Trial Design and Oversight

After the approvals from ethics committees and data-protection agencies were obtained, patients in 32 general ICUs in Denmark, Sweden, Norway, and Finland underwent screening and randomization between December 3, 2011, and December 26, 2013. Written informed consent was obtained from all the patients or their legal surrogates before or after enrollment. In all cases, consent was obtained from the patient when possible. If consent was withdrawn or not granted, we asked the patient or surrogate for permission to continue registration of trial data and to use these data in the analyses. The protocol, including details regarding trial conduct and the statistical analysis plan, has been published previously15 and is available with the full text of this article at NEJM.org. The management committee (see the Supplementary Appendix, available at NEJM.org) designed the trial and vouches for the adherence of the study to the protocol and for the accuracy of the data and the analyses. The members of the management committee wrote the drafts of the manuscript and made the decision to submit the manuscript for publication. The funders had no role in the design of the protocol, the trial conduct, or the analyses or reporting of the data.

This trial was a multicenter, stratified, parallel-group, clinical trial. Randomization was performed with the use of a centralized computer-generated assignment sequence, with stratification according to study site and the presence or absence of active hematologic cancer, because these characteristics may influence outcome.16,17 Patients with septic shock were randomly assigned in a 1:1 ratio, with the use of permuted blocks of varying sizes of 6, 8, or 10, to blood transfusion at the higher hemoglobin threshold or the lower hemoglobin threshold. Treatment assignments were concealed from the investigators assessing mortality, the data and safety monitoring committee, and the trial statistician. The conduct of the trial and the safety of the participants were overseen by the data and safety monitoring committee, which performed an interim analysis after 500 patients had been followed for 90 days. The trial data were monitored by staff from the coordinating center.

Trial Patients

Figure 1. Figure 1. Assessment, Randomization, and Follow-up. Patients were excluded if they had undergone randomization in this study previously, if there were medical reasons, if they had received a blood transfusion during the current intensive care unit (ICU) admission, if there was a documented wish not to receive a transfusion, or if informed consent could not be obtained. A total of 15 patients met two exclusion criteria. One patient was excluded immediately after randomization when it was determined that an inclusion criterion had not been met, and 4 were excluded because consent was withdrawn during the trial. Thereafter, 5 additional patients underwent randomization in order for the study to obtain the full sample. All the patients who withdrew from the trial at their own request or at a surrogate's request allowed the use of their data, but 14 patients or surrogates in the lower-threshold group (hemoglobin level, less than or equal to 7 g per deciliter) and 7 in the higher-threshold group (hemoglobin level, less than or equal to 9 g per deciliter) did not want further data registered except for mortality data, which were obtained from national registries. The process data (hemoglobin assessments and numbers of transfusions and temporary protocol suspensions and protocol violations) and some of the secondary-outcome data for these patients are missing.

We screened patients 18 years of age or older who were in the ICU, fulfilled the criteria for septic shock,18 and had a blood concentration of hemoglobin of 9 g per deciliter or less as measured by means of valid point-of-care testing (see the Supplementary Appendix). The reasons for the exclusion of some patients are shown in Figure 1 and listed in the Supplementary Appendix.

Intervention

Enrolled patients were given single units of cross-matched, prestorage leukoreduced red cells suspended in a saline–adenine–glucose–mannitol solution when the blood concentration of hemoglobin had decreased to the assigned transfusion threshold (≤7 g per deciliter [lower threshold] or ≤9 g per deciliter [higher threshold]). These levels of hemoglobin have frequently been used as thresholds for transfusion in patients with septic shock.15 Hemoglobin concentrations were reassessed within 3 hours after termination of the transfusion or before the initiation of another transfusion. The intervention period was the entire ICU stay, to a maximum of 90 days after randomization.

In the event that life-threatening bleeding or ischemia developed while a patient was in the ICU or a patient required the use of extracorporeal membrane oxygenation, the patient could receive a transfusion at a hemoglobin threshold decided by the attending doctor. The attending doctor decided when the patient again was to receive a transfusion at the assigned hemoglobin threshold. After the unmasking of trial data showing harm from hydroxyethyl starch,3 we recommended against the use of all starch products in trial patients. All other interventions were at the discretion of the clinicians, including transfusion during surgery and after ICU discharge.

