the studies than the he-moglobin concentration of patients ran-domized to a higher threshold for trans-

fusion (mean difference,!1.48 g/dL;95% CI, !1.92 to !1.03).

The relative risk (RR) for 30-day all-cause mortality was 0.85 (95% CI, 0.70to 1.03) (FIGURE). Hospital mortalitywas lower in patients randomized to alower hemoglobin threshold for trans-fusion vs those randomized to a higherhemoglobin threshold (RR,0.77; 95%CI, 0.62 to 0.95). There were no dif-ferences in all-cause mortality at 14-day or 60-day follow-up or in inten-sive care unit (ICU) mortality.

Clinical Question: Is a lower vs higher hemoglobin threshold best for minimizing both red bloodcell use and adverse clinical outcomes when used to trigger red blood cell transfusions in anemicpatients in critical care and acute care settings?

Bottom Line: Compared with higher hemoglobin thresholds, a hemoglobin threshold of 7 or 8 g/dLis associated with fewer red blood cell units transfused without adverse associations with mortal-ity, cardiac morbidity, functional recovery, or length of hospital stay.

For editorial comment see p 89.

Author Affiliations are listed at the end of thisarticle.Corresponding Author: Jeffrey L. Carson, MD, Divi-sion of General Internal Medicine, UMDNJ-RobertWood Johnson Medical School, 125 Paterson St, NewBrunswick, NJ 08903 ([email protected]).JAMA Clinical Evidence Synopsis Section Editor:Mary McGrae McDermott, MD, ContributingEditor. We encourage authors to submit papersfor consideration as a JAMA Clinical Evidence Syn-opsis. Please contact Dr McDermott at [email protected].

Figure. Association of a Higher vs Lower Hemoglobin Threshold on 30-Day Mortality inPatients With Anemia

Favors LowerHemoglobin

Threshold

Favors HigherHemoglobinThreshold

LowerHemoglobinThreshold

HigherHemoglobinThreshold

SourceBlair, 1986Bracey, 1999Bush, 1997Carson, 1998Carson, 2011Foss, 2009Hajjar, 2010Hebert, 1995Hebert, 1999Lacroix, 2007

Events,No.

0341

435

158

7814

0

Total,No.

26215

5042

100960

24933

418320

62

Events,No.

2641

520

139

9814

0

Total,No.

24222

4942

100760

25336

420317

65Lotke, 1999

Heterogeneity: I2 = 0%Test for overall effect: P = .10

Overall random effects model

Risk Ratio(95% CI)

0.19 (0.01-3.67)0.52 (0.13-2.04)0.98 (0.26-3.70)1.00 (0.06-15.47)0.83 (0.56-1.22)

11.00 (0.62-194.63)1.17 (0.57-2.41)0.97 (0.42-2.22)0.80 (0.61-1.04)0.99 (0.48-2.04)

NA

0.85 (0.70-1.03)

0.005 0.1 1 10 200Risk Ratio (95% CI)

30-d Mortality

30-Day mortality was evaluated in 4975 patients included in 11 of 19 trials. Adapted from Analysis 3.2 in Car-son JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood celltransfusion. Cochrane Database Syst Rev. 2012;4:CD002042. doi:10.1002/14651858.CD002042.pub3

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JAMA 2013


30-Day MortalityCarson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews Update 2012

UpdateThursday, October 31, 13

Updated 30-Day MortalityCarson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews 2012 Updated 10-13


Myocardial InfarctionCarson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews Update 2012

Update


InfectionCarson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews Update 2012

Update


Summary-Clinical Trial Data

• 7,167 patients enrolled in clinical trials evaluating transfusion thresholds

• Most trials are small and only one (FOCUS) is larger than 1000 patients

• Results consistently suggest restrictive transfusion approach is safe

• No adequately powered RCT in acute coronary syndrome


Efficacy of Transfusion Observational Studies


Meta-analysis of Observational Studies

• Evaluate efficacy of RBC transfusion

• 45 observational studies; 272,596 patients

• In 42 of 45 studies, the risk of transfusion out-weighed the benefit


Transfusion and Mortality

Marik and Corwin Crit Care Med 2008Thursday, October 31, 13

Association of Blood Transfusion With Increased Mortality in Myocardial Infarction:

