Low hemoglobin levels are frequently observed in patients with septic shock and may have several underlying causes, including reduced red blood cell (RBC) production due to systemic inflammatory response and increased RBC destruction due to hemolysis and bleeding [1]. In these patients, low hemoglobin levels may augment tissue oxygenation impairment by decreasing arterial oxygen concentration. Therefore, maintenance of adequate blood hemoglobin levels has been proposed as a strategy to diminish shock-induced tissue damage [2].

Although immediate hemoglobin correction <7.0 g/dl is one of the goals of transfusion, the critical hemoglobin concentration in critically ill patients at which oxygen delivery get impaired, tissue hypoxia ensues, and the risk of adverse outcomes increases has not been determined yet. In patients with septic shock, targeting a hematocrit value of 30% in those with a low central venous oxygen saturation during the first 6 hours of resuscitation [3] has been proposed [4]. However, blood transfusion has been associated with increased mortality in subgroups of critically ill patients, both in cohort studies and in randomized trial [5-8]. In a recent study investigating optimal hemoglobin levels in cases of septic shock, transfusion thresholds of 7 g/dl and 9 g/dl were compared and similar 90-day mortality rates were observed [9]. Current Surviving Sepsis Campaign guidelines recommend that RBC transfusion should be performed only when hemoglobin levels decrease to <7.0 g/dl in adults in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, or acute hemorrhage [10].

Low hemoglobin levels at the time of admission to the emergency department (ED) may indicate insufficient tissue oxygenation and may reflect that inflammation is more severe in such patients than in those with septic shock with normal hemoglobin levels. However, it remains unclear whether the severity of decrease in these levels correlates with patient outcomes. Therefore, we aimed to evaluate the association between initial hemoglobin levels and mortality in patients with septic shock treated with protocol-driven resuscitation bundle therapy at a hospital’s ED.

A total of 2,265 adult patients with septic shock were enrolled in the ED septic shock registry during the study period. The median age was 70.0 years (IQR, 60 to 78 years), and 58.3% patients were male. Hypertension was the most common comorbidity, observed in 41.2% of patients. Initial low hemoglobin levels (< 9.0 g/dl) were observed in 457 patients (20.2%). The characteristics of each group are detailed in Table 1. For the four groups, 90-day mortality rates were as follows: 29.1%, 43.0%, 46.5%, and 46.9% for ≥9.0 g/dl (n=1,808), 8.0−8.9 g/dl (n=217), 7.0−7.9 g/dl (n=135), and <7.0 g/dl (n=105), respectively, (P<0.001); 90-day mortality increased with decreasing initial hemoglobin levels. Analyses of white blood cell and platelet counts and prothrombin time revealed that the group with low hemoglobin levels had decreased leukocyte and platelet counts and increased prothrombin time (Table 1).

Patients with septic shock were treated with bundle therapy including fluid therapy, empirical antibiotics, and vasopressors. Intubation, mechanical ventilation, and renal replacement therapy results are summarized in Table 2. No significant differences were observed among the four groups for bundle therapy. Not surprisingly, transfusion frequency was higher in patients with low hemoglobin levels (Table 2).

Multivariate logistic regression analyses revealed that age, chronic pulmonary disease and initial SOFA score were associated with 90-day mortality rate (Table 3). Initial hemoglobin levels were independently associated with 90-day mortality, and mortality proportionally increased with decreasing hemoglobin levels (OR, 1.88; 95% CI, 1.36 to 2.61 for 8.0−8.9 g/dl; OR, 1.97; 95% CI, 1.31 to 2.95 for 7.0–7.9 g/dl; and OR, 2.35; 95% CI, 1.52 to 3.63 for <7.0 g/dl). However, there was no statistical correlation between RBC transfusion within 6 hours and 90-day mortality rate. Further analysis about the association of 28-day mortality and hemoglobin level were summarized in Supplementary Table 1.

