In this cohort study, our results first show compared to > 80 g/L group, septic patients with hemoglobin ≤ 80 g/L within 48 h after admission to ICU has higher rates of in-hospital, 180-d and one-year mortality. The rates of CRRT and MV usage are also higher in ≤ 80 g/L hemoglobin group. Furthermore, hemoglobin ≤ 80 g/L within 48 h on admission,the occurrence of ARDS, the use of CRRT and septic shock are the independent risk factors of one-year mortality for septic patients. While the frequency of infectious source from abdomen was the only independent protective factor for one-year mortality in septic patients.
The comparison between survival and non-survival groups demonstrates the higher mortality rate for male septic patients, which is consistent with recent experimental studies (16, 17), sex-hormone-driven innate antibodies protect female from infection. And non-survival group has earlier hematologic and coagulation function turbulence, with higher rates of hemoglobin ≤ 80 g/L and ≤ 70 g/L, lower platelet, longer APTT as shown by our data. So hematologic system plays a key role at the beginning of sepsis. Serum lactic acid level is higher in non-survival group partially represents tissue hypoxia in early stage. Higher rates of complications including septic shock and ARDS, higher frequency of use of life support, covering CRRT, MV and vasopressors usage, longer days of vasopressors and higher SOFA score in non-survival group reflect more serious of sepsis.
The nearly similar baseline precludes bias affecting results. Intriguingly, there are significantly higher in-hospital, 180-d, one-year mortality in ≤ 80 g/L hemoglobin group compared to > 80 g/L group in septic patients. While ≤ 90 g/L hemoglobin group has the same in-hospital and 180-d mortality compared with > 90 g/L group. These results hint at 80 g/L hemoglobin could be the potential key cutoff to differentiate septic prognosis. However, there are significant differences of survival rates among all three hemoglobin groups within one year shown by Kaplan-Meier survival analysis.
Furthermore, we find ≤ 80 g/L hemoglobin within 48 h after admission to ICU, the occurrence of ARDS, the use of CRRT, and septic shock are the independent risk factors of mortality of sepsis patients by multiple Cox hazard analysis to control possible cofounders. And the rate of infection site from abdomen is the only independent protective factor. Hemoglobin ≤ 90 g/L is not the independent risk factor as not included in the multiple Cox hazard model. Hemoglobin ≤ 70 g/L not incorporated into the model is possibly due to fewer cases. Albeit several large cohort shows 70 g/L is the optimal transfusion threshold for critical patients including sepsis (9, 10), these results are not in contradiction with ours. Because we try to explore the best early hemoglobin level closely affecting sepsis prognosis, instead of blood transfusion threshold. We discuss the effective early hemoglobin level for delivering oxygen to important organs in early stage of sepsis, rather than the adverse reaction nor decreased oxygen utilization ability brought by transfusing stored-blood products (18). Our conclusion is in line with early goal-directed therapy (EGDT) study which emphasizes maintaining early tissue perfusion and correcting early tissue hypoxia are the core therapy strategy for sepsis (19). Time course of hemoglobin in nonbleeding ICU patients shows that hemoglobin of sepsis patients persists to decrease in whole course in ICU compared to non-septic patients, and the change rate of hemoglobin concentration is inversely correlated to the severity of diseases (5). Several other studies results support our conclusion (20–23), while recent Sung’ research has shown that 90 g/L is the befitting cutoff hemoglobin level of 90-days mortality of patients with septic shock which is different from ours (24). However, there are two main differences between our study and Sung’s: our study investigates much longer term, one year, prognosis of sepsis than Sung’s, and our study subjects are septic patients while Sung’s is the sick with septic shock. Patients with septic shock have more unstable hemodymic status thus probably requiring higher hemoglobin level to fulfill tissue oxygen need. Moreover, according our results hemoglobin ≤ 90 g/L not influences in-hospital or 180-days mortality, secondly hemoglobin ≤ 90 g/L is not independent risk factor of one-year mortality of septic patients in the process of using multivariate cox hazard model to control confounding bias. Studies with bigger data are needed to validate our results. In conclusion, we first report early hemoglobin level > 80 g/L best fits better outcome and longer survival rate, this level is also recommended by experts consensus focused on hemodynamic support of sepsis and adopted by extensive clinicians, although lack of robust evidences (25).