A Meta-analysis

Chatterjee et al. Arch Intern Med. 2012


Association of Transfusion and ACS

Nadir Hematocrit Adjusted Odds Ratio of 30-Day Death (95% CI)

0.35 291 (10-827)

0.30 169 (7-3798)

0.25 1.13 (0.70-1.82)

0.20 1.59 (0.95-2.66)

JAMA. 2004;292:1555-1562Thursday, October 31, 13

effect of red cell transfusion on health-related quality of life after cardiac surgery.Ann Thorac Surg. 2006;82(1):13-20.

24. Deeks JJ, Dinnes J, D’Amico R, et al; International Stroke Trial Collaborative Group;European Carotid Surgery Trial Collaborative Group. Evaluating non-randomised intervention studies. Health Technol Assess. 2003;7(27):iii-x, 1-173.

25. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals in-sufficient information size and potentially false positive results in manymeta-analyses. J Clin Epidemiol. 2008;61(8):763-769.

26. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may estab-lish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol.2008;61(1):64-75.

27. Thorlund K, Imberger G, Walsh M, et al. The number of patients and events re-quired to limit the risk of overestimation of intervention effects in meta-analysis—a simulation study. PLoS One. 2011;6(10):e25491. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196500/. Accessed October 6, 2012.

28. Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information sizeby quantifying diversity in random-effects model meta-analyses. BMC MedRes Methodol. 2009;9:86. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809074/. Accessed October 5, 2012.

29. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics.1979;35(3):549-556.

30. Aronson D, Dann EJ, Bonstein L, et al. Impact of red blood cell transfusion onclinical outcomes in patients with acute myocardial infarction. Am J Cardiol. 2008;102(2):115-119.

31. Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red celltransfusion in acute myocardial infarction (the CRIT Randomized Pilot Study).Am J Cardiol. 2011;108(8):1108-1111.

32. Jani SM, Smith DE, Share D, et al. Blood transfusion and in-hospital outcomesin anemic patients with myocardial infarction undergoing percutaneous coro-nary intervention. Clin Cardiol. 2007;30(10)(suppl 2):II49-II56.

33. Jolicoeur EM, O’Neill WW, Hellkamp A, et al; APEX-AMI Investigators. Transfu-sion and mortality in patients with ST-segment elevation myocardial infarctiontreated with primary percutaneous coronary intervention. Eur Heart J. 2009;30(21):2575-2583.

34. Nikolsky E, Mehran R, Sadeghi HM, et al. Prognostic impact of blood transfu-sion after primary angioplasty for acute myocardial infarction: analysis from theCADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angi-oplasty Complications) Trial. JACC Cardiovasc Interv. 2009;2(7):624-632.

35. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion andclinical outcomes in patients with acute coronary syndromes. JAMA. 2004;292(13):1555-1562.

36. Shishehbor MH, Filby SJ, Chhatriwalla AK, et al. Impact of drug-eluting versusbare-metal stents on mortality in patients with anemia. JACC Cardiovasc Interv.2009;2(4):329-336.

37. Singla I, Zahid M, Good CB, Macioce A, Sonel AF. Impact of blood transfusionsin patients presenting with anemia and suspected acute coronary syndrome. AmJ Cardiol. 2007;99(8):1119-1121.

38. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion inelderly patients with acute myocardial infarction. N Engl J Med. 2001;345(17):1230-1236.

39. Yang X, Alexander KP, Chen AY, et al; CRUSADE Investigators. The implicationsof blood transfusions for patients with non-ST-segment elevation acute coro-nary syndromes: results from the CRUSADE National Quality ImprovementInitiative. J Am Coll Cardiol. 2005;46(8):1490-1495.

40. Stroup DF, Berlin JA, Morton SC, et al; Meta-analysis of Observational Studiesin Epidemiology (MOOSE) Group. Meta-analysis of observational studies in epi-demiology: a proposal for reporting: Meta-analysis Of Observational Studies inEpidemiology (MOOSE) group. JAMA. 2000;283(15):2008-2012.

41. Wells GA, Shea B, O’Connell D, et al; Ottawa Hospital Research Institute. TheNewcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised stud-ies in meta-analyses: case-control studies. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed March 2012.

42. Song F. Exploring heterogeneity in meta-analysis: is the L’Abbe plot useful? J ClinEpidemiol. 1999;52(8):725-730.

43. Kumbhani DJ, Bhatt DL. Platelet activation: yet another strike against routineTRANSFUSION. Eur Heart J. 2010;31(22):2712-2714.

44. Silvain J, Pena A, Cayla G, et al. Impact of red blood cell transfusion on plateletactivation and aggregation in healthy volunteers: results of the TRANSFUSIONstudy. Eur Heart J. 2010;31(22):2816-2821.

45. Carson JL, Grossman BJ, Kleinman S, et al; Clinical Transfusion Medicine Com-mittee of the AABB. Red blood cell transfusion: a clinical practice guideline fromthe AABB. Ann Intern Med. 2012;157(1):49-58.

46. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategiesfor guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev.2012;4:CD002042.

47. Valente S, Lazzeri C, Chiostri M, et al. The impact of blood transfusion on shortand long term prognosis in STEMI patients treated with primary percutaneouscoronary intervention: a single center–experience. Int J Cardiol. 2012;157(2):281-283.

48. Alexander KP, Chen AY, Wang TY, et al; CRUSADE Investigators. Transfusionpractice and outcomes in non-ST-segment elevation acute coronary syndromes.Am Heart J. 2008;155(6):1047-1053.

49. Twomley KM, Rao SV, Becker RC. Proinflammatory, immunomodulating, andprothrombotic properties of anemia and red blood cell transfusions. J ThrombThrombolysis. 2006;21(2):167-174.

50. Urbich C, Dernbach E, Aicher A, Zeiher AM, Dimmeler S. CD40 ligand inhibitsendothelial cell migration by increasing production of endothelial reactive oxy-gen species. Circulation. 2002;106(8):981-986.

INVITED COMMENTARY

Here We Go Again—Blood Transfusion Kills Patients?

D o blood transfusions kill more patients with anacute myocardial infarction than anemia? Chat-terjee and colleagues1 would have you believe

that they do. We remain unconvinced.In reviewing the study, we first wondered whether the

authors asked the right question. As physicians, we be-lieve that profound anemia is life threatening,2 and as aconsequence transfusions in many patients are life sav-ing. Therefore, we expected that more nuanced, clini-cally relevant questions would be addressed.

For instance, we should be asking: “What is a safe he-moglobin transfusion trigger in most patients?” Or, “Whichpatients experiencing an acute myocardial infarction areat greater risk for transfusions or anemia than others?”

In a synthesis of the literature focused on the issue ofharms, the authors summarized results from 10 studies

that included a total of 203 665 patients.1 The system-atic review identified only one small randomized trial3

and went on to conduct a meta-analysis of observa-tional studies that compared patients who underwenttransfusion with patients who did not undergo transfu-sion. Chatterjee and colleagues1 documented that18.2% of patients transfused died compared with 10.2%of patients not transfused. This represented a weightedabsolute risk increase of 12% or a number needed toharm of 8.

Clinically important information is missing from thisanalysis. Perhaps most important, the investigators didnot adequately consider the hemoglobin concentrationbefore transfusion. The authors did analyze the studystratified by a pretransfusion hemoglobin concentra-tion of less than 10 g/dL (to convert hemoglobin con-

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Summary-Observational Studies

• Results from observational studies mostly found that transfusion was harmful

• The effect of transfusion cannot be reliably evaluated in an observational study


Optimal Transfusion Threshold

The Sweet Spot:Benefit Outweigh Risks?


