Thiamine (vitamin B1) is a cofactor for pyruvate dehydrogenase and essential for the conversion of pyruvate to acetyl coenzyme A. In cardiac patients, several factors may increase the risk of thiamine deficiency such as heart failure, age, malnutrition,1 unintended weight loss,2 advanced age, frequent hospitalisation3 and disease or surgery-related stress.2 Lack of sufficient thiamine results in high blood lactate concentrations as a consequence of the failure of pyruvate to enter into the citric acid cycle.2 This results in high-output cardiac failure and death when untreated.4 Higher thiamine concentrations in critically ill patients are associated with a lower mortality rate.5 In addition, lactate concentration, as a prognostic indicator, may be predictive of a favourable outcome.6
To the best of our knowledge, no study has evaluated thiamine concentrations in patients undergoing cardiac surgery and, in particular, thiamine substitution as an intervention preoperatively. We hypothesised that the stress of surgery would result in decreased thiamine and consequently higher lactate concentrations. Therefore, the objective of this pilot study was to increase thiamine concentration by thiamine supplementation and therefore reduce concentrations of lactate in cardiac patients, as this might minimise perioperative metabolic stress. Furthermore, we aimed to identify the prevalence of thiamine deficiency and risk factors for high lactate concentrations.
Materials and methods
Ethics approval for this study (Ethical Committee No. 732/2011) was provided by the Ethical Committee of the Medical University of Vienna, Austria (Chairperson Prof E. Singer) on 7 September 2011 and approval from the Austrian Federal Office for Safety in Healthcare. Informed written consent was obtained from all eligible patients willing to participate in the study. The study was registered at EudraCT (Ref: 2011-004080-70) and clinicaltrials.gov (Identifier: NCT01524315) and complies with the Declaration of Helsinki 2008.7
We considered 39 adult patients scheduled for elective cardiac surgery with cardiopulmonary bypass on the cardiothoracic surgery ward of the Vienna General Hospital for eligibility. Thirty were assigned randomly to either the thiamine supplementation group or a placebo group. Nine patients were excluded from further study participation (Fig. 1).
Patients with the following conditions or treatments were excluded: known allergy to ingredients of the drug used, prior intake of thiamine supplements, impaired renal function, inflammatory bowel conditions, bariatric surgery, inability to give consent and to perform study procedures, infection (e.g. HIV or hepatitis) and participation in another clinical trial.
In order to achieve a homogeneous study group, we recruited patients scheduled for cardiac surgery with cardiopulmonary bypass. After randomisation (using a web-based randomisation system with block size, which reduced bias and achieved a balance in the allocation of participants to treatment arms), a single dose of thiamine chloride hydrochloride 300 mg in 100 ml of 0.9% normal saline or placebo (0.9% normal saline) was given directly before surgery. The infusion was administered over a period of up to 30 min. This dosage exceeds daily requirement8 by far, because the bioavailability of oral thiamine is low.9 Consequently, a high intravenous dose of thiamine might be necessary to assure a measurable effect, as it is a water-soluble vitamin and excreted in the urine.
We collected blood samples for determination of thiamine concentration and thiamine diphosphate (a thiamine derivative that is produced by the enzyme thiamine pyrophosphatase) concentration before supplementation and 48 h postoperatively, measured by HPLC; the determination of thiamine involves the oxidation of thiamine to thiochrome, which fluoresces in ultraviolet light. As part of the clinical routine, blood gas analysis during surgery and ICU stay was performed to determine blood lactate concentration (ABL 700; Radiometer Medical, Copenhagen, Denmark). Creatinine and thiamine concentrations in urine samples were measured 24 h after surgery. To compare our results with reference concentrations of thiamine, we used the reference range (275 to 675 ng g–1 haemoglobin (Hb)] of Talwar et al.10
The preoperative variables were collected in questionnaires: SF-12,11 which measures physical and mental health with a range from 0 to 100 indicating: worst to best health; Subjective Global Assessment (SGA),12 which assesses malnutrition (three groups: A, well nourished; B, mild to moderate malnourishment; and C, severely malnourished); and the Dietary Interview Software for Health Examination Studies (DISHES 98),13 which assesses nutrient consumption. Other variables assessed were the classification of cardiac disease [New York Heart Association Classification, NYHA; left ventricular ejection fraction, LVEF; EuroScore by calculating predicted operative mortality; preoperative conditions (medication and comorbidities); and lengths of ICU and hospital stays, LOS]. Anthropometric measurements (height, weight) and body composition by bioelectrical impedance analysis (BIA) (Data Input GmbH, Frankfurt, Germany) were assessed. Several body compartments such as body cell mass (BCM) and extracellular mass (ECM) were calculated. Furthermore, BIA can reflect directly the proportions between intracellular and extracellular spaces (ECM/BCM), which is, apart from the phase angle, one of the most sensitive indices of malnutrition.14
The statistical software SPSS Statistics, version 20 (IBM Armonk, New York, USA) was used for data analysis. All tests were two-sided and P values less than 0.05 were considered as statistically significant. This study was conducted as a pilot study and, using the results of our study for calculating sample size, 50 patients per group would be needed to reach 80% statistical power. Study groups were compared regarding baseline and postoperative continuous variables using t-test or Mann–Whitney U-test. Group comparisons were undertaken by χ2, paired t-test or Wilcoxon test. Pearson's and Spearman's correlation coefficients were used. For comparison of repeated lactate concentrations and laboratory values at different time points, we used repeated measures analysis of covariance (ANCOVA). A logistic regression model was used to demonstrate the odds ratio (OR) of patients with an ECM/BCM-index above and below 1 with regard to lactate concentrations [adjusted for sex, BMI, heart disease, ejection fraction, C-reactive protein (CRP) and albumin concentrations preoperatively, and the duration of surgery]. Values are expressed as mean ± SD for continuous variables and as frequency (%) for categorical variables.
