Professional Documents
Culture Documents
Randomized Trial of Transfusion Triggers in Post-Operative Abdominal Surgical Oncology Patients - Anesthesiology 2015
Randomized Trial of Transfusion Triggers in Post-Operative Abdominal Surgical Oncology Patients - Anesthesiology 2015
Randomized Trial of Transfusion Triggers in Post-Operative Abdominal Surgical Oncology Patients - Anesthesiology 2015
ABSTRACT
Background: Several studies have indicated that a restrictive erythrocyte transfusion strategy is as safe as a liberal one in critically ill
patients, but there is no clear evidence to support the superiority of any perioperative transfusion strategy in patients with cancer.
Methods: In a randomized, controlled, parallel-group, double-blind (patients and outcome assessors) superiority trial in the intensive
care unit of a tertiary oncology hospital, the authors evaluated whether a restrictive strategy of erythrocyte transfusion (transfusion
when hemoglobin concentration <7g/dl) was superior to a liberal one (transfusion when hemoglobin concentration <9g/dl) for
reducing mortality and severe clinical complications among patients having major cancer surgery. All adult patients with cancer having major abdominal surgery who required postoperative intensive care were included and randomly allocated to treatment with the
liberal or the restrictive erythrocyte transfusion strategy. The primary outcome was a composite endpoint of mortality and morbidity.
Results: A total of 198 patients were included as follows: 101 in the restrictive group and 97 in the liberal group. The primary composite
endpoint occurred in 19.6% (95% CI, 12.9 to 28.6%) of patients in the liberal-strategy group and in 35.6% (27.0 to 45.4%) of patients
in the restrictive-strategy group (P = 0.012). Compared with the restrictive strategy, the liberal transfusion strategy was associated with an
absolute risk reduction for the composite outcome of 16% (3.8 to 28.2%) and a number needed to treat of 6.2 (3.5 to 26.5).
Conclusion: A liberal erythrocyte transfusion strategy with a hemoglobin trigger of 9g/dl was associated with fewer major
postoperative complications in patients having major cancer surgery compared with a restrictive strategy. (Anesthesiology
2015; 122:29-38)
This article is featured in This Month in Anesthesiology, page 1A. Corresponding article on page 3.
Submitted for publication January 9, 2014. Accepted for publication August 8, 2014. From the Surgical Intensive Care Unit and Department of Anesthesiology, Cancer Institute, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
( J.P.d.A., F.R.B.G.G., E.P.M.d.A., J.T.F., E.A.O., F.B., C.L.P., R.E.N., S.M.R.F., J.I.A., M.B., S.V., A.C.V.S., H.P., R.K.F., J.O.C.A., L.A.H.); Department
of Intensive Care, Erasme Hospital, Universit Libre de Bruxelles, Brussels, Belgium ( J.-L.V.); Department of Intensive Care Medicine, St.
Georges Healthcare NHS Trust, London, United Kingdom (A.R.); Department of Surgery, Cancer Institute, Hospital das Clinicas da Faculdade
de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil (G.C., U.R., A.C., M.D.); and Department of Oncology, Cancer Institute, Hospital
das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil (M.d.P.E.D.).