Assumptions

• Transfusion saves lives

• Issue is at what hemoglobin level

• Likely to vary depending on clinical setting and predominant pathophysiology


Risks (Constant) vs Benefits (Vary)

Lower...............Hemoglobin..............Higher

Risk Benefit

Optimal Threshold


Risks (Vary) vs Benefits (Constant)

Risk Benefit

Optimal Threshold



Risks (Constant) vs Benefits (Vary But Greater)Acute Coronary Syndrome?


Risk Benefit

Optimal Threshold


Risks (Vary) vs Benefits (Vary)GI Bleeding


Risk Benefit

Optimal Threshold


Preliminary Ideas

• The data suggests that possibility of some harm from transfusion

• Amount of harm varies depending on clinical setting

• GI bleed vs cardiac ischemia

• The optimal transfusion threshold will vary depending on the predominant pathophysiology


++

Clinical Guidelines

Annals of Internal MedicineAnnals of Internal Medicinewww.annals.org

First published First published March 26, 2012 on annals.org.March 26, 2012 on annals.org.

Red Blood Cell Transfusion: A ClinicalPractice Guideline From the AABBJeffrey L. CarsonJeffrey L. Carson, MD, MD; ; Brenda J. GrossmanBrenda J. Grossman, MD, MPH, MD, MPH; ; Steven KleinmanSteven Kleinman,,MDMD; ; Alan T. TinmouthAlan T. Tinmouth, MD, MD; ; Marisa B. MarquesMarisa B. Marques, MD, MD; ; Mark K. FungMark K. Fung, MD,, MD,PhDPhD; ; John B. HolcombJohn B. Holcomb, MD, MD; ; Orieji IllohOrieji Illoh, MD, MD; ; Lewis J. KaplanLewis J. Kaplan, MD, MD;;Louis M. KatzLouis M. Katz, MD, MD; ; Sunil V. RaoSunil V. Rao, MD, MD; ; John D. RobackJohn D. Roback, MD, PhD, MD, PhD;;Aryeh ShanderAryeh Shander, MD, MD; ; Aaron A.R. TobianAaron A.R. Tobian, MD, PhD, MD, PhD; ; Robert WeinsteinRobert Weinstein,,MDMD; ; Lisa Grace Swinton McLaughlinLisa Grace Swinton McLaughlin, MD, MD; and ; and Benjamin DjulbegovicBenjamin Djulbegovic,,MD, PhDMD, PhD, , for the Clinical Transfusion Medicine Committee of thefor the Clinical Transfusion Medicine Committee of theAABBAABB*

Author Affiliations

Abstract

Description:Description: Although approximately 85 million units of red blood cells (RBCs)are transfused annually worldwide, transfusion practices vary widely. The AABB(formerly, the American Association of Blood Banks) developed this guideline toprovide clinical recommendations about hemoglobin concentration thresholdsand other clinical variables that trigger RBC transfusions in hemodynamicallystable adults and children.

Methods:Methods: These guidelines are based on a systematic review of the literature onrandomized clinical trials evaluating transfusion thresholds. We performed aliterature search from 1950 to February 2011 with no language restrictions. Weexamined the proportion of patients who received any RBC transfusion and thenumber of RBC units transfused to describe the effect of restrictive transfusionstrategies on RBC use. To determine the clinical consequences of restrictivetransfusion strategies, we examined overall mortality, nonfatal myocardialinfarction, cardiac events, pulmonary edema, stroke, thromboembolism, renalfailure, infection, hemorrhage, mental confusion, functional recovery, and lengthof hospital stay.

Recommendation 1:Recommendation 1: The AABB recommends adhering to a restrictivetransfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strongrecommendation; high-quality evidence).

