Sepsis is a life-threatening condition with a high incidence, mortality, and cost. It is recognized as a primary priority by the World Health Organization [1]. There is an urgent need for a safe, effective, and inexpensive treatment. A retrospective clinical study has recently found that hydrocortisone combined with ascorbic acid (vitamin C) and thiamine (HAT therapy), also called as metabolic resuscitation therapy, can significantly reduce mortality and improve organ dysfunction in patients with sepsis [2]. Marik showed that sepsis management should include early diagnosis and timely treatment with antibiotics, source control, and a conservative approach, including fluid management, the administration of vasopressors, and early use of metabolic resuscitation drugs, including vitamin C, hydrocortisone, and thiamine [3]. This notion has caused widespread concern. Theoretically, these drugs may improve sepsis by inhibiting an excessive inflammatory response, reversing shock, restoring organ perfusion, and promoting cell metabolism recovery [4]. Some Randomized Controlled Trials (RCTs) have been conducted to validate the efficacy of metabolic resuscitation drugs alone or in combination [4].

Unlike previous sepsis studies, the primary outcome in most RCTs using metabolic resuscitation drugs for treating sepsis has been transformed from mortality to improvement in the Sequential Organ Failure Assessment (SOFA) score or the shortening of septic shock duration. The cause of mortality in patients with sepsis is complicated; undoubtedly, these transformations can reduce the confusion caused by some competing mortality risks and directly reflect the improvement of organ function. However, in most of published RCTs, except the ORANGES study, which demonstrated a shorter duration of vasopressor use in patients with HAT therapy [5], the SOFA score or shock status of patients with sepsis with metabolic resuscitation drugs alone or in combination has not showed any excepted improvement. Two small-sample RCTs showed that vitamin C could positively impact organ function and reverse shock [6,7]. Some intensivists believe that RCTs do not replicate real-world efficacy. This belief may be related to different exclusion criteria, including patient heterogeneity, non-standardized joint intervention, and different dose ranges and timings of the three drugs [8]. It is also imperfect to choose SOFA score improvement or the reversal of septic shock as the primary outcome of the efficacy of metabolic resuscitation drugs. The endpoint SOFA score may not be available for patients who died or were ICU-discharged earlier. This situation can lead to attrition bias and underestimating the true benefit of metabolic resuscitation drugs [9]. Regarding the reversal of shock as the primary outcome, mortality during the study period may also affect the duration of vasopressors. The reasons mentioned above probably affect the trial results.

A series of negative outcomes in RCTs have not made intensivists lose heart and enthusiasm for vitamin C, hydrocortisone, and thiamine [8]. Evaluations of the effectiveness of these drugs alone or in combination in patients with sepsis will certainly continue for a long time. To better detect the benefits of vitamin C, hydrocortisone, and thiamine in patients with sepsis and avoid wasting trial resources, it is time to summarize and make changes. First, the current negative outcomes cannot reflect the economic effect of the three drugs. In addition, the low cost and continued availability of vitamin C, hydrocortisone, and thiamine are important reasons to stimulate widespread interest among intensivists [2]. Therefore, some pharmacoeconomic analysis maybe necessary, such as cost-effectiveness, to evaluate the cost and benefit of these drugs. Cost-effectiveness is an analytic tool in which a certain therapy and at least one alternative treatment are compared in terms of cost per unit of effectiveness [10]. Effects include health outcomes, such as Quality-adjusted Life-Years (QALY), rather than monetary measures, as in cost-analysis, proposed as an outcome measure for critical care trials [11]. By comparing the cost of generating one additional QALY, we can determine whether these resuscitation drugs are more cost effective and worthwhile than placebo. Second, the ORANGES study showed that HAT therapy can shorten vasopressor duration in patients with sepsis. It may also be related to its performance in two non-teaching hospitals because its minimal resource utilization better reflects real-world clinical management [5]. Therefore, recruiting some patients in non-teaching hospitals may help to reduce the interference of other combination treatments. Third, sepsis is an overly heterogeneous syndrome with different subsets or phenotypes, resulting in different risks for poor outcomes and different responses to some interventions, such as glucocorticoid and fluid resuscitation [12–14]. Based on this feature, sepsis should be managed by stratifying patients into subphenotypes, in which different types can be targeted depending on the intervention strategy. Accordingly, it is crucial for the future RCTs to identify the subclass of sepsis and its responses to the resuscitation drugs through a secondary analysis of published RCTs. Lastly, even if these drugs cannot improve sepsis prognosis, their efficacy in preventing patients with suspected infection in the ICU or emergency room from suffering sepsis or septic shock is still unclear, thus, an urgent need for its determination.

In conclusion, metabolic resuscitation therapy in patients with sepsis has not yet been established, and beneficial evidence of metabolic resuscitation drugs for sepsis is still urgently expected. However, maybe it is time to make adjustments to the protocol of future RCTs on metabolic resuscitation therapy.