In our results, the higher rates of septic shock and ARDS are independent risk factors for septic mortality is reasonable. However, whether the use of CRRT is beneficial or detrimental to septic patients is always in eternal debate. There are other factors that cannot be ignored should be taken into comprehensive consideration, that is, various pharmacokinetic changes of diverse antibiotics under different renal replacement therapies among distinct individuals in sepsis (26–28). So in order to maximize therapeutic effect of antibiotics and minimize its adverse effects, dynamic monitoring of individual pharmacokinetic change of specific antibiotic is needed when accessing effect of certain kind of renal replacement therapy on sepsis. As for infection site, one study shows abdominal infection site is the independent protective factor of in-hospital mortality of sepsis associated acute lung injury, which is consistent with our results (29). To verify the exact mechanism needs further experimental studies.
We suppose the underlying rationality for our conclusion is mainly associated with relationship between decreasing hemoglobin and early tissue and organ hypoxia at the beginning of sepsis. Hypoxia works in pathophysiology of abundant diseases including sepsis (30). We propose that hypoxia in early stage of sepsis plays an important role in the progress and bad outcome of sepsis, as the only carrier for oxygen in circulation, hemoglobin level in early phase of sepsis should be paid more attention. In addition, erythrocyte has many other important functions for defending against infection and sepsis except for oxygen carrier, for instance red blood cells can help kill bacteria more efficiently (31). Changes in properties of erythrocyte are also early sensitive warning signals for monitoring progress of sepsis (32, 33).
On the other hand, we want to emphasize that a simple hemoglobin cutoff should not be overemphasized against every unique scene in clinical practice. Because individual variation is universal between every two single persons, and different age, background co-morbidities, etiologies of sepsis, every respect should be taken into careful consideration for physicians to make decisions to cure patients. The latest editorial warns that the only hemoglobin concentration strength cannot be exaggerated instead we should take all the factors into account in every specific clinical scene (34), which is in line with our viewpoint. So we must stand beside the beds of patients, keep looking the specific dynamic change of conditions of every unique individual, weight the advantages and disadvantages for making transfusion and other decisions to achieve best clinical outcome for patients (35).
There are some limitations for our study. First, the type of our research is single centered, retrospective design and unavoidable for bias. We try our best to reduce confounding bias by using Cox proportional hazards regression model to prove the unique ability of early hemoglobin level predicting sepsis prognosis. What’ more, we minimize cases that lose to follow-up and guaranteed follow-up equality to decrease withdraw bias; Secondly, our sample size is relatively not very big to enhance convince ability, while we complement the data to the greatest extent and do our best to decrease missing and guarantee data integrity and quality to strengthen stringency. Third, the single centered design restricts the generalizability of our conclusion, but we conducte the research in different ICUs setting to narrow generalizability reduction, multiple centered plan is suggested in the future. Fourth, ≤ 70 hemoglobin not including in multivariate cox hazard model is due to the case number of ≤ 70 hemoglobin was so small, future study with larger data is needed to verify our result.
There are some strengthens of our study. First, we focus on the influence of early hemoglobin level, grouped by 70, 80 and 90 g/L, on the long term prognosis of sepsis, which was not investigated before. And we found ≤ 80 g/L hemoglobin is the independent risk factor for sepsis longer mortality, which is meaningful to raise awareness to value maintaining early hemoglobin stable in therapy for sepsis. Secondly, we suggest readers to interpret our results with discretion and call for uniting our results with actual situation of patient at the bedside to make best clinical decisions.