Copyright 2014, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2015; 122:29-38
Anesthesiology, V 122 No 1 29
Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/Journals/JASA/931854/ on 01/23/2015
January 2015
PERIOPERATIVE MEDICINE
Liberal Strategy
Restrictive Strategy
97
64 (14)
55 (56.7)
25 (5)
51 (53.1)
20 (20.6)
10 (10.3)
11 (11.3)
42 (43.3)
5 (5.2)
1 (1.0)
2 (2.1)
3 (3.1)
6 (6.2)
1 (1.0)
6 (49)
101
64 (12)
55 (54.5)
25 (5)
46 (45.5)
26 (25.7)
10 (9.9)
8 (7.9)
41 (40.6)
9 (8.9)
1 (1.0)
8 (7.9)
6 (5.9)
8 (7.9)
1 (1.0)
7 (59)
57 (58.8)
30 (30.9)
9 (9.3)
1 (1.0)
67 (66.3)
25 (24.8)
8 (7.9)
1 (1.0)
20 (20.6)
21 (21.6)
21 (21.6)
23 (23.7)
8 (8.2)
4 (4.1)
18 (17.8)
25 (24.8)
33 (32.7)
17 (16.8)
3 (3.0)
5 (5.0)
47 (49.0)
11 (11.5)
38 (39.6)
12.4 (1.7)
2.6 (0.6)
34 (2945)
79 (45116)
52 (51.5)
5 (5.0)
44 (43.6)
12.6 (1.8)
2.6 (0.5)
37 (3146)
73 (49117)
We compared the baseline characteristics, follow-up measures, and clinical outcomes on an intention-to-treat basis
according to randomized study-group assignment. Continuous variables were compared using a t test or the MannWhitney U test, and categorical variables were compared using
Pearson chi-square test, Fisher exact test, or a likelihood ratio
test. We compared hemoglobin levels during the ICU stay
between groups using a mixed-design ANOVA model because
many patients died or were discharged from the ICU at different times. The model was constructed using the lowest daily
average hemoglobin concentrations during the ICU stay.
Results are expressed as means with SDs or medians
with interquartile ranges (IQRs). We calculated unadjusted
30-day KaplanMeier survival estimates, dividing patients
according to the transfusion strategy and the number of
transfused erythrocyte units. A two-sided P value less than
0.05 was considered to be statistically significant. The
PERIOPERATIVE MEDICINE
Table 2. Characteristics Related to the Underlying Malignancies of Patients and Types of Surgical Procedure
Variables (%)
Type of tumor
Upper gastrointestinal
Lower gastrointestinal
Pancreas
Liver and biliary tract
Urogenital
Other
Extent of cancer
Localized
Metastatic
Karnofsky performance status
ECOG performance status
0
1
2
3
4
Chemotherapy in the 4wk before ICU admission
Type of procedure
Esophagectomy
Gastrectomy
Gastroduodenopancreatectomy
Liver resection
Biliary duct resection
Colectomy
Peritonectomy with intraperitoneal chemotherapy
Abdominoperineal rectal amputation
Resection of retroperitoneal tumor
Emergency laparotomy
Pelvic exenteration
Radical cystectomy
Radical hysterectomy
Duration of surgery (min)
Type of anesthesia
General
Spinal
Spinal + general
Intraoperative fluid (l)
20 (20.6)
33 (34.0)
6 (6.2)
1 (1.0)
27 (27.8)
11 (11.3)
20 (19.8)
45 (44.6)
5 (5.0)
3 (3.0)
22 (21.8)
7 (6.9)
65 (67.0)
32 (33.0)
90 (80100)
62 (61.4)
39 (38.6)
90 (80100)
38 (40.0)
41 (43.2)
7 (7.4)
7 (7.4)
2 (2.1)
6 (6.2)
45 (45.0)
41 (41.0)
10 (10.0)
4 (4.0)
0 (0)
8 (7.9)
5 (5.2)
12 (12.4)
3 (3.1)
9 (9.3)
2 (2.1)
23 (23.7)
2 (2.1)
2 (2.1)
3 (3.1)
9 (9.3)
1 (1.0)
17 (17.5)
9 (9.3)
355 (250493)
7 (6.9)
8 (7.9)
7 (6.9)
13 (12.9)
2 (2.0)
18 (17.8)
7 (6.9)
7 (6.9)
2 (2.0)
13 (12.9)
1 (1.0)
9 (8.9)
7 (6.9)
323 (188476)
33 (34.0)
1 (1.0)
63 (64.9)
4.5 (3.56.0)
32 (31.7)
2 (2.0)
67 (66.3)
4.5 (3.56.5)
Results
Study Population
A total of 1,521 patients were screened for eligibility and 234
met the inclusion criteria (fig.1). After exclusions for medical reasons or lack of consent, 198 patients were enrolled in
the study; of whom, 97 were randomized to the liberal group
and 101 to the restrictive group. All patients completed the
study and were followed up for outcome criteria. Baseline
characteristics were well balanced between the study groups
(table1). The majority of the patients had a good performance status and localized disease and had an elective surgical procedure for gastrointestinal cancer (table2).
