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From the Critical Care Programs (Dr. Hébert) and the Clinical Epidemiology Unit (Dr. Wells, Mr. Schweitzer, Ms. Yetisir), University of Ottawa, Ottawa, Ontario; the University of Toronto (Dr. Marshall), Toronto, Ontario; and the Departments of Pathology (Dr. Blajchman) and Medicine and Epidemiology (Dr. Cook), McMaster University, Hamilton, Ontario, Canada.
A list of other study investigators is given in the Appendix.
Correspondence to: Paul C. Hébert, MD, MHSc(Epid), Department of Medicine, Ottawa Hospital, General Site, 501 Smyth Rd, Box 201, Ottawa, Ontario K1H 8L6, Canada; e-mail: phebert{at}ottawahospital.on.ca
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Methods: Seven hundred thirteen patients receiving mechanical ventilation, representing a subgroup of patients from a larger trial, were randomized to either a restrictive transfusion strategy, receiving allogeneic RBC transfusions at a hemoglobin concentration of 7.0 g/dL (and maintained between 7.0 g/dL and to 9.0 g/dL), or to a liberal transfusion strategy, receiving RBCs at 10.0 g/dL (and maintained between 10.0 g/dL and 12.0 g/dL). The larger trial was designed to evaluate transfusion practice rather than weaning per se.
Results: Baseline characteristics in the restrictive-strategy group (n = 357) and the liberal-strategy group (n = 356) were comparable. The average durations of mechanical ventilation were 8.3 ± 8.1 days and 8.3 ± 8.1 days (95% confidence interval [CI] around difference, - 0.79 to 1.68; p = 0.48), while ventilator-free days were 17.5 ± 10.9 days and 16.1 ± 11.4 days (95% CI around difference, - 3.07 to 0.21; p = 0.09) in the restrictive-strategy group vs the liberal-strategy group, respectively. Eighty-two percent of the patients in the restrictive-strategy group were considered successfully weaned and extubated for at least 24 h, compared to 78% for the liberal-strategy group (p = 0.19). The relative risk (RR) of extubation success in the restrictive-strategy group compared to the liberal-strategy group, adjusted for the confounding effects of age, APACHE (acute physiology and chronic health evaluation) II score, and comorbid illness, was 1.07 (95% CI, 0.96 to 1.26; p = 0.43). The adjusted RR of extubation success associated with restrictive transfusion in the 219 patients who received mechanical ventilation for > 7 days was 1.1 (95% CI, 0.84 to 1.45; p = 0.47).
Conclusion: In this study, there was no evidence that a liberal RBC transfusion strategy decreased the duration of mechanical ventilation in a heterogeneous population of critically ill patients.
Key Words: critical care • mechanical ventilation • oxygen delivery • RBC transfusion • transfusion trigger • weaning
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Although the use of allogeneic RBCs is common in critical care practice, there have been very few large studies examining the consequences of anemia and RBC transfusions, before the recent publication of the results of the Transfusion Requirements in Critical Care (TRICC) trial.9 In this randomized trial9 comparing a restrictive transfusion strategy vs a liberal transfusion strategy, 713 of the patients enrolled (85%) required mechanical ventilation, 357 patients in the restrictive transfusion strategy arm and 356 patients in the liberal transfusion strategy arm. An analysis of these patients receiving mechanical ventilation afforded an opportunity to examine the effects of anemia and RBC transfusion on mechanical ventilation outcomes.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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9.0 g/dL within 72 h of ICU admission, and were
considered volume resuscitated by the attending ICU staff. Patients
with chronic anemia and acute severe blood loss, defined as a decrease
in hemoglobin concentration > 30 g/L or a requirement for three RBC
units in 12 h, were excluded from the TRICC trial, as well as this
analysis. Physicians caring for patients allocated to the restrictive
RBC transfusion strategy were instructed to transfuse one RBC unit when
a patient’s hemoglobin concentration fell to < 7.0 g/dL, and to
maintain the patient’s hemoglobin concentration between 7.0 g/dL and
9.0 g/dL. In the liberal-strategy group, hemoglobin concentrations were
maintained between 10.0 g/dL and 12.0 g/dL. RBC units were administered
when a patient’s hemoglobin values fell to < 10.0 g/dL in this
group. Hemoglobin concentrations were measured after each RBC unit was
transfused in all study patients. The primary outcome in the study was
30-day all-cause mortality. Secondary outcomes included other mortality
rates and organ failure. Details of the TRICC protocol and overall
results have been reported previously.9
The present
analysis is limited to those patients who required mechanical
ventilation through an endotracheal tube or tracheostomy regardless of
their duration of ventilation subsequent to being enrolled in the TRICC
trial. Patients receiving noninvasive ventilation were not considered.
