By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: Based on a retrospective review, septic shock patients who were administered thiamine within 24 hours of admission showed improved lactate clearance and reduced 28-day mortality.

SOURCE: Woolum JA, et al. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med 2018;46:1747-1752.

Often, critically ill patients are thiamine-deficient. Since septic shock is a metabolically demanding state, Woolum et al pursued a retrospective, single-center, matched cohort study to see if critically ill patients with septic shock exposed to thiamine would show improved lactate clearance and better clinical outcomes vs. patients without thiamine supplementation. All adult medical and surgical ICU patients admitted to a tertiary care academic center from 2013-2017 with an International Classification of Diseases, 9th Revision, or an International Classification of Diseases, 10th Revision, septic shock diagnosis code were included. Exclusion criteria included patients younger than 18 years of age or the development of septic shock that was not evident at admission. The primary outcome was whether thiamine administration was associated with faster time to lactate clearance. Secondary outcomes included acute kidney injury, 28-day mortality, mechanical ventilation-free days, vasopressor-free days, and need for renal replacement therapy.

Out of 2,272 patients screened, 1,049 were eligible. Among those who were eligible, 123 thiamine-treated patients were matched with 246 patients who were not treated with thiamine. The authors did not detail the reason for thiamine administration. Patients were matched in a 1:2 (thiamine:control) fashion based on ICU service (medical ICU vs. surgical ICU), peak lactate, presence of liver disease, race, age, sex, Elixhauser comorbidity index, and Sequential Organ Failure Assessment (SOFA) score on ICU admission day. The most common protocol for administration of thiamine within the study was 500 mg every eight hours for three days.

Results from the Fine-Bray survival model revealed that treatment with thiamine was associated with an improved likelihood of lactate clearance (subdistribution hazard ratio [HR], 1.307; 95% confidence interval [CI], 1.002-1.704) and a reduction in 28-day mortality (HR, 0.666; 95% CI, 0.490-0.905). There were no further differences revealed in secondary outcomes. These findings were more pronounced in women. A randomized trial is necessary to further evaluate this intervention for septic shock patients.

COMMENTARY

One in every three hospitalized patients who die in that facility is diagnosed with sepsis.1 For decades, researchers have worked earnestly to discover new interventions and treatments to decrease sepsis-related mortality. More recently, thiamine, an essential vitamin for aerobic metabolism, has gained special attention as a potential avenue to augment the dangerous effects of septic shock.2,3 Thiamine acts at critical points in both the Krebs cycle and the pentose-phosphate shuttle. It provides assistance as a key cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in the Krebs cycle and for transketolase as a key enzyme for the pentose phosphate pathway and production in nicotinamide adenine dinucleotide phosphate hydrogen. Without these steps, mitochondrial aerobic metabolism is halted and anaerobic metabolism ensues, leading to refractory acidosis, cardiovascular collapse, and possible death.4,5 The theoretical benefits of thiamine in septic shock may be even more pronounced in subpopulations of illness as many critically ill patients admitted to the ICU are thiamine-deficient at baseline.2,5

One of the first published studies that addressed thiamine in septic shock was a two-center, randomized, double-blind trial. Those authors evaluated the administration of thiamine 200 mg twice daily for seven days in septic shock patients and observed its effect on lactate.2 Interestingly, patients with liver dysfunction, those who abused alcohol, and those who required thiamine supplementation (the subpopulations at significant risk for thiamine deficiency) were excluded. Although results revealed that thiamine administration did not improve lactate levels in the overall group of patients with septic shock and elevated lactate, the authors observed that lactate levels were lower at 24 hours, with a possible decrease in mortality over time in patients with baseline thiamine deficiency. Despite no significant difference in other secondary outcomes, including proportion and time to shock reversal, SOFA score at 24 hours, mortality rates, and ICU and overall length of stay between the thiamine and placebo groups, it must be recognized that the thiamine dose may not have been adequate because no dose-finding trial was completed prior to the study. Another interesting aspect of this study was that 35% of patients presented with thiamine deficiency at baseline despite the exclusion criteria of liver dysfunction, alcohol abuse, and thiamine supplementation.

To further highlight the potential benefit of thiamine in thiamine-deficient septic shock patients, Holmberg et al published the results of a retrospective cohort trial in 2018. They examined the association between the administration of thiamine vs. no thiamine in septic shock patients with alcohol use disorders.3 Although thiamine 100 mg was the most commonly prescribed thiamine dose in this retrospective trial (88% of the initial doses and 97% of the total doses), investigators still found that thiamine administration in this patient population was associated with decreased mortality.

Although the study by Woolum et al revealed that thiamine administration within 24 hours of admission in septic shock patients was associated with improved lactate clearance and a reduction in 28-day mortality, there were significant limitations. Unfortunately, the authors did not include a protocol for when and how often to measure repeat lactate. Obviously, this limitation could affect lactate clearance profoundly. This trial also was not randomized, which may lead to substantial confounding. Further, the dose of thiamine was not standardized.

Despite these limitations and considering previous publications, this study is at the very least thought-provoking. Although it is not likely to change current practice significantly, thiamine is relatively safe and inexpensive. These findings highlight the need for future larger randomized studies to further explore the effect of thiamine in septic shock, specifically examining subpopulations after an appropriate dose-response trial.

REFERENCES

  1. Centers for Disease Control and Prevention. Sepsis. Data & Reports. Available at: https://bit.ly/2FhjlsQ. Accessed Jan. 8, 2019.
  2. Donnino MW, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: A pilot study. Crit Care Med 2016;44:360-367.
  3. Holmberg MJ, et al. Thiamine in septic shock patients with alcohol use disorders: An observational pilot study. J Crit Care 2018;43:61-64.
  4. Oriot D, et al. Severe lactic acidosis related to acute thiamine deficiency. JPEN J Parenter Enteral Nutr 1991;15:105-109.
  5. Manzanares W, Hardy G. Thiamine supplementation in the critically ill. Curr Opin Clin Nutr Metab Care 2011;14:610-617.