HAT therapy for sepsis: A review of the therapeutic rationale and current clinical evaluation status

Abstract

Vitamin C-based cluster therapy, which involves the combined application of hydrocortisone, vitamin C, and thiamine (HAT), is a recently proposed new treatment option for sepsis on top of conventional treatment. This therapy has a strong theoretical basis, but its clinical efficacy remains inconclusive. This review summarizes the rationale for HAT therapy for sepsis and describes the evaluation of its efficacy in clinical observational studies and randomized controlled trials, with the aim of providing a reference for the future clinical practice application of HAT therapy in sepsis.

Introduction

Sepsis is a dysregulation of the body's response to infection, resulting in life-threatening organ dysfunction.^[1,2] Approximately 1/5 of patients in intensive care units (ICUs) suffer from sepsis, and 1/3 of them die, thus sepsis poses a serious threat to human health.^[3] Current clinical treatments of sepsis predominantly include active control of the primary infected lesion, early empirical use of broad-spectrum antibacterial drugs, organ support, and other comprehensive treatment measures. Increasing research on sepsis has revealed that mitochondrial dysfunction plays a key role in the pathophysiology of sepsis, characterized by reduced adenosine triphosphate (ATP) production and enhanced oxidative stress, resulting in oxidative damage to cells and tissues, bioenergetic failure, immune responses, injury, and ultimately organ dysfunction.^[4,5] Consequently, modulation of mitochondrial function may be a promising strategy for metabolic resuscitation in sepsis.

In recent years, the combined application of hydrocortisone, vitamin C, and thiamine—in addition to the conventional treatment for sepsis—has been proposed as a triple cocktail therapy (HAT therapy) for sepsis and is essentially metabolic resuscitation. HAT therapy significantly improved in-hospital mortality in a study of patients with severe sepsis and septic shock.^[6] However, a series of further studies evaluating the clinical effectiveness of HAT therapy reached mixed conclusions. This review summarizes the existing studies on HAT therapy with a view to providing a reference for the future application of HAT therapy in sepsis.

Vitamin C

Vitamin C has immunomodulatory, antioxidant, and antithrombotic properties, and deficiency of this vitamin can cause abnormal blood coagulation and damage to endothelial function.[7], [8], [9] During sepsis, mitochondrial oxidative stress increases and the body is in a hypermetabolic state, resulting in a significant decrease in vitamin C.^[10] Vitamin C supplementation in patients with sepsis could directly scavenge excess reactive oxygen species and limit the oxidation of mitochondrial proteins, enzymes, lipoproteins, and cell membranes in pathological states. This antioxidant effect also protects the tight junctions between vascular endothelial cells and epithelial cells, attenuates apoptosis, and ultimately reduces oxidative stress and improves vascular endothelial permeability and microcirculation (Figure 1).^[11] Several clinical studies have evaluated the effectiveness of vitamin C on sepsis with mixed findings.[12], [13], [14], [15], [16], [17], [18], [19] One influential trial was The LOVIT study,^[17] which included a total of 872 adult patients with sepsis receiving vasopressors in the ICU and found a higher risk of 28-day mortality or persistent organ dysfunction in the vitamin C-treated group. However, the study included patients with relatively high severity of disease and did not perform a subgroup analysis of the heterogeneity of the included subjects (e.g., whether serum vitamin C levels were reduced, whether the patients were also in a hyperinflammatory state), which may have an impact on the negative conclusions. The latest meta-analysis found that vitamin C reduced the short-term mortality rate and duration of vasopressor, but there was no significant improvement in the sequential organ failure assessment (SOFA) score.^[20,21] Overall, considering the varying evidence of clinical efficacy and potential adverse drug reactions (such as nephrotoxicity) of vitamin C, further trials are needed to explore the appropriate patient population and optimal dose and duration of vitamin C use.

Figuer 1.

Mechanism of metabolic resuscitation by HAT therapy for sepsis.

Acetyl CoA: Acetoacetyl coenzyme A; ATP: Adenosine triphosphate; NADPH: Nicotinamide adenine dinucleotide phosphate oxidase; ROS: Reactive oxygen species.