Because RBC transfusions might have a greater effect on patients
requiring a longer course of mechanical ventilation, a
priori, we also decided to examine the subgroup of patients who
received mechanical ventilation for > 7 days.
Outcome Measures
Outcomes from mechanical ventilation included a comparison of
(1) the proportion of patients considered successfully weaned and
extubated (defined as not requiring mechanical ventilation for at least
24 h); (2) the total duration of mechanical ventilation during the
30-day study period; (3) the time to successful extubation; and (4)
ventilator-free days, defined as the number of days not requiring
mechanical ventilation during 30 days of observation. A patient had to
be free of mechanical ventilation for at least 24 h to have any
day counted as being ventilator free. Patients were assigned zero
ventilator-free days if they died within the 30-day observation period.
Statistical Analysis
The analysis was conducted on an intention-to-treat basis. The
numbers of mechanical ventilation days and ventilator-free days were
compared using independent t tests. The proportion of
patients who were considered to have been successfully weaned and
extubated were compared using the Fisher’s Exact Test. For this
analysis, we opted to evaluate successful weaning and extubation using
similar definitions with two cutoff points. First, patients were
considered successfully weaned and extubated if alive and free from
mechanical ventilation for at least 24 h; and second, if alive and
free from mechanical ventilation for a 30-day period. Using time to
extubation success with both definitions, Kaplan-Meier survival curves
were constructed and compared using log-rank tests. Cox
proportional-hazards modeling was used to adjust for differences in
duration of ventilation. Covariates were submitted for analysis in the
survival model at p 0.20. A second Cox model was constructed,
forcing potential confounders, including patient age, APACHE (acute
physiology and chronic health evaluation) II score, comorbid illness,
including ischemic heart disease and other cardiac diagnoses, and
treatment, into the model. The effect of hemoglobin concentrations was
forced into the model as a continuous variable, while the effect of the
number of RBC transfusions was examined in a separate model. We
performed these analyses in all surviving patients and the subgroup of
surviving patients who received mechanical ventilation for at least 7
days. Complications were compared using the Fisher’s Exact Test.
Lengths of ICU and hospital stay were analyzed using the Wilcoxon
rank-sum test for independent samples. Comparisons of primary outcomes
were considered statistically significant using an overall two-sided
of 0.05. No adjustments were made for multiple comparisons.
Absolute p values and 95% confidence intervals (CIs) were also
reported.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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All baseline characteristics were equally balanced between the treatment groups among patients who required mechanical ventilation (p > 0.05; Table 1 ). Study participants had a mean APACHE II score of 22, and > 95% were receiving mechanical ventilation at baseline.
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There were no study protocols for mechanical ventilation during the trial; however, assist control, assist control with pressure control, and synchronized intermittent mandatory ventilation with pressure support were the primary modes of mechanical ventilation employed in all centers. Assessments of weaning readiness, weaning methods, and extubation decisions were made at the discretion of the ICU team.