At baseline, no differences in patient characteristics and clinical outcome variables were observed between the two groups (Table 1).
At study entry, the patients had a body weight of 82.8 ± 15.6 kg and BMI of 28.0 ± 4.2 kg m−2. Seventy-three percent of patients were overweight or obese, 90% well nourished and 10% moderately malnourished according to SGA. Forty-six percent of patients had an ECM/BCM ratio less than 1 assessed by BIA, which reflects directly the proportions between intracellular and extracellular spaces and gives an indication of poorer nutritional status.
Fifty-four percent of patients were in good physical condition as assessed by the Physical Condition Summary (PCS) (41 ± 11 points) and 82% were in good mental health using the mental health component scale (MCS) (51 ± 8 points). The PCS and ECM/BCM index significantly correlated with LOS in ICU (r = –0.573, P < 0.01 and r = 0.466, P < 0.01, respectively) and hospital (r = –0.415, P < 0.05; r = 0.429, P < 0.05, respectively). The mean thiamine intake of 1.4 ± 0.7 mg was above the D-A-CH (European countries with German-speaking majorities) recommendations of 1.0 mg,8 as assessed by dietary history. There were no statistically significant differences between preoperative blood thiamine concentrations in the two groups (thiamine group 449.1 ± 168.1 ng per g Hb, placebo group 419.4 ± 88.4 ng g–1 Hb). Our results revealed a 10% prevalence of thiamine deficiency. Forty-eight hours postoperatively, the blood thiamine concentration was significantly higher in the thiamine group (805.2 ± 189.8 ng g–1 Hb) than in the placebo group (591.2 ± 100.7 ng g–1 Hb, P < 0.01). Mean excretion of thiamine in the thiamine supplement group was 172.3 ± 74.9 mg per 24 h (this equals 57 ± 25% of the initial 300 mg of thiamine) and 0.2 ± 0.1 mg per 24 h in the placebo group (P < 0.001). There was a significant difference in thiamine excretion, normalised for creatinine excretion over 24 h, between groups (thiamine group 38 661 ± 34 423 nmol per mmol creatinine vs. placebo 26 ± 13 nmol per mmol creatinine, P < 0.001). By 24 h postoperatively, all patients in the thiamine group had normal concentrations. In contrast, in the placebo group, 53% of patients had normal and 40% had low thiamine concentrations (9.1 to 22 ng g–1 Hb), and 7% were deficient (<9.1 ng g–1 Hb), according to Sauberlich.15
Mean blood lactate concentration changed significantly over time, but did not differ significantly between the groups. Blood lactate concentration was higher in the placebo group than in the thiamine group on admission to ICU (2.0 ± 0.6 vs. 1.7 ± 0.7 nmol l−1), and at 4 h (1.8 ± 0.5 vs. 1.7 ± 0.6 nmol l−1), between 6 and 16 h (1.7 ± 0.5 vs. 1.6 ± 0.6 nmol l−1) after surgery and on day 1 postoperatively (1.5 ± 0.3 vs. 1.4 ± 0.4 nmol l−1). Lactate concentration increased during surgery and thereafter returned to the preoperative value.
Patients with an ECM/BCM index more than 1 had higher blood lactate concentrations than those with an index less than 1 on admission to ICU (2.1 ± 0.7 vs. 1.7 ± 0.6, P = 0.09). We found significant correlations between ECM/BCM index and lactate concentration on admission to ICU (r = -0.394, P < 0.05), ICU LOS (r = 0.466, P < 0.01) and hospital LOS (r = 0.429, P < 0.05). Moreover, patients with an ECM/BCM index more than 1 had a significantly higher risk of having a higher lactate concentration on admission to ICU than those with an index less than 1 [OR 13.5, 95% confidence interval (95% CI) 1.0 to 179.4, adjusted for sex, BMI, heart disease, ejection fraction grade, CRP and albumin concentrations preoperatively, and the duration of surgery; Fig. 2].
All other laboratory and clinical measures were similar in both groups. Changes over the study period were not statistically significant between the groups but were significant over time (Table 2).
To the best of our knowledge, this is the first study to assess the effects of parenteral thiamine infusion in patients undergoing elective cardiac surgery with cardiopulmonary bypass. Regarding lactate as a biochemical marker, we failed to find a protective effect of thiamine supplementation and therefore could not confirm the study hypothesis of reducing lactate concentration by thiamine supplementation. Possible reasons for the negative findings in this study may be the lack of efficacy of thiamine supplementation when administered just before surgery and the low prevalence of thiamine deficiency.
Concerning nutritional status, the majority of cardiothoracic patients are overweight.16 BMI is not a reliable measure of body composition and nutritional status, and so we used BIA. Two-thirds of the study population had a good nutritional status as assessed by the ECM/BCM index. The prevalence of moderate malnutrition in 10% of our study population determined by SGA is in contrast to a report on 460 Turkish patients, who had an incidence of malnutrition of 58%.17 Malnutrition has been shown to be associated with an increased risk of thiamine deficiency,18 which was not confirmed in our study. Nevertheless, the prevalence of malnutrition should be taken into account when identifying patients at risk of thiamine deficiency. The prevalence of thiamine deficiency ranges from 12 to 91%3,19,20 and our results are comparable to those of Pfitzenmeyer et al.3 Moreover, the blood thiamine concentration, a good measure of body stores, diminishes at a rate comparable to those in other major organs21 and is similar to that reported by Herve et al.22
In the placebo group, urinary thiamine concentration decreased within 24 h and about half of all patients exhibited concentrations below the reference values, indicating that the stress of surgery may deplete thiamine concentrations. In the thiamine group, urinary thiamine concentrations were increased during the first 24 h after surgery. Donnino et al.4 reported a significant decrease in plasma thiamine concentration from pre to postsurgery and the authors suggested that major surgery, as a trigger for the stress of critical illness, depletes thiamine concentration. Postoperatively, in our pilot study the blood thiamine concentration was significantly higher in the thiamine group than in the placebo group. The blood thiamine concentration was within the reference range in all patients.
Due to failure of the conversion of pyruvate, thiamine deficiency may lead to high blood lactate concentrations as shown in a subgroup of patients undergoing cardiopulmonary bypass surgery.23 Blood lactate concentration may predict the outcome of surgery in high-risk patients.24 Because thiamine is a key factor in metabolism, we hypothesised that higher thiamine concentrations would be associated with lower lactate concentrations. When measuring lactate concentration in the postoperative period as described by Maillet et al.,23 we failed to find statistically significant differences between the thiamine and placebo groups. Using the ECM/BCM index as a marker for nutritional status, we found an association between this variable and lactate concentration on admission to ICU. Moreover, patients with higher lactate concentrations on admission to ICU had significantly longer ICU stays and hospital LOS, a finding supporting recent studies.24,25
Our study has several limitations. First, we found a relatively low prevalence of malnutrition, which is comparable with the findings of Pirlich et al.26 In more severely ill cardiac patients (e.g. with cardiac cachexia), malnutrition occurs more often and body composition is altered. As a consequence, malnutrition and thiamine deficiency are expected to be worse.27 Second, the sample size of 30 patients might be too small to show significant differences for changes in lactate concentration. However, the majority of previous studies investigating thiamine concentrations in cardiac patients were also limited by a small sample size. This study was conducted as a pilot study and, using the results of our study for calculating a sample size, 50 patients per group would be needed to reach 80% statistical power. Despite the small sample size in this pilot study, we did find higher lactate concentrations in the placebo group. Therefore, our study suggests some benefit of thiamine that needs to be confirmed in larger studies. Third, the sexual distribution was not balanced in this study but is the usual sexual distribution of cardiac surgical patients.4,28,29 In our study blood thiamine concentration was measured directly using HPLC, which has advantages in terms of sensitivity, precision, recovery and robustness.30,31 Indirect measurement as erythrocyte transketolase activity has rather weak inter-assay precision, difficulty in standardisation and instability of sample storage.32
The current study suggests that larger studies investigating potential beneficial effects of thiamine in cardiac patients are required.
In conclusion, our data show that parenteral administration of thiamine prior to cardiac surgery prevents postoperative depletion of thiamine. However, thiamine supplementation failed to improve biochemical markers such as lactate concentration or clinical outcome. The findings from our pilot study demonstrated an association between body composition and both lactate concentration and outcome.
Acknowledgements relating to this article
Assistance with the study: the authors would like to thank George Mare for technical assistance and Dorota Majchrzak for advice.
Financial support and sponsorship: this work was supported by the Division Cardiac Thoracic Vascular Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Vienna, Austria.
Conflicts of interest: none.
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