Effects of thiamine on vasopressor requirements in patients with septic shock: a prospective randomized controlled trial

Suttasinee Petsakul, Sunthiti Morakul, Viratch Tangsujaritvijit, Parinya Kunawut, Pongsasit Singhatas, Pitsucha Sanguanwit, Suttasinee Petsakul, Sunthiti Morakul, Viratch Tangsujaritvijit, Parinya Kunawut, Pongsasit Singhatas, Pitsucha Sanguanwit

Abstract

Background: Thiamine, an essential vitamin for aerobic metabolism and glutathione cycling, may decrease the effects of critical illnesses. The objective of this study was to determine whether intravenous thiamine administration can reduce vasopressor requirements in patients with septic shock.

Methods: This study was a prospective randomized double-blind placebo-controlled trial. We included adult patients with septic shock who required a vasopressor within 1-24 h after admission between March 2018 and January 2019 at a tertiary hospital in Thailand. Patients were divided into two groups: those who received 200 mg thiamine or those receiving a placebo every 12 h for 7 days or until hospital discharge. The primary outcome was the number of vasopressor-free days over 7 days. The pre-defined sample size was 31 patients per group, and the study was terminated early due to difficult recruitment.

Results: Sixty-two patients were screened and 50 patients were finally enrolled in the study, 25 in each group. There was no difference in the primary outcome of vasopressor-free days within the 7-day period between the thiamine and placebo groups (mean: 4.9 days (1.9) vs. 4.0 days (2.7), p = 0.197, mean difference - 0.9, 95% CI (- 2.9 to 0.5)). However, the reductions in lactate (p = 0.024) and in the vasopressor dependency index (p = 0.02) at 24 h were greater among subjects who received thiamine repletion vs. the placebo. No statistically significant difference was observed in SOFA scores within 7 days, vasopressor dependency index within 4 days and 7 days, or 28-day mortality.

Conclusions: Thiamine was not associated to a significant reduction in vasopressor-free days over 7-days in comparison to placebo in patients with septic shock. Administration of thiamine could be associated with a reduction in vasopressor dependency index and lactate level within 24 h. The study is limited by early stopping and low sample size.

Trial registration: TCTR, TCTR20180310001. Registered 8 March 2018, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=3330 .

Keywords: Septic shock; Thiamine; Vasopressor requirement.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Consort flow diagram
Fig. 2
Fig. 2
Kaplan-Meier failure estimation 28-day mortality
Fig. 3
Fig. 3
Post hoc exploratory analysis of changes in SOFA scores within 4 days
Fig. 4
Fig. 4
Post hoc exploratory analysis of changes in the vasopressor dependency index within 4 days

References

    1. Butterworth RF: Thiamine. Modern Nutrition in Health and Disease. Edited by: Shils ME. 2006, Lippincott: Williams & Wilkins, 426–433. 10.
    1. de Andrade JAA, Gayer CRM, Nogueira NPA, Paes MC, Bastos V, Neto J, et al. The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis. J Inflamm (Lond) 2014;11:11.
    1. Gioda CR, de Oliveira BT, Primola-Gomes TN, de Lima DC, Campos PP, Capettini Ldos S, et al. Cardiac oxidative stress is involved in heart failure induced by thiamine deprivation in rats. Am J Physiol Heart Circ Physiol. 2010;298(6):H2039–H2045.
    1. Moskowitz A, Andersen LW, Huang DT, Berg KM, Grossestreuer AV, Marik PE, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018;22(1):283.
    1. Shimon I, Almog S, Vered Z, Seligmann H, Shefi M, Peleg E, et al. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med. 1995;98(5):485–490.
    1. Cruickshank AM, Telfer AB, Shenkin A. Thiamine deficiency in the critically ill. Intensive Care Med. 1988;14(4):384–387.
    1. Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. 2018;46(11):1747–1752.
    1. Miyamoto Y, Aso S, Iwagami M, Yasunaga H, Matsui H, Fushimi K, et al. Association between IV thiamine and mortality in patients with septic shock: a Nationwide observational study. Crit Care Med. 2020;48(8):1135–1139.
    1. Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, 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(2):360–367.
    1. Lomivorotov VV, Moroz G, Ismoilov S, Shmyrev V, Efremov S, Abubakirov M, et al. Sustained high-dose thiamine supplementation in high-risk cardiac patients undergoing cardiopulmonary bypass: a pilot feasibility study (the APPLY trial) J Cardiothorac Vasc Anesth. 2020;34(3):594–600.
    1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis campaign: international guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304–377.
    1. Lu J, Frank EL. Rapid HPLC measurement of thiamine and its phosphate esters in whole blood. Clin Chem. 2008;54(5):901–906.
    1. Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301(23):2445–2452.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. The SOFA (Sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on Sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–710.
    1. Heyland DK, Dhaliwal R, Jiang X, Day AG. Identifying critically ill patients who benefit the most from nutrition therapy: the development and initial validation of a novel risk assessment tool. Crit Care. 2011;15(6):R268.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–829.
    1. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016;5(2):94–100.
    1. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–887.
    1. Carre JE, Singer M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta. 2008;1777(7–8):763–771.
    1. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe Sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229–1238.
    1. Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a renal protective agent in septic shock. A secondary analysis of a randomized, double-blind, placebo-controlled trial. Ann Am Thorac Soc. 2017;14(5):737–741.
    1. Andersen LW, Holmberg MJ, Berg KM, Chase M, Cocchi MN, Sulmonte C, et al. Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial. Crit Care. 2016;20:92.
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for Sepsis and septic shock (Sepsis-3) JAMA. 2016;315(8):801–810.
    1. Hwang SY, Ryoo SM, Park JE, Jo YH, Jang DH, Suh GJ, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-Centre, double-blinded randomized, controlled study. Intensive Care Med. 2020. Available from: . [cited 2020 Oct 26].
    1. Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642–650.
    1. Wrenn KD, Murphy F, Slovis CM. A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med. 1989;18(8):867–70.
    1. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020;323(5):423–31.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi