Core Clinical Question

Does intravenous thiamine administration within 24 hours of hospital admission improve lactate clearance and reduce 28-day mortality in adult patients with septic shock compared to those not receiving thiamine? (PICO: Population - Adult septic shock patients; Intervention - IV thiamine administration; Comparison - No thiamine; Outcome - Lactate clearance and 28-day mortality)

Background

Disease Overview:

Septic shock is a severe and metabolically demanding condition characterized by persistent hypotension requiring vasopressors and elevated lactate levels despite adequate fluid resuscitation.

Prior Data on the Topic:

Critically ill patients are commonly thiamine deficient due to metabolic stress, poor nutritional intake, and comorbidities.

A pilot study by Donnino et al. found no overall mortality benefit of thiamine in septic shock but suggested potential benefits in patients with confirmed thiamine deficiency.

Current Standard of Care:

Management of septic shock includes fluid resuscitation, antibiotics, vasopressors, and supportive care. Thiamine supplementation is not routinely part of standard protocols.

Knowledge Gaps Addressed by Study:

The potential role of thiamine as a metabolic resuscitator in improving lactate clearance and reducing mortality in a broader septic shock population.

Study Rationale:

Given the safety, low cost, and biological plausibility of thiamine improving mitochondrial function, this study aims to evaluate its effectiveness in a larger, real-world septic shock population.

Methods Summary

Study Design:

Retrospective, single-center, matched cohort study.

Setting and Time Period:

Tertiary care academic medical center from January 1, 2013, to January 1, 2017.

Population Characteristics:

Adult patients (≥18 years) admitted to the medical or surgical ICU with a diagnosis of septic shock based on ICD-9 or ICD-10 codes.

Inclusion required a peak lactate >2 mmol/L and need for vasopressor therapy.

Inclusion/Exclusion Criteria:

Included: Adults with septic shock upon admission.

Excluded: Patients under 18, those without septic shock at admission, or with missing baseline data.

Intervention Details:

IV thiamine supplementation at any dose within 24 hours of hospital admission.

Most frequent dose: 500 mg IV every 8 hours for a median of 3 days.

Control/Comparison Group Details:

Matched cohort not receiving thiamine, matched in a 1:2 ratio based on ICU service, liver disease, peak lactate, SOFA score, Elixhauser comorbidity index, age, sex, and race.

Primary and Secondary Outcomes:

Primary Outcome: Time to lactate clearance (≤2 mmol/L).

Secondary Outcomes: 28-day mortality, vasopressor-free days, ventilator-free days, ICU-free days, acute kidney injury (AKI), and need for renal replacement therapy (RRT).

Statistical Analysis Approach:

Competing risks regression models using Fine-Gray method.

Cox proportional hazards models for 28-day mortality.

Adjustments for age, sex, race, and clinical factors.

Interaction terms assessed for sex.

Sample Size Calculations:

Not explicitly stated; study included 123 thiamine-treated patients matched with 246 controls.

Ethics and Funding Information:

Approved by institutional review board.

Funding: Dr. Flannery received funding from Nova Biomedical; other authors disclosed no conflicts of interest.

Detailed Results

Participant Flow and Demographics:

Inclusion:

• 2,272 patients screened; 1,049 eligible after Sepsis-3 validation.
• 123 received thiamine; 246 matched controls.

Demographics:

Characteristic	No Thiamine	Thiamine	P-value
Median Age (years)	54	52	p = 0.238
Sex (Male)	56.1%	56.1%	p = 1.000
Race (White)	91.9%	91.9%	p = 1.000
Liver Disease	65.0%	65.0%	p = 1.000
SOFA Score on ICU Admission	Median 10	Median 10	p = 0.972
Peak Lactate (mmol/L)	Median 6	Median 6	p = 0.904

Primary Outcome Results:

Lactate Clearance:

Thiamine group had improved lactate clearance with SHR ≈ 1.3

Statistical Significance: p = 0.018 (model with thiamine, age, sex, race, and clinical factors SHR 1.307; 95% CI, 1.002–1.704)

Effect Sizes: SHR >1 indicates higher likelihood of lactate clearance.

Confidence Intervals: 95% CI does not cross 1 for the primary model.

Secondary Outcome Results:

28-Day Mortality:

Thiamine associated with reduced mortality: HR 0.666; 95% CI, 0.490–0.905; p = 0.018

Absolute Risk Reduction: From higher baseline mortality to lower mortality in thiamine group.

Other Secondary Outcomes:

• No significant differences in vasopressor-free days, ventilator-free days, ICU-free days, AKI, or need for RRT.

Subgroup Analyses:

Sex Interaction:

• Female patients: SHR 1.724 (95% CI, 1.175–2.532)
• Male patients: SHR 1.065 (95% CI, 0.764–1.484)
• Statistical Significance: Females showed significant benefit; males did not.