Thiamine

Thiamine is a coenzyme necessary for cellular glucose metabolism, acting in the tricarboxylic acid cycle and the pentose phosphate pathway.^[22] Figure 1 shows the specific mechanism of thiamine on cellular metabolism. Thiamine deficiency impairs aerobic cellular respiration and increases the risk of lactic acidosis, hypotension, and even death in critically ill patients.^[23,24] Theoretically, thiamine supplementation could reduce lactate clearance levels, attenuate mitochondrial dysfunction, and improve organ dysfunction in sepsis. However, the effectiveness of thiamine in treating patients with sepsis is controversial, although there is no evidence that thiamine supplementation is associated with serious adverse effects.[25], [26], [27] Therefore, thiamine is still considered a low-risk and potentially high-reward intervention in critically ill patients, especially those with septic shock who are severely thiamine-deficient.

Hydrocortisone

Corticosteroids have strong immunomodulatory properties and can exert anti-inflammatory effects by inhibiting the differentiation, maturation, proliferation, and migration of various subtypes of leukocytes and producing anti-inflammatory factors,^[28] making corticosteroids commonly used in the clinical treatment of sepsis and septic shock.^[29] Corticosteroids showed potential to reduce ICU and hospital mortality in some patients with sepsis.^[30] However, due to the inhibitory effect of corticosteroids on immune function, long-term use carries the risk of inducing or exacerbating infections. Furthermore, the latest Survival Sepsis Campaign (SSC) guidelines recommend the use of corticosteroids for patients in septic shock (weak recommendation, moderate quality evidence).^[31]

Combination of Hydrocortisone, Vitamin C, and Thiamine

Compared with each drug alone, the combination of hydrocortisone, vitamin C, and thiamine appears to have more significant effects on the course of sepsis, which may be related to the synergistic effect of all three agents.^[6,8]Figure 1 illustrates the detailed mechanisms by which the three drugs cooperatively regulate cellular metabolism. Thiamin could attenuate cellular oxidative stress together with vitamin C and may protect against possible renal injury caused by high doses of vitamin C by inhibiting oxalate conversion. Vitamin C could cooperate with hydrocortisone to inhibit activation of the nuclear factor (NF)-kB signaling pathway, downregulate the production of pro-inflammatory mediators, and maintain vascular endothelial function and microcirculation. In addition, hydrocortisone may promote vitamin C absorption by inducing the expression of ascorbate transporter protein (sodium-vitamin C transporter [SVCT2]), while vitamin C may reduce the oxidation of hydrocortisone receptor and enhance its efficacy. Hydrocortisone combined with vitamin C was shown to synergistically prevent and repair lipopolysaccharide (LPS)-induced damage to human pulmonary microvascular endothelial cells and reverse shock compared with vitamin C or hydrocortisone alone.^[32] In addition, the combination of vitamin C and thiamine was associated with lower SOFA scores and a shorter duration of vasopressor use in patients with sepsis and septic shock.^[33] In summary, this triple therapy can theoretically interact to synergistically regulate cellular metabolism and function and finally alleviate sepsis-associated organ injury.

Clinical Practice of HAT Therapy for Sepsis in Observational Studies

HAT therapy was first described in a study published in Chest in December 2016, which included a total of 94 patients with severe sepsis and septic shock categorized by Sepsis 1.0 criteria.^[6] Patients in the treatment group were given intravenous vitamin C (1500 mg every 6 h for 4 days or until ICU discharge), hydrocortisone (50 mg every 6 h for 7 days or until ICU discharge), and thiamine (200 mg every 12 h for 4 days or until ICU discharge) within 24 h of ICU admission, and the control group was treated conventionally. The clinical course and outcomes of patients in both groups were collected before and after treatment. Compared with the control group, the HAT group had a significantly decreased SOFA score at 72 h (4.8 ± 2.4 vs. 0.9 ± 2.7, P<0.001), significantly reduced in-hospital mortality (8.5% vs. 40.4%, adjusted odds ratio [OR]=0.13; 95% confidence interval [CI]: 0.04–0.48; P=0.002), and a significantly shorter duration of vasopressor use (18.3 ± 9.8 h vs. 54.9 ± 28.4 h, P<0.001). These results suggested that HAT therapy was associated with significant reduction in septic organ injury (especially acute kidney injury), time-to-shock reversal, and mortality. However, the study had a limited sample size and a single-center retrospective “before-and-after” design in terms of methodology, that is, the participations were non-concurrent control subjects, and although the baseline characteristics of the two groups were not statistically different, this design did result in an overall average level of evidence for the study. In addition, the optimal dosage and course of treatment of drugs need to be further explored.^[6]