Anemia is a common problem in critically ill patients. The present study showed that approximately 20% of patients with septic shock who visited ED had low hemoglobin levels (<9 g/dl). A large observational study including 3,534 patients from European intensive care units reported mean hemoglobin levels at admission to be 11.3 g/dl, with 29% patients having levels <10 g/dl [16]. In a prospective cohort study [17], 55% of all patients had hemoglobin levels <9 g/dl, a higher rate than that observed in the present septic shock cohort. One possible explanation is the fact that blood loss (due to trauma, surgical procedures, or occult gastrointestinal bleeding), one of the most common cause of anemia in critically ill patients, is less common in patients with septic shock. Sepsis is a complex pathophysiological process, and possible underlying mechanisms include microcirculation alterations, decreased RBC production, pre-existing chronic anemia, hemodilution, and increased RBC destruction due to alterations in RBC membranes.

Current guidelines recommend that the transfusion threshold should be hemoglobin levels <7 g/dl, aiming at levels between 7 g/dl and 9 g/dl in patients without myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic coronary artery disease [10]. However, there are limited data supporting these recommendations [10], and many clinicians do not comply with these, despite findings from the transfusion requirements in septic shock trial, which compared transfusion thresholds of 7 g/dl and 9 g/dl, showing similar 90-day mortality rates (45% vs. 43%) in patients with septic shock [9].

In the present study, we found that percentage of patients with 90-day mortality increased with decreasing initial hemoglobin levels. Moreover, multivariate logistic regression analysis revealed that initial hemoglobin levels were independently associated with 90-day mortality and mortality proportionally increased with decreasing hemoglobin levels. These data suggest that, apart from being a therapeutic target, initial hemoglobin levels may also be a prognostic factor. This hypothesis is consistent with the results from a recent small observational study by Muady et al. [1] reporting that hemoglobin levels on admission independently correlate with survival (OR, 0.83; 95% CI, 0.75 to 0.92). Furthermore, a study of patients with community-acquired pneumonia found that hemoglobin levels <10 g/dl were independently associated with 90-day mortality [18]. Although it is known that lower hemoglobin levels in the setting of increased oxygen demand, frequently observed in septic shock cases, may play a negative role and augment organ dysfunction, the prognostic relevance of low hemoglobin levels may alternatively be explained by the fact that it may also reflect older age or a high rate of comorbidities.

Although this study showed that transfusion had no significant association with mortality, previous studies investigating the correlation between blood transfusion and mortality in sepsis found conflicting results [19-21]. As previously mentioned, at the hospital where this study was conducted, decision regarding a blood transfusion relies on the treating physician’s discretion rather than on a specific transfusion protocol. Thus, it would be actively administration of blood products in more severely ill patients. The present study revealed poor patient outcomes associated with low hemoglobin levels at presentation. However, due to the observational nature of our study, these results do not support definite conclusions about optimal hemoglobin levels and about an optimal blood transfusion strategy for patients with septic shock. Another limitation of this study that is worth mentioning is its retrospective design, which necessarily impacted data collection, analysis, and interpretation. Although this was addressed through an adjusted multivariate analysis, the potential for bias due to an unmeasured confounder remains. For example, the initial patient’s condition may affect mortality, but the physician’s management, such as appropriate selection of empirical antibiotics, may also affect patient’s mortality. However, data beyond the contents of the registry could not be evaluated. Additionally, this cohort comprised patients from a single medical center; thus, the results may be influenced by referral bias. Conversely, the consecutive enrollment of patients with septic shock with a prospective registry reflects a realworld scenario, free of typically observed inclusion biases.

In this study, low hemoglobin levels (<9.0 g/dl) were observed in approximately 20% of patients with septic shock, and the severity of decrease in these levels correlated with mortality. However, transfusion itself was not an independent factor affecting mortality. These findings suggest that initial hemoglobin levels may play a role as a prognostic factor and that a better understanding of the etiology of low hemoglobin levels may prompt the investigation of new preventive therapeutic strategies.