Primary Outcome
The primary composite endpoint at 30-daysall-cause mortality, cardiovascular complication, ARDS, AKI requiring
renal replacement therapy, septic shock, or reoperation
occurred in 19 patients (19.6%) in the liberal-strategy group
and in 36 patients (35.6%) in the restrictive-strategy group
(P = 0.012). This represents an absolute risk reduction for the
liberal strategy of 16% (95% CI, 3.8 to 28.2) and a number
needed to treat of 6.2 (95% CI, 3.5 to 26.5) to avoid the
composite outcome.
Secondary Outcomes
In total, 31 patients (15.7%) died during the 30-day follow-up. The 30-day mortality rate was lower in the liberalstrategy group than in the restrictive group (8 [8.2%] vs. 23
Fig. 2. KaplanMeier curves showing the probability of 30day survival in patients randomized to a restrictive strategy
of erythrocyte transfusion (transfusion when hemoglobin concentration <7g/dl) and those randomized to a liberal strategy
(transfusion when hemoglobin concentration <9g/dl). The P
value was calculated with the use of the log-rank test.
Discussion
In this trial involving 198 critically ill patients who were
admitted to a surgical ICU after major surgery for abdominal cancer, a blood transfusion strategy using a hemoglobin trigger of 9.0g/dl was superior to a transfusion
strategy using a trigger of 7.0g/dl in terms of the primary
outcome (30-day mortality or severe clinical complications). The restrictive erythrocyte transfusion strategy was
also associated with an increased rate of severe complications, including intraabdominal infections, cardiovascular
complications, and 60-day mortality, compared with the
liberal group.
Our study enrolled patients with active cancer who had
a high risk of postoperative complications. The aim was to
assess the trade-off between the complications of postoperative anemia and the benefits of blood transfusion in
this high-risk population using two different blood transfusion strategies and a composite endpoint of cardiovascular events, severe surgical complications, infection, organ
failure, and death.
In two previous randomized controlled trials in highrisk surgical patients, one concerning cardiac surgery (the
Transfusion Requirements After Cardiac Surgery study)19
and the other major orthopedic surgery (the Transfusion
Trigger Trial for Functional Outcomes in Cardiovascular
PERIOPERATIVE MEDICINE
P Value
19.6 (12.928.6)
35.6 (27.045.4)
0.012
8.2 (4.215.4)
0 (03.8)
13.4 (8.021.6)
45.4 (35.855.3)
2.1 (0.67.2)
5.2 (2.211.5)
0 (03.8)
0 (03.8)
0 (03.8)
1.0 (0.25.6)
1.0 (0.25.6)
2.1 (0.67.2)
1.0 (0.25.6)
10.3 (5.718.0)
21.6 (14.630.8)
22.8 (15.731.9)
2.0 (0.56.9)
21.8 (14.930.8)
43.6 (34.353.3)
3.0 (1.08.4)
13.9 (8.421.9)
1.0 (0.25.4)
3.0 (1.08.4)
1.0 (2.05.4)
2.0 (0.56.9)
4.0 (1.69.7)
5.0 (2.111.1)
1.0 (2.05.4)
16.8 (10.825.3)
30.7 (22.540.3)
0.005
0.498
0.122
0.799
1.00
0.038
1.00
0.247
1.00
1.00
0.369
0.445
1.00
0.181
0.148
5.2 (2.211.5)
7.2 (3.514.2)
3.1 (1.18.7)
4.1 (1.610.1)
1.0 (0.25.6)
4.1 (1.610.1)
1.0 (0.25.6)
30.9 (22.640.7)
14.9 (9.223.1)
7.9 (4.114.9)
3.0 (1.08.4)
3.0 (1.08.4)
2.0 (0.56.9)
3.0 (1.08.4)
0 (03.7)
39.6 (30.149.4)
0.024
0.851
1.00
0.717
1.00
0.717
0.490
0.202
2 (13)
2 (12)
58.8 (48.868.0)
2 (24)
15.5 (9.624.0)
4 (37)
13 (1020)
11.3 (6.519.2)
0.803
56.4 (46.765.7)
2 (14)
17.8 (11.626.4)
4 (38)
14 (1022)
23.8 (16.532.9)
0.740
0.476
0.656
0.758
0.686
0.022
hematocrit of 24% and a hemoglobin level of approximately 8.0g/dl) compared with the hemoglobin threshold
of 7.0g/dl used in the current study. In the Functional
Outcomes in Cardiovascular Patients Undergoing Surgical
Hip Fracture Repair study,20 the hemoglobin threshold was
again 8.0g/dl or symptoms of anemia; as a result of this less
restrictive strategy, 41% of the patients in the Functional
Outcomes in Cardiovascular Patients Undergoing Surgical
Hip Fracture Repairrestrictive group received erythrocyte
transfusions compared with 21% in our study. Furthermore, only 3% (approximately 60) of the patients in the
Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair study were transferred to
the ICU. Conversely, all of the participants in our study
were critically ill.
Other factors may also help explain some of the differences
in our results compared with those of previous studies. First,
we used leukodepleted blood in all transfused patients. The
Liberal Strategy
(N = 97)
Restrictive Strategy
(N = 101)
11.0 (1.6)
7.9 (0.5)
7.5 (0.6)
11.2 (1.8)
6.8 (0.5)
7.5 (0.9)
70 (72.2)
27 (27.8)
2 (13)
76 (75.2)
25 (24.8)
1 (12)
56 (57.7)
14 (14.4)
8 (8.2)
13 (13.4)
6 (6.2)
80 (79.2)
12 (11.9)
3 (3)
2 (2)
4 (4)
50 (51.5)
47 (48.5)
134
13 (13.4)
10 (1215)
68 (67.3)
33 (32.7)
88
7 (6.9)
13 (916)
P Value
0.458
<0.001
0.99
0.622
0.105
0.005
0.024
0.131
0.743
PERIOPERATIVE MEDICINE
Conclusion
In this controlled, randomized trial of patients admitted to
the ICU after major surgery for abdominal cancer, a liberal
erythrocyte transfusion strategy using a hemoglobin threshold of 9.0g/dl was superior to a restrictive strategy with a
hemoglobin threshold of 7.0g/dl. Our findings are highly
relevant because a restrictive erythrocyte transfusion policy
has been advocated for surgical patients with cancer because
of the potential association between erythrocyte transfusion
and cancer recurrence. The association of a restrictive postoperative blood transfusion strategy with poorer short-term
outcomes, even from a single-center study, should alert physicians to the possibility that a restrictive strategy, based on a
hemoglobin concentration of 7.0g/dl, may not be as safe as
previously perceived.
Acknowledgments
Support was provided solely from institutional and/or departmental sources.
Competing Interests
The authors declare no competing interests.
Correspondence
Address correspondence to Dr. Vincent: Erasme University
Hospital, Route de Lennik 808, B-1070 Brussels, Belgium.
jlvincen@ulb.ac.be. This article may be accessed for personal use at no charge through the Journal Web site, www.
anesthesiology.org.
References
1. Law S, Wong KH, Kwok KF, Chu KM, Wong J: Predictive
factors for postoperative pulmonary complications and
mortality after esophagectomy for cancer. Ann Surg 2004;
240:791800
2. Masoomi H, Kang CY, Chen A, Mills S, Dolich MO, Carmichael
JC, Stamos MJ: Predictive factors of in-hospital mortality in
colon and rectal surgery. J Am Coll Surg 2012; 215:25561
3. Pearse RM, Moreno RP, Bauer P, Pelosi P, Metnitz P, Spies C,
Vallet B, Vincent JL, Hoeft A, Rhodes A; European Surgical
Outcomes Study (EuSOS) Group for the Trials Groups of
the European Society of Intensive Care Medicine and the
European Society of Anaesthesiology: Mortality after surgery
in Europe: A 7 day cohort study. Lancet 2012; 380:105965
4. Weber RS, Jabbour N, Martin RC II: Anemia and transfusions
in patients undergoing surgery for cancer. Ann Surg Oncol
2008; 15:3445
5. Acheson AG, Brookes MJ, Spahn DR: Effects of allogeneic
red blood cell transfusions on clinical outcomes in patients
undergoing colorectal cancer surgery: A systematic review
and meta-analysis. Ann Surg 2012; 256:23544
6. Dicato M, Plawny L, Diederich M: Anemia in cancer. Ann
Oncol 2010; 21(suppl 7):vii16772
7. Koch M, Antolovic D, Reissfelder C, Rahbari NN, Holoch
J, Michalski I, Sweiti H, Ulrich A, Bchler MW, Weitz J:
Leucocyte-depleted blood transfusion is an independent predictor of surgical morbidity in patients undergoing elective
colon cancer surgery-a single-center analysis of 531 patients.