Successful Implementation of the Study
Hemoglobin concentrations averaged 8.4 ± 0.62 g/dL throughout
the ICU stay in the restrictive-strategy group and 10.4 ± 0.71 g/dL
in the liberal-strategy group (p < 0.01). Once randomized, an
average of 2.7 ± 4.0 U of RBCs per patient were administered in the
restrictive-strategy group, compared to 5.5 ± 5.1 U of RBCs per
patient in the liberal-strategy group (p < 0.01). Physicians
maintained hemoglobin concentrations within the prespecified limits in
> 97% of patients. Cointerventions potentially modifying oxygen
delivery, including the use of vasoactive drugs, overall fluid balance,
and pulmonary artery catheter use, were comparable in the two groups
throughout the ICU stay (p > 0.05).
Outcome Measures
In the 713 patients receiving mechanical ventilation, the mean
duration of mechanical ventilation was 8.3 ± 8.1 days in the
restrictive-strategy group and 8.3 ± 8.1 days in the
liberal-strategy group (95% CI for the difference between groups,
- 0.79 to 1.68; p = 0.48; Table 2
). Ventilator-free days were 17.5 ± 10.9 days and 16.1 ± 11.4 days
in the restrictive-strategy group vs the liberal-strategy group,
respectively (95% CI for the difference between groups, - 3.07 to
0.21; p = 0.09). Eighty-two percent of the patients in the
restrictive-strategy group were considered successfully weaned and
extubated for at least 24 h, compared to 78% for the
liberal-strategy group (p = 0.19). The unadjusted relative risk (RR)
of successful extubation for the restrictive vs liberal strategies was
1.08 (95% CI, 0.92 to 1.27; p = 0.35). The RR for being successfully
weaned and extubated was not significantly different after adjustment
for the confounding influence of age, APACHE II score, and comorbid
illness (RR, 1.07; 95% CI, 0.91 to 1.26; p = 0.43). Using 30 days as
the threshold for extubation success, both the unadjusted RR (1.12;
95% CI, 0.94 to 1.34; p = 0.21) and adjusted RR (1.09; 95% CI, 0.92
to 1.30; p = 0.33) were similar to each other and to the
results when successful weaning and extubation were measured at 24
h.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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The consequences of anemia on lung function, work of breathing, and weaning from mechanical ventilation have not been studied extensively.11 12 The two studies11 12 evaluating posttransfusion lung function in patients with chronic anemia have divergent conclusions, with one study finding worsened gas exchange and the other finding improved gas exchange. Limited research has addressed the role of RBC transfusions in treating anemic patients requiring ongoing ventilatory support or being weaned from mechanical ventilation. Two case series7 8 describe weaning successes in a small group of anemic patients who received RBC transfusions. In five patients with severe COPD who failed repeated attempts to wean from mechanical ventilation, Schonhofer et al8 described successfully weaning all patients after increasing their hemoglobin concentrations to > 12.0 g/dL. In a second study of mechanical ventilation,7 the same investigators measured the effects of RBC transfusions on the work of breathing and other respiratory parameters in 10 anemic patients with severe COPD and in 10 anemic patients who required mechanical ventilation associated with other diagnoses. They observed a decrease in work of breathing and minute ventilation after transfusion in the group of patients with severe COPD. From this small study, it is unclear whether the work of breathing was improved because of higher cardiac output as a result of increased preload or because of increased oxygen delivery to the respiratory muscles.
Because anemia may result in a limitation in oxygen delivery, the left ventricle may not be able to increase cardiac output during the weaning process and oxygen delivery to the respiratory muscles may not keep up with the increased oxygen requirements. The weaning process may precipitate myocardial ischemia because of the increased strain on left ventricular function. In this heterogeneous group of patients receiving mechanical ventilation, we did not identify adverse effects of low hemoglobin values; however, we did not conduct systematic screening for adverse effects, such as ECG evidence of myocardial ischemia. In a study by Srivastava and colleagues,13 among 83 patients with coronary artery disease who received mechanical ventilation for a mean of 4.6 days, 8 patients had ECG ischemia during weaning and 7 patients failed to be liberated on the first day; ischemia was associated with a risk ratio of weaning failure of 2.1 (95% CI, 1.4 to 3.1). However, we did observe a significant increase in rates of pulmonary edema in patients transfused according to a liberal strategy. The increase in effective circulating volume and subsequent pulmonary edema seen in many liberally transfused patients may have offset any potential benefit from increased oxygen delivery.
