transfusion triggers: how low can we go?

4
218 Vox Sanguinis (2004) 87 (Suppl. 2), S218–S221 ORIGINAL PAPER TH01.02 © 2004 Blackwell Publishing Blackwell Publishing, Ltd. Transfusion triggers: how low can we go? J. L. Carson & G. Ferreira Department of Medicine, University of Medicine and Dentistry of New Jersey, USA Introduction Despite the widespread global use of red blood cell trans- fusion, we have very limited high quality evidence to guide transfusion decisions. If blood transfusion were considered by drug regulatory authorities for approval as a new drug there is no doubt it would be rejected because there is no randomized evidence that documents improved outcome. Despite this lack of evidence, few clinicians doubt that blood transfusion can save lives when used in severely anaemic patients. Most clinicians use a haemoglobin trigger to make decisions regarding transfusion unless symptoms occur first, but what this trigger should be is often bitterly debated. In fact, haemoglobin triggers may vary depending on the goals of blood transfusion and the clinical setting. The goals of blood transfusion include alleviating symp- tomatic anaemia and its consequences, such as myocardial ischaemia, exertional fatigue, and possibly other, unknown benefits. If clinicians are willing to tolerate some morbidity and slow recovery then perhaps it is reasonable to use as little blood as possible. However, if we want to minimize mortality and morbidity and maximize speed of recovery, then perhaps we should accept a more liberal transfusion threshold. Two very different conclusions regarding the proper transfusion trigger are likely to emerge depending on the goal of red blood cell transfusion therapy. Current blood transfusion practices throughout western societies that emphasizes minimizing risk suggests that most clinicians prefer to use blood to maximize outcome. Thus, we should not be seeking the answer to ‘how low can you go’. Besides understanding the goals of blood transfusion therapy, it is also necessary to explore the effect of blood transfusion in different clinical settings. We have very little evidence in most settings. However, important, high quality data does exist on transfusion triggers in intensive care unit patients. This evidence suggests lower transfusion triggers are safe. Another area of great importance is patients with underlying cardiovascular disease. There is a substantial body of evidence in this setting, although most of the studies are of lesser quality study design. In this paper, we review the evidence on the optimal use of blood transfusion in intensive care unit patients and those with cardiovascular disease. Intensive care unit patients The best study to address transfusion triggers in any setting was performed in ICU patients (Table 1). The Transfusion Requirement in Critical Care (TRICC) trial [1,2]. randomized 838 volume resuscitated intensive care unit patients to either a ‘restrictive’ or ‘liberal’ transfusion strategy. The ‘restrictive’ group received allogeneic red blood cell transfusions when the haemoglobin concentration was less than 7 g/dl and haemoglobin was maintained between 7 and 9 g/dl. The ‘liberal’ group received red blood cells when the haemoglobin concentration was less than 10 g/dl and haemoglobin was maintained between 10 and 12 g/dl. The restrictive group had lower average haemoglobin levels (8·5 vs. 10·7 g/dl) and fewer transfusions (2·6 vs. 5·6) compared to the liberal group. The 30-day mortality was slightly lower in the restrictive transfusion group (18·7% vs. 23·3%) although this finding was not statistically significant ( P = 0·11). However, the restrictive group did have statistically sig- nificant decreased mortality compared to the liberal transfusion group in two subgroups, patients who were less than 55 years of age and those who were less ill as defined by an APACHE score below 20 [1]. The restrictive group also had significant reductions in myocardial infarction and congestive heart failure compared to the liberal transfusion group. Two trials have been performed in ICU patients undergoing coronary artery bypass graft surgery. A trial of 428 patients undergoing a first elective coronary artery bypass surgery, randomized patients into two arms, with transfusion triggers of 9 g/dl vs. 8 g/dl [3]. No differences in outcomes were found between the two groups, although the haemoglobin levels were similar and the event rates were very low. In a small study including 39 autologous blood donors under- going coronary artery bypass surgery, patients were random- ized to a ‘liberal’ group that received transfusions to reach a haematocrit level of 32%, and a ‘conservative’ group who Correspondence: Jeffrey L. Carson, Division of General Internal Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA E-mail: [email protected]

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Page 1: Transfusion triggers: how low can we go?

218

Vox Sanguinis

(2004)

87

(Suppl. 2)

, S218–S221

ORIGINAL PAPER TH01.02

©

2004 Blackwell Publishing

Blackwell Publishing, Ltd.

Transfusion triggers: how low can we go?