Outcome Measures

The primary outcome measure was death by 90 days after randomization. Secondary outcome measures were the use of life support (defined as the use of vasopressor or inotropic therapy, mechanical ventilation, or renal-replacement therapy) at days 5, 14, and 28 after randomization19; the number of patients with serious adverse reactions while in the ICU (allergic reaction, hemolysis, transfusion-associated acute lung injury, or transfusion-associated circulatory overload) (see the Supplementary Appendix); the number of patients with ischemic events while in the ICU, which included cerebral ischemia (identified from the results of imaging), acute myocardial ischemia (defined by symptoms, electrocardiographic signs, or elevated biomarker levels resulting in an intervention), intestinal ischemia (as observed during endoscopic examination or surgery), or limb ischemia (defined as clinical signs resulting in an intervention) (for full definitions, see the Supplementary Appendix); the percentage of days alive without vasopressor or inotropic therapy, mechanical ventilation, or renal-replacement therapy in the 90 days after randomization; and the percentage of days alive and out of the hospital in the 90 days after randomization. Data for the outcome measures were obtained by TRISS trial investigators or their delegates from patient files and national and regional registries for the entire 90-day follow-up period.

Statistical Analysis

We calculated that we would need to enroll 1000 patients for the trial to have 80% power to show mortality at 90 days that was 9 percentage points lower in the lower-threshold group than in the higher-threshold group, at a two-sided alpha level of 5%, assuming a mortality in the higher-threshold group of 45% (estimated from two previous cohorts).20,21 The estimated difference of 9 percentage points was derived from the 20% reduction in relative risk observed with a restrictive versus liberal transfusion strategy in the subgroup of patients with severe infection in the Transfusion Requirements in Critical Care (TRICC) trial.9 During our trial, 5 patients were excluded after randomization (4 patients did not allow the use of their data, and 1 did not have sepsis, which was realized immediately after randomization). A total of 5 additional patients underwent randomization in order for the study to obtain the full sample (Figure 1).

An author who was the statistician for the study and who was unaware of the study-group assignments performed all the analyses according to International Conference on Harmonisation Good Clinical Practice guidelines22 and the statistical analysis plan.15 We performed the primary analyses in the intention-to-treat population, which included all the patients who underwent randomization, except for those whose data were deleted from the database during the trial (i.e., the 5 patients, noted above, who were excluded after randomization) and after the trial (2 patients who withdrew consent for the use of their data) (Figure 1). In the per-protocol populations, we excluded patients who had one or more bleeding or ischemic episodes or one or more major protocol violations (see the Supplementary Appendix).22

In the primary analyses (including the analysis of the primary outcome measure), we compared data between the two groups by means of logistic-regression analysis for binary outcome measures with adjustment for the stratification variables (study site and presence or absence of active hematologic cancer),23 and we converted odds ratios to relative risks.24 We also performed unadjusted chi-square testing for binary outcome measures and Wilcoxon signed-rank testing for rate and ordinal data. We compared the primary outcome in the per-protocol populations and in prespecified subgroups defined according to the presence or absence of chronic cardiovascular disease (i.e., any history of myocardial infarction, any history of stable or unstable angina pectoris, previous treatment with nitrates, percutaneous coronary intervention, coronary-artery bypass grafting or noncoronary vascular interventions, any history of chronic heart failure [defined as New York Heart Association class III or IV], or any history of cerebral infarction or transitory cerebral ischemia), an age of 70 years or younger versus an age older than 70 years, and a Simplified Acute Physiology Score (SAPS) II above 53 versus 53 or lower at baseline (with the score calculated from 17 variables and ranging from 0 to 163, with higher scores indicating higher severity of disease) and used multiple logistic-regression analyses in the intention-to-treat population to adjust for differences in prespecified risk factors at baseline. Details regarding the handling of missing data are provided in the Supplementary Appendix. We performed all analyses using SAS software, version 9.3 (SAS Software), and SPSS software, version 17.0 (SPSS). A two-sided P value of less than 0.05 was considered to indicate statistical significance.