After the publication of this study by Marik et al.,^[6] the clinical use of HAT therapy increased significantly and immediately. Most observational studies reported similar positive findings to those of Marik et al.,^[6] including that HAT therapy was associated with reduction in ICU mortality and SOFA scores or inflammatory markers.^[[34], [35], [36], [37]^] In contrast, Vail et al.^[38] conducted a retrospective cohort study on the clinical data of adult septic shock patients from 379 hospitals in the United States and found that receiving HAT therapy within 2 days of hospitalization was not associated with an improvement in-hospital mortality. However, septic shock in the study was diagnosed according to International Classification of Diseases 10th Revision (ICD-10) criteria, the dose and duration of drugs used were inconsistent across hospitals, and the greater severity of disease in the treatment group may have affected the efficacy of HAT therapy; consequently, the results should be interpreted with caution.^[38] A real-world retrospective study found similar negative results, but it was likely that the overall benefit of HAT therapy in that study was markedly reduced by the late administration of drugs and the fact that more than half of the patients in the treatment group did not receive HAT therapy for various reasons.^[39]

Clinical Practice of HAT Therapy for Sepsis in Randomized Controlled Trials (RCTs)

As of November 2022, there were 21 registered clinical trials of HAT therapy for sepsis (https://clinicaltrials.gov/) and 11 RCTs had published mixed findings. Among them, a randomized, double-blind, placebo-controlled study by Iglesias et al.^[40] explored the efficacy of HAT therapy in sepsis and septic shock patients in terms of metabolic resuscitation. The study found that early application of HAT therapy (vitamin C 1500 mg q6h, thiamine 200 mg q12h, hydrocortisone 50 mg q6h, for up to 4 days, with most starting within 1 h of enrollment) significantly reduced the duration of vasopressin administration (27 ± 22 h vs. 53 ± 38 h, P<0.001), suggesting the independent reversal of shock with HAT therapy. However, the study did not find an association between HAT therapy and improvement in hospital and ICU mortality, or reduction in SOFA scores in patients with septic shock, which may be due to limitations such as the small study cohort and the homogeneous (predominantly white) study population. Additional monitoring in the study found no serious adverse events associated with the drugs, suggesting the therapy is relatively safe. Four other RCTs reported similar results,^[[41], [42], [43], [44]^] that is, HAT therapy reduced the duration of vasopressors or time to shock reversal in patients with sepsis and septic shock but did not significantly reduce mortality. However, unlike these studies, a related trial from China found that HAT therapy did not reduce the duration of vasopressor use in patients with sepsis and septic shock but did significantly improve SOFA scores at 72 h (ΔSOFA, 3.5 ± 3.3 and 1.8 ± 3.0; P=0.02). Further subgroup analysis in the study suggested a lower mortality rate when the intervention was started within 48 h of sepsis diagnosis, although there was no difference in 28-day all-cause mortality between the two groups. However, the study was a single-center, single-blind design, and most control patients did not actually receive the appropriate placebo (normal saline), which we speculate may have confounded the trial findings and was associated with the increased incidence of hypernatremia—an adverse condition—in the treatment group (P=0.005). In addition, a study by Jamshidi et al.^[46] showed significant decreases in 72-h SOFA score, mean duration of vasopressor dependency, and in-hospital mortality after HAT treatment (P<0.05), but the level of evidence was limited by the small sample size and single-center study design.