J. L. Carson & G. Ferreira

Department of Medicine, University of Medicine and Dentistry of New Jersey, USA

Introduction

Despite the widespread global use of red blood cell trans-fusion, we have very limited high quality evidence to guidetransfusion decisions. If blood transfusion were consideredby drug regulatory authorities for approval as a new drugthere is no doubt it would be rejected because there is norandomized evidence that documents improved outcome.Despite this lack of evidence, few clinicians doubt that bloodtransfusion can save lives when used in severely anaemicpatients. Most clinicians use a haemoglobin trigger to makedecisions regarding transfusion unless symptoms occur first,but what this trigger should be is often bitterly debated. Infact, haemoglobin triggers may vary depending on the goalsof blood transfusion and the clinical setting.

The goals of blood transfusion include alleviating symp-tomatic anaemia and its consequences, such as myocardialischaemia, exertional fatigue, and possibly other, unknownbenefits. If clinicians are willing to tolerate some morbidityand slow recovery then perhaps it is reasonable to use as littleblood as possible. However, if we want to minimize mortalityand morbidity and maximize speed of recovery, then perhapswe should accept a more liberal transfusion threshold. Twovery different conclusions regarding the proper transfusiontrigger are likely to emerge depending on the goal of redblood cell transfusion therapy. Current blood transfusionpractices throughout western societies that emphasizesminimizing risk suggests that most clinicians prefer to useblood to maximize outcome. Thus, we should not be seekingthe answer to ‘how low can you go’.

Besides understanding the goals of blood transfusiontherapy, it is also necessary to explore the effect of bloodtransfusion in different clinical settings. We have very littleevidence in most settings. However, important, high qualitydata does exist on transfusion triggers in intensive care unitpatients. This evidence suggests lower transfusion triggers

are safe. Another area of great importance is patientswith underlying cardiovascular disease. There is a substantialbody of evidence in this setting, although most of the studiesare of lesser quality study design. In this paper, we review theevidence on the optimal use of blood transfusion in intensivecare unit patients and those with cardiovascular disease.

Intensive care unit patients

The best study to address transfusion triggers in any settingwas performed in ICU patients (Table 1). The TransfusionRequirement in Critical Care (TRICC) trial [1,2]. randomized838 volume resuscitated intensive care unit patients to eithera ‘restrictive’ or ‘liberal’ transfusion strategy. The ‘restrictive’group received allogeneic red blood cell transfusions whenthe haemoglobin concentration was less than 7 g/dl andhaemoglobin was maintained between 7 and 9 g/dl. The‘liberal’ group received red blood cells when the haemoglobinconcentration was less than 10 g/dl and haemoglobin wasmaintained between 10 and 12 g/dl. The restrictive grouphad lower average haemoglobin levels (8·5 vs. 10·7 g/dl) andfewer transfusions (2·6 vs. 5·6) compared to the liberal group.The 30-day mortality was slightly lower in the restrictivetransfusion group (18·7% vs. 23·3%) although this findingwas not statistically significant (

P

= 0·11).However, the restrictive group did have statistically sig-

nificant decreased mortality compared to the liberal transfusiongroup in two subgroups, patients who were less than 55 yearsof age and those who were less ill as defined by an APACHEscore below 20 [1]. The restrictive group also had significantreductions in myocardial infarction and congestive heartfailure compared to the liberal transfusion group.

Two trials have been performed in ICU patients undergoingcoronary artery bypass graft surgery. A trial of 428 patientsundergoing a first elective coronary artery bypass surgery,randomized patients into two arms, with transfusion triggersof 9 g/dl vs. 8 g/dl [3]. No differences in outcomes werefound between the two groups, although the haemoglobinlevels were similar and the event rates were very low. In asmall study including 39 autologous blood donors under-going coronary artery bypass surgery, patients were random-ized to a ‘liberal’ group that received transfusions to reacha haematocrit level of 32%, and a ‘conservative’ group who

Correspondence

: Jeffrey L. Carson, Division of General Internal Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAE-mail: [email protected]

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2004 Blackwell Publishing Ltd.