There are a number of limitations to this study. The most important is that this study was designed to assess the overall effects of transfusion practices in the critically ill, rather than evaluate the effects of RBC transfusions on outcomes from mechanical ventilation. Consequently, decision algorithms for weaning and extubation were not used. However, different approaches to weaning from mechanical ventilation have not generated conclusions about consistently superior approaches,14 15 making it difficult to estimate the effect of this potential confounding variable. If such protocols had been shown to impact on the duration of ventilation and if they were differentially applied in these two groups, our conclusions would be different. Some randomized trials of different approaches to achieve safe and rapid extubation, including respiratory therapy-driven protocols16 17 and noninvasive ventilation,18 19 were not used in this study. Nevertheless, the lack of a standard approach to weaning may increase the variability in this trial and may have decreased our ability to detect meaningful differences between the two groups. Second, the majority of patients receiving mechanical ventilation can be rapidly and safely extubated14 20 and may easily tolerate low hemoglobin values during a relatively rapid process of liberation from mechanical ventilation. Therefore, the potential benefit or harm associated with transfusion may have been attenuated because we enrolled all patients receiving mechanical ventilation regardless of their duration of mechanical support; however, we did not observe any benefit to a liberal transfusion strategy among the subgroup of patients receiving mechanical ventilation for > 7 days. Another limitation to this study is that the analysis was based on a subgroup of patients from a larger randomized trial; therefore, all inferences should be interpreted cautiously, given that unknown prognostic variables may not be completely balanced between the groups. However, baseline differences between these two groups were similar, and multivariate analysis did not indicate any significant changes in the direction or magnitude of the RR compared to the unadjusted analysis. Finally, a post hoc power calculation revealed that this analysis would have been able to detect relative differences of 25% in duration of mechanical ventilation, 20% in ventilator-free days, and 10% for extubation success. Therefore, it is possible that our sample size may have been too small to detect clinically important differences in mechanical ventilation outcomes.
In summary, this study does not support the hypothesis that RBC transfusions improve outcomes from mechanical ventilation. A restrictive transfusion policy maintaining hemoglobin concentrations between 7.0 g/dL and 9.0 g/dL seems reasonable based on this analysis until further studies measure the interaction between hemoglobin values and different methods of weaning from mechanical ventilation. Careful observational studies will advance our understanding of the relation between myocardial and respiratory muscle function and hemoglobin values. Additional research should determine what RBC transfusion strategy should be advocated for patients who are difficult to liberate from mechanical ventilation,21 whether hemoglobin concentrations influence the success of unassisted breathing trials of different duration,22 23 and whether a liberal RBC transfusion strategy is advantageous for patients receiving mechanical ventilation with acute coronary syndromes.
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Appendix 1 |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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TRICC Investigators
Paul C. Hébert, MD, Ottawa Hospital, General Campus;
Guiseppe Pagliarello, MD, Ottawa Hospital, Civic Campus; John Marshall,
MD, Toronto Hospital, General Division; Patricia Houston, MD, Toronto
Hospital, Western Division; Martin Tweeddale, MD, PhD, Vancouver
General Hospital; Richard Hall, MD, Queen Elizabeth II Health Sciences
Centre, Halifax; David Mazur, MD, St. Michael’s Hospital, Toronto;
Thomas Stewart, MD, MSc, Wellesley Hospital, Toronto; Thomas Hillers,
MD, MSc, Hamilton General Hospital; Dean Sandham, MD, Foothills
Hospital, Calgary; James A. Russell, MD, St. Paul’s Hospital,
Vancouver; Yoanna Skrobik, MD, Hôpital Maisonneuve-Rosemont,
Montreal; John Muscedere, Hôtel Dieu-Grace Hospital, Windsor;
Claudio Martin, MD, MSc, Victoria Hospital, London; Sharon Peters, MD,
Health Sciences Centre, St. John’s; David Fleiszer, MD, Montreal
General Hospital; Alan Spanier, MD, Jewish General Hospital, Montreal;
Ann Kirby, MD, Saint Joseph’s Hospital, London; Jaime Pinilla, MD,
Royal University Hospital, Saskatoon; Mary van Wijngaarden, MD,
University of Alberta Hospital, Edmonton; Sheldon Magder, MD, Royal
Victoria Hospital, Montreal; Gordon Wood, MD, Daren Heyland, MD,
Kingston General Hospital; Navdeep Mehta, MD, Dr. Everett Chalmers
Hospital, Fredericton; Michael Jacka, MD, St. John Regional Hospital;
Sidney Viner, MD, Calgary General Hospital/Peter Lougheed Centre.