In contrast, several clinical trials did not find any significant benefits of HAT therapy for sepsis or septic shock. The RCT by Sevransky et al.^[47] revealed that HAT therapy did not reduce the number of days without ventilators and vasopressors in a 30-day period or the 180-day mortality in patients with septic shock. The study was methodologically rigorous and credible but employed an open hydrocortisone strategy (that is participants could be treated with open-label corticosteroids by the clinical team: for daily doses of at least 200 mg of hydrocortisone (or equivalent), hydrocortisone or matching placebo was withheld by the investigational pharmacy) and was terminated early for administrative reasons, which may have affected the conclusion. Another single-center, double-blind, open glucocorticoid therapy RCT likewise did not find any significant improvement in sepsis-related clinical outcomes, including 90-day mortality. However, the patients in this trial were relatively critically ill (a previous study found that mortality benefits were observed only in a subset of patients with lower SOFA scores^[42]) and were not monitored for vitamin C and thiamine concentrations, which may explain the observed absence of beneficial effects on clinical outcomes of HAT therapy.^[48] Moskowitz et al.^[49] conducted a similar multicenter clinical trial that was not open to hydrocortisone treatment, but the findings were still negative. Both studies of Lyu et al.^[48] and Moskowitz et al.^[49] administered the same dose of HAT therapy as that of Marik et al.,^[6] but the median time to receipt of intervention was more than 12 h; however, earlier intervention would likely to improve the outcomes. Fujii et al.^[50] conducted a multicenter, open-label RCT across countries to compare the efficacy of HAT therapy with hydrocortisone alone in the relief of septic shock. The study found that HAT therapy did not significantly improve the survival or the duration of vasoactive drug requirements, suggesting that this therapy did not contribute to a more rapid resolution of septic shock. However, the study was limited by the open-label design and lacked a blinded outcome assessment, which may have created ascertainment bias. Notably, none of the above studies reported unexpected serious adverse events associated with the therapy.

The clinical efficacy of HAT therapy for sepsis has been refined through additional original studies in recent years.^[51] The most recent meta-analysis found that HAT therapy was not associated with improved long-term mortality in sepsis compared with placebo or conventional therapy, but the study did not separate observational studies from those of RCTs.^[52] Another meta-analysis that specifically searched for relevant RCTs revealed that HAT therapy significantly reduced the duration of the need for vasopressors and improved SOFA scores over 72 h.^[53] Additionally, HAT therapy appears to have different outcomes for gut-derived sepsis vs. pulmonary-derived sepsis. Our preliminary analysis of the included population of published RCTs found that HAT therapy significantly reduced the duration of vasoactive drugs or multi-organ function in studies with a relatively large proportion of patients with pulmonary-derived sepsis and less gut-derived sepsis (at least 30% difference in the proportion).^[40,41,45] In contrast, in studies with a relatively large proportion of patients with gut-derived sepsis and less pulmonary-derived sepsis, HAT therapy did not demonstrate any significant benefit.^[48,50] Moreover, when there were more patients with pulmonary-derived sepsis than with gut-derived sepsis but the difference in proportion was less than 30%, the conclusions were not consistent.^[42,47,49] Unfortunately, there are currently no RCTs evaluating the efficacy of HAT therapy for septic patients with a specific source of infection. Lyu et al.^[48] performed a subgroup analysis for the distribution of infection sites and indicated that HAT therapy did not show a better therapeutic effect regardless of whether the patient had abdominal infections or not. Therefore, is the type of infection site the key determinant for the effectiveness of HAT therapy? Future studies are needed to elucidate this issue.