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87 (Suppl. 2)

, S218–S221

Tranfusion triggers

219

Table 1

Key Studies in Intensive Unit and cardiovascular patients

Study Clinical setting Subjects Outcomes

Non-randomized studies

Nelson

et al

. (1993) [11] Vascular surgery

(

n

= 27)

High-risk patients who had undergone

elective infra-inguinal bypass vascular

procedures

MI occurred in 14% of pts with Hct > 28%

compared to 77% with Hct < 28%

Anaemic group: (

n

= 13) No deaths in either group

Non-anaemic group: (

n

= 14)

Hebert

et al

. (1997) [5] Critical care Critically ill patients admitted to ICU Survivors had higher Hgb levels than non-survivors

(

n

= 4470) Survivors: (

n

= 3469)

Non-survivors: (

n

= 1001)

Paone

et al

. (1997) [8] Cardiac surgery Patients undergoing isolated CABG No difference in clinical outcomes

(

n

= 100) Transfusion group: (

n

= 13) Length of ICU stay longer in transfused patients

No transfusion group: (n = 87): 2·6 + 0.3 days vs. non-transfused group, 1·6 + 0·1 days

Patients were transfused allogeneic RBC

on bypass for low Sv0

2

(< 55%) and

transfused postoperatively for a Hct < 20%

or at any Hct level if deemed clinically

warranted

Hogue

et al

. (1998) [12] Urological surgery

(

n

= 190)

Patients undergoing radical prostatectomy

Hct < 28% group vs. Hct > 28% group

Patients with Hct levels < 28% immediately after

surgery were significantly (

P

= 0·05) more likely

to have ischaemic episodes

Spiess

et al

. (1998) [6] Cardiac surgery

(

n

= 2202)

CABG

High IHCT > 34% group

n

= 410

MI highest in IHCT (8·3%) then medium IHCT (5·5%)

and low IHCT (3·6%)

Medium IHCT group 25% to 33%

n

= 1544;

Low IHCT < 24% group

n

= 248; mean age

(

±

SD) 64·3

±

10·2 years

Wu

et al

. (2001) [10] Myocardial infarction

(

n

= 78 794)

Myocardial infarction patients 65 years old

or older

Transfusion was associated with reduction in 30-day

mortality in patients with Hct 5·0% to 33%

5·0–24·0%,

n

= 380

24·1–27·0%,

n

= 838

27·1–30·0%,

n

= 2106

30·1–33·0%,

n

= 4848

33·1–36·0%,

n

= 9885

36·1–39·0%,

n

= 16 218

or 39·1–48·0%,

n

= 44 699

Vincent

et al

. (2002) [7] Critical care

(

n

= 3534)

ntensive care unit patients IICU mortality (18·5% in transfusion, 10·1% no

transfusion), overall mortality (29·0% vs14·9%),

and 28 day mortality (22·7% vs. 17·1%) as higher

in patients receiving transfusion as compared to

patients not receiving transfusion

Randomized clinical trials

Johnson

et al

. (1992) [4] Cardiac surgery

(

n

= 38)

Liberal: patients received blood transfusion

to achieve a Hct value of 32% so long as

autologous blood was available. Restrictive

strategy: patients received transfusions only

if the Hct value fell below 25%

No difference in outcomes

Hebert

et al

. (1999) [1] Critical care

(

n

= 838)

Liberal: patients were transfused with PRBC

to maintain Hb concentration at

10·0–12·0 g/dl

Restrictive: patients were transfused to

maintain Hb concentration maintained

between 7·0 and 9·0 g/dl

23·3% 30-day mortality in liberal group

18·7% 30-day mortality in restrictive group

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J. L. Carson & G. Ferreira

©

2004 Blackwell Publishing Ltd.

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(2004)

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, S218–S221

Bracey

et al

. (1999) [3] Cardiac surgery

(

n

= 428)

Liberal Hb level received an RBC

transfusion < 9·0 g/dl

Restrictive: received an RBC transfusion

for Hb level < 8·0 g/dl

2·7% 30-day mortality in liberal group

1·4% 30-day mortality in restrictive group

Hebert

et al

. (2001) [9] Critical care

(

n

= 357 with cardio-

vascular disease)

(

n

= 257 with ischaemic

heart disease

Subanalysis from TRICC trial. Patients with

cardiovascular disease and ischaemic

heart disease

Cardiovascular patients

23% 30-day mortality in liberal group

23% 30-day mortality in restrictive group

Ischaemic heart disease

21% 30-day mortality in liberal group

26% 30-day mortality in restrictive group

Hct = haematocrit, Hg = haemoglobin.

Study Clinical setting Subjects Outcomes

Table 1

Continued

were transfused for haematocrit level less than 25% [4].There were no differences in clinical complications or exerciseendurance 5–6 days after surgery between the two groups.