Recommendation 2:Recommendation 2: The AABB suggests adhering to a restrictive strategy inhospitalized patients with preexisting cardiovascular disease and consideringtransfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less(Grade: weak recommendation; moderate-quality evidence).

Recommendation 3:Recommendation 3: The AABB cannot recommend for or against a liberal orrestrictive transfusion threshold for hospitalized, hemodynamically stablepatients with the acute coronary syndrome (Grade: uncertain recommendation;very low-quality evidence).

Recommendation 4:Recommendation 4: The AABB suggests that transfusion decisions beinfluenced by symptoms as well as hemoglobin concentration (Grade: weakrecommendation; low-quality evidence).

Approximately 15 million red blood cell (RBC) units are transfused annually in theUnited States (1); about 85 million are transfused annually worldwide (2).Although there are many potential reasons for the different RBC transfusionpractices that exist throughout the world, one reason may be the limited high-quality evidence of the benefits and harms of RBC transfusions.


Key Principles• Focus on hemoglobin concentration thresholds

and other clinical parameters that might trigger transfusion

• Hemodynamically stable

• Based on Cochrane systematic review

• We limited the systematic review to randomized clinical trials because this study design provides the best unbiased evidence of treatment effect


In hospitalized hemodynamically stable patients, at what Hgb should a decision to transfuse RBC be considered?

• We recommend adhering to a restrictive transfusion strategy.

• In adult and pediatric ICU patients, transfusion should be considered at Hgb < 7 g/dL.

• In surgical patients, transfusion should be considered at Hgb < 8 g/dL or for symptoms.

• Quality of evidence: High

• Strength of recommendation: Strong


In hospitalized hemodynamically stable patients, with pre-existing cardiovascular disease, at what Hgb should a decision to transfuse RBC be considered?

• We suggest adhering to a restrictive transfusion strategy.

• Transfusion should be considered at Hgb < 8 g/dL or for symptoms.

• Quality of evidence: Moderate

• Strength of recommendation: Weak


In hospitalized hemodynamically stable patients, should transfusion be guided by symptoms rather than hemoglobin concentration?

• We suggest that transfusion decisions should be influenced by symptoms as well as hemoglobin concentration

• Quality of evidence: Low

• Strength of recommendation: Weak


In hospitalized hemodynamically stable patients, with acute coronary syndrome, at what Hgb should a decision to transfuse RBC be considered?

• We cannot recommend for or against liberal or restrictive transfusion threshold. Further research is needed to determine optimal RBC transfusion threshold.

• Quality of evidence: Very low

• Strength of recommendation: Uncertain


Cases


Case 1

• 68 year old male with COPD is admitted to hospital with increasing dyspnea. He is hypoxic and has large infiltrate on chest xray. The patient is transferred to MICU, intubated and treated with antibiotics.

• Over the next 3 days Hgb falls from 11 to 8.5 g/dL. He appears to be euvolemic and BP is stable.


Case 2

• 80 year old women 2 days postop for hip fracture repair

• PMH- hypertension, DM, history of MI three years ago

• Symptoms- tired and weak

• Exam ok

• Hgb 8.5


Case 3

• 66 year old male presents with chest pain to ER and ECG shows anterior wall MI

• Patient taken to cardiac catherization lab and stent inserted in LAD

• Admission Hgb 12.1. Following day Hgb 9.2

• Large hematoma in groin. Vitals normal

• Transfuse?


Transfusion Recommendations• The best data suggests that a restrictive

transfusion trigger should be used

• The need for transfusion should be carefully assessed for each patient

• Choose a Hgb to CONSIDER transfusion

• There is limited trial data and the lowest threshold that has been tested is 7 g/dL


Transfusion Recommendations• However, don’t pull the trigger right away if

that magic level is reached

• Do a quick history and physical examination

• If the patient is clinically stable, hold off transfusing

• It is likely that the patient will do fine without blood


transfusion thresholds: how low can we go?transfusion-related acute lung injury (trali) • acute...

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