Adverse Events/Safety Data:

Not explicitly reported; thiamine is noted as a safe therapy.

Results Tables

Outcome	Thiamine Group	Control Group	Difference (95% CI)	P-value
Lactate Clearance SHR	1.307 (1.002–1.704)	N/A	Increased likelihood	<0.05
28-Day Mortality HR	0.666 (0.490–0.905)	N/A	Reduced mortality	0.018
Sex Interaction (Female SHR)	1.890 (1.267–2.825)	N/A	Significant benefit for females	<0.05
Sex Interaction (Male SHR)	1.032 (0.732–1.456)	N/A	No significant benefit for males	>0.05

Authors' Conclusions

Primary Conclusions:

Thiamine administration within 24 hours of ICU admission in septic shock patients was associated with improved lactate clearance and reduced 28-day mortality compared to those not receiving thiamine.

Authors' Interpretation of Results:

Thiamine may enhance metabolic resuscitation, improving mitochondrial function leading to better lactate clearance and survival.

Clinical Implications Stated by Authors:

Thiamine supplementation could be a beneficial, safe, and cost-effective adjunctive therapy in septic shock management.

Future Research Recommendations:

Larger randomized controlled trials are warranted to confirm these findings and explore the gender-specific benefits observed.

Literature Review

Comparisons to Other Studies:

Unlike the pilot study by Donnino et al., which showed benefits only in thiamine-deficient patients, this study demonstrated broader benefits in a larger septic shock population.

Positioning within Existing Evidence:

Supports the hypothesis that thiamine can be a valuable metabolic resuscitator in sepsis, aligning with previous evidence of thiamine deficiency in critical illness.

References to Current Guidelines:

Not explicitly compared to current sepsis guidelines; however, suggests potential integration into standard care pending further evidence.

Critical Analysis

A. Strengths

Methodological Strengths:

• Large matched cohort enhances comparability between groups.
• Use of Sepsis-3 criteria ensures current and accurate identification of septic shock patients.

Internal Validity Considerations:

• Robust statistical methods, including competing risks models and adjustments for confounders.
• Identification and adjustment for sex interaction strengthen causal inferences.

External Validity Considerations:

• Conducted in a tertiary academic center, which may limit generalizability but provides a well-controlled environment.

B. Limitations

Study Design Limitations:

• Retrospective and observational, limiting causal inferences.

Potential Biases:

• Selection bias due to non-randomized thiamine administration based on clinician judgment.
• Unmeasured confounders may exist despite matching.

Generalizability Issues:

• High prevalence of liver disease and cirrhosis in the cohort may not represent the general septic shock population.

Statistical Limitations:

• Interaction findings (e.g., sex) may be hypothesis-generating and require further validation.

Missing Data Handling:

• Dependence on electronic medical records may miss undocumented variables.

C. Literature Context

A. Previous Studies and Meta-Analyses:

1. Donnino et al. (J Crit Care 2010;25:576–581): Found no overall mortality benefit of thiamine in septic shock but suggested benefits in thiamine-deficient patients.
2. Marik et al. (Chest 2017;151:1229–1238): Suggested potential benefits of thiamine as part of a combination therapy in sepsis.
3. Han et al. (Crit Care Med 2018;43:61–64): Observed potential benefits of thiamine in specific subgroups.

B. Contrasting Methodological Quality:

Previous studies were smaller, predominantly single-center trials with varied dosing regimens compared to the higher-dose regimen in this study.

C. Comparisons with Guidelines:

Current sepsis guidelines do not routinely recommend thiamine supplementation; this study suggests potential reevaluation pending further evidence.

D. This Trial's Contribution:

• Adds evidence supporting thiamine's role in improving metabolic outcomes and survival in septic shock beyond thiamine-deficient populations.
• Contradicts earlier findings of limited benefit by demonstrating broader applicability.

Clinical Application

How Findings Change Current Practice:

May support the integration of thiamine supplementation into septic shock protocols, especially given its safety and low cost.

Specific Patient Populations or Scenarios:

Particularly applicable to critically ill septic shock patients, potentially more beneficial in female patients as indicated by subgroup analysis.

Implementation Considerations:

Requires consideration of dosing protocols and monitoring for potential interactions, though thiamine is generally safe.

Integration with Existing Evidence:

Complements prior studies suggesting metabolic support can improve outcomes in sepsis; aligns with the metabolic resuscitation approach.

How To Use This Info In Practice

Practitioners should consider prescribing intravenous thiamine supplementation for adult patients with septic shock within the first 24 hours of ICU admission, given its association with improved lactate clearance and reduced mortality.