Three large observational studies evaluated transfusiontriggers in ICU patients. The first study evaluated 4470 criti-cally ill patients admitted to six Canadian tertiary intensivecare units [5]. The outcomes were better for intensive careunit patients who had been transfused, especially those withcardiovascular disease. The second study involved 2202patients undergoing coronary artery bypass graft surgery[6]. Upon admission to the intensive care unit, the patientswere divided into three groups based on their haematocritlevels: a High > 34%, Medium 25% to 33%, and, Low < 24%.Patients in the High group were more than twice as likelyto have a myocardial infarction as those in the Low group.The third study was performed in 146 European ICUs andinvolved 3534 patients. Patients who received a transfusionhad a higher mortality (22·7% vs. 17·1%) than those whowere not transfused after adjusting for differences in patientseverity of illness and comorbidity [7]. A fourth small studyin patients undergoing cardiac surgery found no differencein clinical outcomes in those receiving or not receiving trans-fusion [8].

Patients with cardiovascular disease

The Transfusion Requirement in Critical Care (TRICC) trialevaluated outcomes in the 43% of patients with cardio-vascular disease [9]. Cardiovascular disease was defined intwo ways. Overall cardiovascular disease (

n

= 357) includedall patients with diagnoses related to ischaemic heartdisease (myocardial infarct, angina, congestive heart failure,and cardiogenic shock), rhythm disturbances, cardiac arrest,other forms of shock, uncontrolled hypertension, and cardiacand vascular surgical procedures such as abdominal aorticaneurysm repair and peripheral vascular surgical procedures.

A subset of these patients with ischemic heart disease(

n

= 257) was also examined. These patients had confirmedischemic heart disease, severe peripheral vascular disease, orsevere comorbid cardiac disease. There were 160 patients inthe restrictive red blood cell transfusion group and 197 in theliberal red blood cell transfusion group. The 30 day mortalityrate for the patients with cardiovascular disease was 23% inboth groups. In patients with ischemic heart disease, 30 daymortality was 21% among patients in the liberal transfusiongroup and 26% in the restrictive group, but this was not sta-tistically significant (

P

= 0·30). This more favourable trend inmortality in patients with ischaemic heart disease receivingmore blood (liberal group) suggests that in patients withischemic heart disease might benefit from a higher trans-fusion trigger improves outcome. A larger randomized trialis needed to evaluate this hypothesis.

Several observational studies also suggest that patients withcardiovascular disease may benefit from higher transfusiontriggers. A study using Medicare billing data in patients withmyocardial infarction found the admission haematocrit levelwas associated with adjusted 30-day mortality [10]. Patientswho received transfusions for a haematocrit less than 33%had lower mortality than patients with similar haematocritswho did not receive a transfusion (adjusted Odds ratio 0·69).As the haematocrit fell, the protective effect of bloodtransfusion increased (i.e. haematocrit 27·1%–30%; adjustedOdds ratio 0·60 and haematocrit 24·1–27%; adjusted Oddsratio of 0·48). Interestingly, when the haematocrit was above36% mortality was higher in patients who were transfused.Two small studies in patients undergoing vascular andprostate surgery found more ischaemic events in anaemicpatients [11,12].

A study in patients who decline blood transfusion for relig-ious reasons also suggests that patients with cardiovasculardisease are less tolerant of anaemia. The relationship betweenmortality and preoperative haemoglobin was evaluated in

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, S218–S221

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221

1958 patients who underwent surgery [13]. Mortality roseas haemoglobin fell but was significantly higher in patientswith underlying cardiovascular disease than patients withoutcardiovascular disease. This study suggests the risk of deathassociated with anaemia is higher in patients with cardio-vascular disease but did not evaluate whether transfusionmodifies that risk.

Summary

The goal of transfusion therapy should be to provide enoughblood to meet the oxygen carrying needs of a patient to min-imize mortality and morbidity, and to maximize functionaloutcomes. Pursuing the goal of ‘how low can you go?’ shouldbe abandoned since the risks of blood transfusion are low andinconsistent with the goal of optimizing outcome. One welldesigned clinical trial in intensive care unit patients suggeststhat a 7-g/dl threshold is as safe, and perhaps safer, than a10-g/dl threshold. Observational studies have confirmed thisresult. In patients with cardiovascular disease the evidenceon the ideal transfusion trigger is less clear. A subgroupanalysis of patients with cardiovascular disease from theTRICC trial found a non-significant trend towards lowermortality in patients receiving enough blood transfusion tokeep the haemoglobin level above 10 g/dl. Several observa-tional studies also suggest that higher red cell concentrationsmay be advantageous in patients with underlying cardio-vascular disease. However, firm conclusion awaits furtherclinical trials in patients with cardiovascular disease like theone that is starting soon [14].

Acknowledgement

Supported in part by grant from the National Heart Lung andBlood Institute 1 R01 HL73958-01

References

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