Woolum

Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock

Woolum. Crit Care Med 2018; 46:1747-1752. doi:10.1097.CCM.0000000000003311

Clinical Question

  • In patients with septic shock, does the administration of thiamine lead to more rapid lactate clearance and improved clinical outcomes?

Background

  • Septic shock is characterised by a hypermetabolic state that resembles thiamine deficiency
  • Thiamine, also known as Vitamin B1, can be deficient in critically ill patients
  • Previous pilot randomised, controlled trials have shown significantly lower lactate levels and improved mortality over time in patients with septic shock who were thiamine deficient

Design

  • Retrospective, matched cohort study, based on data collected from medical records
    • Cohorts were matched using Mahalanobis distance matching (a multivariate statistical method to detect outliers from a normal distribution) according to
      • ICU service (medical vs surgical)
      • Presence of liver disease
      • Peak lactate
      • SOFA score on day of ICU admission
      • Elixhauser comorbidity index
      • Age
      • Gender
      • Race
  • Regression analysis was performed with mortality as a competing event
    • If the patient died before lactate clearance was achieved, clearance was considered not achieved
    • That is to say, death and lactate clearance were considered mutually exclusive outcomes
  • Three models were constructed
    • with lactate levels alone
    • after adjustment for age, gender and race
    • with age, gender, race and other likely factors that influence mortality and lactate clearance
  • A Cox proportional hazards model was constructed along the same lines for 28-day mortality according to event-rate analysis

Setting

  • A single academic centre in the USA
  • January 2013 to December 2017

Population

  • An electronic medical database was queried based on the diagnostic code for septic shock according to 9th or 10th edition of the International Classification of Diseases (ICD)
  • Inclusion: Patients who were coded as septic shock on the electronic medical database; 18 years and older; admission to medical or surgical services
  • Exclusion: Septic shock not present at admission (lactate < 2 mmol/L or vasopressor therapy not required); missing baseline data
  • After validation using the Sepsis-3 criteria:
    • 1049 patients were included out of the 2270 patients who were initially screened
      • Comparing Thiamine (n=123) vs No Thiamine (n=926), where * means P value is less than 0.05:
        • Mean age: 52 vs 60 years*
        • Gender: 56% vs 51%
        • Race: 92% vs 93% white
        • Liver disease: 65% vs 34%*
        • Elixhauser comorbidity index: 4 vs 4
        • Medical admission: 97% vs 83%*
        • SOFA Score: 10 vs 9*
        • Steroid administration: 53% vs 47%
        • Peak lactate: 6.1 vs 5.2 mmol/L*
    • Out of this cohort, 123 patients who received thiamine (any dose within 24 hours of hospital admission) were matched with 246 patients who did not
      • All variables listed above were matched and were almost equal
        • P values were all above 0.238 (most were 1.0)

Intervention

  • Thiamine
    • Intravenous administration of thiamine in any dose within the first 24 hours of hospital admission

Control

  • No thiamine
    • Patients who received thiamine were matched with a cohort who did not receive thiamine in a 1:2 ratio

Management common to both groups

  • All care was delivered at the discretion of the treating clinical team

Outcome

  • Primary outcome:
    • Lactate clearance was defined as
      • Time from hospital admission to lactate of ≤ 2 mmol/L, or
      • Time from hospital admission to lowest lactate plus 24 hours (if no documented lactate < 2 mmol/L and patient survived)
    • Lactate clearance was more rapid in those who were administered intravenous thiamine in the first 24 hours of their hospital admission
    • All three regression models revealed improved lactate clearance with thiamine administration
    • The subdistribution hazard ratios in the three models ranged between 1.292 and 1.339
    • The effect of thiamine on lactate clearance was significantly more in female patients on a gender-based interaction model
  • Secondary outcome:
    • Survival was censored at 28 days or hospital discharge
    • Thiamine was found to significantly reduce 28-day mortality on the three Cox proportional hazard models
      • Hazard ratio for death 0.666 (95% CI 0.490 to 0.905)
    • The benefit was more evident in female patients
    • There was no significant difference in other secondary outcomes including
      • SOFA scores on day 5 compared to baseline
      • Vasopressor-free days
      • Ventilator-free days
      • ICU-free days
      • Incidence of AKI
      • Requirement for renal replacement therapy

Authors’ Conclusions

  • In patients with septic shock, intravenous thiamine, administered within 24 hours of ICU admission resulted in more rapid lactate clearance and a significantly reduced 28-day mortality

Strengths

  • This is a large study that evaluated the effect of thiamine on lactate clearance and mortality in patients with septic shock
  • Matching was carried out between patients who had thiamine and those who did not, in an attempt to remove confounding variables
  • Regression analysis was performed with mortality as the competing event, which is appropriate given the high mortality rate observed

Weaknesses

  • This is a retrospective observational study based on data derived from electronic medical records
    • The baseline differences prior to matching demonstrate that the Thiamine vs No Thiamine cohorts are very different populations, and this suggests that matching will not remove all confounding variables
  • The dose of thiamine was variable and ranged 100–500 mg/
    • The study centre’s protocol was to administer high dose (500 mg x3 daily) thiamine for 72 hours
  • Thiamine levels were not measured
    • It is unclear whether the benefit may be related to thiamine deficiency
  • The mortality of the cohort was high compared to contemporaneous studies (54%), which the authors attribute to a relatively large number of patients with cirrhosis
    • This limits the generalisability of the conclusion to other populations

The Bottom Line

  • This study adds to the growing body of evidence that intravenous thiamine may improve outcomes in patients with sepsis and septic shock
  • However, given the inherent biases in this relatively small observational study, the conclusion should be hypothesis generating and supportive of a larger randomised, controlled trial
  • In my opinion, given that harmful effects are unlikely, intravenous thiamine may be considered in critically ill patients with sepsis

External Links

Metadata

Summary author: Jose Chacko
Summary date: 25 April 2019
Peer-review editor: Duncan Chambler

3 comments

  • Sander

    Thank you for posting this insightful article!
    I’m unsure of whether the following sentence was intended: “Thiamine clearance was more rapid in those who were administered intravenous thiamine in the first 24 hours of their hospital admission”
    Shouldn’t this have been “Lactate clearance was more rapid …”?

    Yours sincerely,

    • Duncan Chambler

      You are correct, and I have amended the post. I apologise for not spotting this when I peer-reviewed and posted this summary, and thank you for your rapid comment and post-publication peer review.

  • A single centre study that is a not a RCT – will not change my practice untill there is a multicentre RCT

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