Impact of transfusion on patients with sepsis admitted in intensive care unit: a systematic review and meta-analysis
This systematic review suggested that a restrictive strategy could be achieved and that transfusion was not associated with increased mortality but rather with the occurrence of nosocomial infections, acute lung injuries or kidney injuries. Nevertheless, because of the limited number of studies on transfusion focusing specifically on patients with sepsis, added to the heterogeneity of the studies dealing with death, no definitive conclusions should be drawn. All those results deserved several comments.
First, the only study focusing specifically on RBCT thresholds among patients with septic shock suggested the safety of the restrictive strategy [9]. This result is in line with the results of two RCTs enrolling both septic and non-septic patients and of our post hoc meta-analysis (Additional file 2: Figure S2) [6, 9, 19]. However, some limits should be underlined. First, previously transfused patients were excluded; therefore, the safety of a restrictive strategy during the early phase of septic shock is still not explored and further study is needed. In that context, three recent RCTs (ProCESS [28], ARISE [29] and ProMISe [30]), included in a meta-analysis from Angus [31] concluded that the EGDT described by Rivers [2] was no more associated with a better outcome. Furthermore, two cohort studies showed that transfusion was safe and even beneficial during this early phase of septic shock [32, 33] and underlined that ScVO2 or lactate should be considered to trigger transfusion. Then, because of a partial blinding in the available RCT, many physicians did not comply with the restrictive strategy in case of risk of ischemic events. Similarly, patients with ongoing ischemic events were excluded. Consequently, the external applicability of the result could not be fully guaranteed, specifically concerning septic patients with cardiovascular events. Of note, two other studies, one after cardiac surgery [34] and another one in onco-hematology [35], were in favor of a liberal RBCT strategy. As a result, the real safety of a drastic systematic restrictive transfusion threshold among patients with sepsis must be addressed and further research is needed to determine which patients with sepsis may actually benefit from restrictive transfusion strategies. Several subgroups should be thus considered with a special interest on older patients, on patients with cardiac comorbidities, with acute ischemic event, acute brain injury or with cancer for whom a Hb threshold of 8–9 g/dL may be more appropriate.
Second, from the cohort studies, we demonstrated that transfusion did not impact death rate. This result differed from those of other studies conducted in ICU patients or after myocardial infarctions [36–42] where transfusion was deleterious. One explanation could be that patients with sepsis increased their basal metabolic and oxygen demands and thus could be more beneficial from transfusion [43]. The improvement of microcirculation by transfusion in case of baseline alteration in septic patients has also been demonstrated [44]. Nevertheless, the meta-analysis pointed out the significant heterogeneity of the transfusion effect in septic patients. The study from Park et al. [13] that showed a protective effect of transfusion was one of the main sources of heterogeneity (Fig. 7). This could be explained in part because of a lower transfusion threshold [13] (Hb = 7.7 (1.2) g/dL). Another source of heterogeneity was the statistical modeling. Indeed, some results were obtained after adjustment, and others without any, and only one study took into account time-dependent covariates by using a Cox model. Of note, the impact of deleukocytation could not be explored because of not systematically reported (Table 1).
Third, it is quite difficult to reach the real causal effect of RBCT because of treatment repetitions and of the many baseline- and time-dependent confounding factors. Until nowadays, none of the studies published have handled all those issues. Furthermore, it is important to know that Cox models with time-dependent covariates might also be biased if the proportional hazard assumption was not ascertained [45] and also because ICU discharge is an informative censor and modifies the risk of mortality and morbidity events [46]. Newer statistical causal models that can handle repetition of the treatments, such as the marginal structural models, should thus be used.
Fourth, our review suggested that transfusion was associated with the occurrence of nosocomial infection. Those results are in accordance with those of another recent meta-analysis [47], which demonstrated that restrictive strategies were associated with a reduction of the occurrence of healthcare-associated infections. Transfusion-related immune modulation (TRIM) should be considered as the main explanation [5, 48]. Mechanisms for TRIM include suppression of cytotoxic cells and monocyte activity, release of immunosuppressive prostaglandins, inhibition of interleukin-2 (IL-2) production and increase in suppressor T-cell activity and leukocytes. In this respect, the occurrence of nosocomial infections could be minimized thanks to deleukocytations of the RBCT, as demonstrated by several studies [49]. However, Jufferman also found an association between RBCT and nosocomial infections even after a systematic leukodepletion [24]. It could be explained by the few remaining leukocytes in RBCT, but also by the presence of biological active cytokines or others immunomodulating components of the red blood cells themselves. Furthermore, patients with sepsis might be more sensitive to the TRIM because of their previous immunosuppressive states.
Fifth, transfusion was associated with an increased risk of acute kidney injury. This result is based on only one study, and only few physiologic studies focused on the impact of transfusion on kidney function [44]. However, some authors believed that transfusion may elicit a renal injury similar to lung injury because of immunologic mechanisms and of overload [27, 50, 51].
Last, transfusion was associated with acute lung injury. From those studies, it was not possible to make the difference between immunologic mechanisms [transfusion-related acute lung injury (TRALI)] or overload [transfusion-associated cardiac overload (TACO)].