Thiamine Supplementation in High Risk Cardiac Surgery Patients (APPLY)

This pilot trial will evaluate the ability of thiamine to affect on postoperative vasoplegia in high risk cardiac surgery patients

Study Overview

• Status: Completed
• Conditions: Cardiac Surgery
• Intervention / Treatment: Drug: Thiamine hydrochloride (200mg) dissolved in 100 ml of normal saline; Drug: Normal saline (100ml)

Detailed Description

Thiamine has a pivotal role and is an essential cofactor for pyruvate dehydrogenase activity. Widely known wet beri-beri is developed due to thiamine deficiency and characterized by vasodilatory shock and despaired oxygen extraction leading to kidney, heart and central nervous system dysfunction. Thiamine deficiency is often underestimated and even in primary absence of vitamin B1 deficiency, high-consumptive state of many critical illness and cardiac surgery itself can lead to its lack. Reported that in patients on chronic dialysis and patients with AKI requiring RRT thiamine deficiency is a usual finding. In cross-sectional observational study it has been shown that up to 33% of patients with a diagnosis of congestive heart failure (CHF) had thiamine deficiency due to chronic loop diuretic use. Also reported that 96% of patients (21 of 23) with heart failure receiving loop diuretic therapy (daily dose: 80-240 mg furosemide) developed thiamine deficiency. In prospective observational trial it has been shown that plasma thiamine levels were decreased after CABG surgery.

In a secondary analysis of a randomized, double-blind, placebo-controlled trial conducted in septic patients, thiamine supplementation showed highly-promising renal protective effect. Need for RRT was 8 patients (21%) in placebo group and 1 patient (3%) in thiamine group (p=0.04).

On the other hand it was unable to show any benefit of thiamine supplementation in patients undergoing CABG surgery. Although, postoperative oxygen consumption was significantly increased among patients receiving thiamine.

Nevertheless, existing evidence suggests that thiamine supplementation might be an attractive strategy in counteracting organ dysfunction and thus morbidity and mortality in high-risk cardiac surgical patients.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Russian Federation
  • Novosibirsk, Russian Federation
    • Meshalkin Research Institute of Pathology of Circulation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Valve surgery + CABG that required cardiac surgery with CPB
• Aged 18 years or older
• Signed informed consent

Exclusion Criteria:

• Emergency surgery
• Chronic kidney disease of G4-G5 categories according to KDIGO criteria (at least one of the following present for > 3 months: glomerular filtration rate ≤ 29 ml/min/1.73 m2, history of kidney transplantation)
• Known allergy to thiamine
• Pregnancy
• Current enrollment into another RCT (in the last 30 days)
• Previous enrollment and randomisation into the APPLY trial
• Administration of thiamine in the previous 30 day

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group	Drug: Normal saline (100ml); After anesthesia induction; After separation from CPB; On the evening of the day of surgery (22:00); On POD 1 twice a day at 8:00 and 22:00; On POD 2 twice a day at 8:00 and 22:00 (if patient is still in ICU); On POD 3 twice a day at 8:00 and 22:00 (if patient is still in ICU)
Active Comparator: Thiamine group	Drug: Thiamine hydrochloride (200mg) dissolved in 100 ml of normal saline; After anesthesia induction; After separation from CPB; On the evening of the day of surgery (22:00); On POD 1 twice a day at 8:00 and 22:00; On POD 2 twice a day at 8:00 and 22:00 (if patient is still in ICU); On POD 3 twice a day at 8:00 and 22:00 (if patient is still in ICU)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Recruitment of trial patients: successful recruitment is defined as 2 patients per week on average	8 month
Compliance with the protocol	Successful compliance with protocol is defined as ≥ 90% of prescribed intervention being administered across all patients	8 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vasoinotropic score	dosage of vasoinotropic agents and total vasopressor/norepinephrine equivalent dose	3 days
Peak lactate level after CPB weaning to 48 hours		48 hours
The value of postoperative peak serum creatinine concentration during 3 postoperative days		3 days
The incidence of acute kidney injury (AKI) according to "Kidney Disease: Improving Global Outcomes (KDIGO) criteria" during ICU stay		30 days
The daily incidence of cardiovascular and renal dysfunction according to Sequential Organ Failure Assessment (SOFA) score during 48 hours postoperatively		48 hours
Rates of postoperative complications		30 days
Incidence of Treatment-Emergent Adverse Events	The safety of high dose IV thiamine supplementation will be evaluated by comparison of adverse, serious adverse events and routinely assessed biochemical parameters (i.e. complete blood count, coagulation parameters, standard biochemistry, etc.)	30 days
Availability of data needed	We expect that loss of follow up will not exceed 5% and data loss less than 10%	8 month
7-day all-cause mortality (or mortality at any time during the first hospitalization)		7 days
30-day all-cause mortality		30 days

Collaborators and Investigators

• Sponsor: Meshalkin Research Institute of Pathology of Circulation

Publications and helpful links

General Publications

• Wiesen P, Van Overmeire L, Delanaye P, Dubois B, Preiser JC. Nutrition disorders during acute renal failure and renal replacement therapy. JPEN J Parenter Enteral Nutr. 2011 Mar;35(2):217-22. doi: 10.1177/0148607110377205.
• Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med. 1991 Aug;91(2):151-5. doi: 10.1016/0002-9343(91)90007-k.
• Donnino MW, Cocchi MN, Smithline H, Carney E, Chou PP, Salciccioli J. Coronary artery bypass graft surgery depletes plasma thiamine levels. Nutrition. 2010 Jan;26(1):133-6. doi: 10.1016/j.nut.2009.06.004. Erratum In: Nutrition. 2011 Sep;27(9):982. Salciccoli, Justin [corrected to Salciccioli, Justin].
• Andersen LW, Holmberg MJ, Doherty M, Khabbaz K, Lerner A, Berg KM, Donnino MW. Postoperative Lactate Levels and Hospital Length of Stay After Cardiac Surgery. J Cardiothorac Vasc Anesth. 2015 Dec;29(6):1454-60. doi: 10.1053/j.jvca.2015.06.007. Epub 2015 Jun 6.

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2017
• Primary Completion (Actual): May 18, 2018
• Study Completion (Actual): June 18, 2018

Study Registration Dates

• First Submitted: September 19, 2017
• First Submitted That Met QC Criteria: October 5, 2017
• First Posted (Actual): October 11, 2017

Study Record Updates

• Last Update Posted (Actual): June 27, 2018
• Last Update Submitted That Met QC Criteria: June 26, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Cardiac surgery; Renal Failure; Thiamine; Thiamine Supplementation; Vasoplegia Syndrome; Inotropic support
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Thiamine
• Other Study ID Numbers: 10

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No