Data Monitoring Committee
Deborah Cook, MD, St. Joseph’s Hospital; Jack Hirsh, MD,
Hamilton Health Sciences Centre; Richard Cook, PhD, University of
Waterloo; Thomas Todd, MD, Toronto General Hospital.
Data Management Committee
Paul C. Hébert, MD, Irwin Schweitzer, MSc, Elizabeth
Yetisir, MSc, Ottawa Hospital, General Campus; George Wells, PhD, MSc,
My-Linh Tran, Fiona Daigle-Campbell, BA, Anne Gray, Ottawa Hospital,
Civic Campus.
Site Research Coordinators
Mustafa Seyidoglu, MD, Charlene Sexton, BScN, Ghulam Dostazadu,
MD, Ottawa Hospital, General Campus; Merrilee Leowen, RN, Ottawa
Hospital, Civic Campus; Debbie Williams, RN, Barbara Plumbstead, BScN,
Vancouver General Hospital; Joan Kearney, RN, Gwen Williams, RN, Vivian
Nedelcu, RN, Queen Elizabeth II Health Sciences Centre, Halifax; Linda
Perkins, RN, Montreal General Hospital; Gail Sloane, BScN, St.
Michael’s Hospital, Toronto; Violet Smirnios, RRT, Chanel McKenna, RN,
Eduardo Ng, MD, Toronto Hospital, Western Division; Marilyn Steinberg,
RN, Debra Foster, RN, BSc, Deborah Baptiste, RN; Toronto Hospital,
General Division; Joanne Kehoe, RPN, Linda McCarthy, RN, Dawn
Gilliland, RT, Brian Martin, RRT, Victoria Hospital, London; Daisy
Gibbons, RN, Health Science Centre, St. Johns; Deborah Jones, BScN,
Sonia Bertleff, BScN, Royal Victoria Hospital, Montreal; Diane Collins,
RN, Jewish General Hospital, Montreal; Diana Schouten, BScN, Wellesley
Hospital, Toronto; Lesley Crenshaw, RN, Linda Knox, RN, Judie Lasante,
Foothills Hospital, Calgary; Mary-Katherine Scott, RN, Saint Joseph’s
Hospital, London; Judee Strickland, RN, Royal University Hospital,
Saskatoon; Michelle Douglas, BScN, Karen Mulcahy, RN, Alana Drummond,
RN, St. Paul’s Hospital, Vancouver; Mario Racine, RN, Hôpital
Maisonneuve-Rosemont, Montreal; Melanie Amos, RN, Dr. Everett Chalmers
Hospital, Fredericton; Carol Gunderson, RN, Calgary General
Hospital/Peter Lougheed Centre; Loree Morrison, RN, Hamilton General
Hospital; Emmy Merkley, RN, Bev Armstrong, RN, University of Alberta
Hospital, Edmonton; Ann Taite, RN, Kingston General Hospital; Karen
Furlong, RN, St. John Regional Hospital; Carol Diemer, RN, Peggy
Oldfield, RN, Hôtel Dieu-Grace Hospital, Windsor.
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Acknowledgements |
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Footnotes |
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Drs. Hébert and Cook are Career Scientists of the Ontario Ministry of Health.
This study was supported by the Medical Research Council of Canada and an unrestricted grant from Bayer Inc.
Received for publication April 10, 2000. Accepted for publication November 3, 2000.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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