Implications for Future Practice

Considering the contradictory findings of published studies and the limited number of studies the future widespread use of HAT therapy in clinical sepsis patients requires further evidence from high-quality (multicenter, large-scale, prospective, RCTs) clinical trials. From the available data, it appears that although HAT therapy does not significantly reduce mortality, it is beneficial in terms of shortening the duration of vasoactive drug requirements and improving organ function, which is consistent with the pathophysiological mechanisms we described previously. That is, HAT therapy protects the endothelium, promotes endogenous vasoactive drug synthesis, and regulates immunity, which in turn can improve vascular reactivity, maintain hemodynamic stability, reduce oxidative stress and inflammatory responses, and ultimately shorten the duration of exogenous vasoactive drug use and reduce multi-organ functional injury. However, further work is needed to determine why HAT therapy did not benefit the survival rate of patients with sepsis and we speculate that there may be multiple underlying reasons. (1) SOFA scores and time of vasoactive drug use are focused on early recovery of organ function, while mortality endpoints, especially long-term mortality, are influenced by multiple factors and theoretically diluted by many confounding factors that may limit the efficacy evaluation of the therapy for long-term prognosis. (2) Patients with sepsis or septic shock are often associated with multi-organ functional injury and always have complex conditions. Consequently, it is unrealistic to expect that one treatment will save all patients with sepsis or septic shock. (3) Previous clinical trials failed to stratify enrolled subjects by the predominant etiology of sepsis or degree of illness, which may be important to discern the benefits of HAT therapy on mortality. For example, animal experiments by Stolarski et al.^[54] found that the inflammatory responses were different in pulmonary sepsis and intra-abdominal sepsis. Furthermore, identical HAT treatment resulted in a significant decrease in oxidative stress and mortality in intestinal sepsis models but not in pulmonary sepsis. In addition, the plasma vitamin C level in pulmonary sepsis was significantly lower compared with that in intra-abdominal sepsis owing to higher consumption during the scavenging of free radicals, suggesting that a larger dose of vitamin C may be required to benefit mortality in patients with pulmonary sepsis.

In terms of the future of HAT therapy, precise treatment may be a breakthrough—that is, HAT therapy for sepsis may benefit specific patient groups but not all patient groups. Whether it is for sepsis or septic shock, the focus of research should not be on confirming whether HAT therapy is effective, but should concentrate on identifying the population that will benefit from the therapy for individualized and precise treatment. The benefit is maximized by finding the right patient at the right time to apply the right dose of HAT treatment. Therefore, we have a number of suggestions for future trial design. (1) Refine the doses of intervention drugs. The doses of HAT therapy in existing studies were predominantly the same as those of Marik et al.^[6] However, it is possible that alternative doses may affect the outcome; for example, high doses of vitamin C were associated with a reduction in mortality in septic patients.^[52] (2) Focus on pre-intervention vitamin levels. There may be differences in the distribution of hypovitaminemic patients after the randomization of patients in a trial, and it has yet to be explored whether a certain drug concentration is required to achieve an optimal therapeutic effect. (3) Perform subgroup analysis on patients with different courses of intervention. The characteristics of ICU departments mean some patients did not receive sufficient courses of intervention as planned, and some patients only received one intervention, which may affect the efficacy determination of the drugs. (4) Study the effect of HAT therapy on patients with sepsis or septic shock caused by a site-specific infection, and use subgroup analyses to explore different disease severities and whether patients have combined hyperinflammation, low hypovascular reactivity, and so on, with the aim of identifying the optimal population for HAT therapy. The complexity of clinical practice poses challenges for the implementation of all of the above protocols, but it should be possible to gradually identify the appropriate population for HAT therapy through a series of trials with increasing complexity. For example, our preferred first step is to limit inclusion criteria in our future clinical practice to patients with pulmonary-derived sepsis of low baseline vitamin levels.

Conclusions

Currently, HAT therapy is not considered to significantly improve mortality in patients with sepsis, but it is likely to be beneficial in terms of duration of vasopressor use and relief of shock. Furthermore, most clinical studies have not reported any serious adverse effects of HAT therapy, suggesting this therapy has a good safety profile. Therefore, HAT therapy remains a promising new treatment for the metabolic resuscitation of sepsis.

Author Contributions

All the authors contributed substantially to the work presented in this article. Tongwen Sun conceived of the study. Yali Sun and Yongfang Yang contributed to the relevant literature retrieval. Yali Sun contributed to the writing of the article, and Zhuoyi Ye and Tongwen Sun revised the article.

Managing Editor: Jingling Bao