Ann Surg Oncol 2011; 18:140411
8. Amato A, Pescatori M: Perioperative blood transfusions for
the recurrence of colorectal cancer. Cochrane Database Syst
Rev 2006;CD005033
9. Vamvakas EC, Blajchman MA: Deleterious clinical effects of
transfusion-associated immunomodulation: Fact or fiction?
Blood 2001; 97:118095
10. Hbert 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; 340:40917
11. Schag CC, Heinrich RL, Ganz PA: Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin Oncol
1984; 2:18793
12. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE,
McFadden ET, Carbone PP: Toxicity and response criteria of
the Eastern Cooperative Oncology Group. Am J Clin Oncol
1982; 5:64955
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method
of classifying prognostic comorbidity in longitudinal studies:
Development and validation. J Chronic Dis 1987; 40:37383
24. Flancbaum L, Ziegler DW, Choban PS: Preoperative intensive care unit admission and hemodynamic monitoring in
patients scheduled for major elective noncardiac surgery:
A retrospective review of 95 patients. J Cardiothorac Vasc
Anesth 1998; 12:39
25. Lobo SM, Salgado PF, Castillo VG, Borim AA, Polachini CA,
Palchetti JC, Brienzi SL, de Oliveira GG: Effects of maximizing oxygen delivery on morbidity and mortality in high-risk
surgical patients. Crit Care Med 2000; 28:3396404
26. Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM,
Bennett ED: Changes in central venous saturation after
major surgery, and association with outcome. Crit Care 2005;
9:R6949
27. Pearse RM, Belsey JD, Cole JN, Bennett ED: Effect of dopexamine infusion on mortality following major surgery:
Individual patient data meta-regression analysis of published
clinical trials. Crit Care Med 2008; 36:13239
28. Sakr Y, Chierego M, Piagnerelli M, Verdant C, Dubois MJ, Koch
M, Creteur J, Gullo A, Vincent JL, De Backer D: Microvascular
response to red blood cell transfusion in patients with severe
sepsis. Crit Care Med 2007; 35:163944
29. Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout
R, Noveck H, Strom BL: Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;
348:105560
30. Carson JL, Noveck H, Berlin JA, Gould SA: Mortality and morbidity in patients with very low postoperative Hb levels who
decline blood transfusion. Transfusion 2002; 42:8128
31. Wu WC, Schifftner TL, Henderson WG, Eaton CB, Poses RM,
Uttley G, Sharma SC, Vezeridis M, Khuri SF, Friedmann PD:
Preoperative hematocrit levels and postoperative outcomes
in older patients undergoing noncardiac surgery. JAMA 2007;
297:24818
32. Park DW, Chun BC, Kwon SS, Yoon YK, Choi WS, Sohn JW,
Peck KR, Kim YS, Choi YH, Choi JY, Kim SI, Eom JS, Kim
HY, Cheong HJ, Song YG, Choi HJ, Kim JM, Kim MJ: Red
blood cell transfusions are associated with lower mortality in
patients with severe sepsis and septic shock: A propensitymatched analysis. Crit Care Med 2012; 40:31405
33. Soares M, Caruso P, Silva E, Teles JM, Lobo SM, Friedman
G, Dal Pizzol F, Mello PV, Bozza FA, Silva UV, Torelly AP,
Knibel MF, Rezende E, Netto JJ, Piras C, Castro A, Ferreira
BS, Ra-Neto A, Olmedo PB, Salluh JI; Brazilian Research in
Intensive Care Network (BRICNet): Characteristics and outcomes of patients with cancer requiring admission to intensive care units: A prospective multicenter study. Crit Care
Med 2010; 38:915