April 2016 E-Journal Club

Greetings,

We hosted several wonderful trainees from Miami, Florida in April.  Of course, it never fails that when we have visitors from warmer climes, Charlottesville will have some unseasonably cool weather!

Our journal club in April was about one of our current favorite vitamins – thiamine.  In the past several years there has been increased scrutiny of the efficacy of the usual protocols for thiamine supplementation and interest in the potential of thiamine as an adjunct in metabolic resuscitation of critically ill patients.

April Citation:

Andersen LW, Holmberg MJ, Berg KM, et al. Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial. Crit Care. 2016 Mar 14;20(1):92.

Summary: 

This was a single-center, randomized, double-blind, placebo-controlled trial of thiamine supplementation in 64 moderate-high risk patients undergoing coronary artery bypass grafting. Patients were randomized to receive either 200 mg intravenous thiamine or placebo both immediately before and again after the surgery. The primary study endpoint was post-operative lactate levels, with secondary endpoints of pyruvate dehydrogenase activity (PDH), post-operative complications, intensive care unit and hospital length of stay, and mortality. Additional endpoints included lactate levels 6 hours after the surgery, time on mechanical ventilation, time on vasopressors and cellular and global oxygen consumption.

Subgroup analysis was planned for low vs. high EuroSCORE II (a validated pre-operative score to predict post-operative morbidity and mortality), pre-surgery thiamine level and according to whether the patient had diabetes (risk factor for thiamine deficiency).

Inclusion and Exclusion Criteria:

Inclusion criteria:

Adult patients (≥21 years) scheduled for CABG with or without concomitant valve procedures, who had a EuroSCORE II score > 1.5%.

Exclusion criteria:

Patients with current thiamine supplementation or known clinical indication for thiamine supplementation (alcohol dependency), known allergy to thiamine, emergent or salvage CABG, CABG without cardiopulmonary bypass (“off-pump” surgery) and protected population (pregnant women, prisoners, and the intellectually disabled).

Major Results:

There were 275 patients screened, 69 randomized and 64 received the first study dose and included in the analysis (“modified intention to treat”), with 31 patients receiving thiamine and 33 patients received placebo.  Baseline characteristics were similar between the groups.

Thiamine levels were similar between the thiamine and placebo group prior to the surgery: one patient in the thiamine group and no patients in the placebo group had serum levels consistent with thiamine deficiency. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 nmol/L vs. 9 nmol/L, p < 0.001) and 6 hours after the surgery (1200 nmol/L vs. 10 nmol/L, p < 0.001).

No patients in the thiamine group had serum levels consistent with deficiency after the surgery as compared to three (9 %) in the placebo group immediately after the surgery (p = 0.24) and five (15 %) patients 6 hours after the surgery (p = 0.05).

There was no difference between the thiamine and placebo groups in the primary endpoint of lactate levels immediately after the surgery, 6 hours after the surgery, or in post-operative lactate levels when analyzed in the repeated measures model, or according to the subgroup analysis.

Relative PDH activity was significantly lower immediately after the surgery in the thiamine group as compared to the placebo group (15% vs. 28% p = 0.02). However, after adjusting for baseline differences in PDH level, this was no longer significantly different. There was no difference relative PDH levels 6 hours after the surgery (23% vs. 29%, p = 0.19). There was no difference in relative PDH quantity immediately after the surgery (43% vs. 50%, p = 0.93) or 6 hours after the surgery (56% vs. 74%, p = 0.27). Relative PDH specific activity was lower in the thiamine group immediately after surgery (19% vs. 39%, p = 0.01), but there was no difference 6 hours after surgery (27% vs. 41%,  p = 0.23).

Global oxygen consumption (VO2) was measured in only 27 patients: 15 in the placebo group and 12 in the thiamine group. The thiamine group had a significantly higher VO2 1 hour after surgery compared to placebo (difference: 0.37 mL/min/kg [95 % CI: 0.03, 0.71], p = 0.03). There was no difference between the groups in change in VO2 over time from 1 to 4 hours after the surgery (p = 0.36).

Basal cellular oxygen consumption was available in 40 patients (20 in the placebo group and 20 in the thiamine group). There was a significant difference in post-operative relative basal oxygen consumption between the thiamine and placebo group (99%, vs. 85%, p = 0.04). Maximal cellular oxygen consumption was available for 38 patients (19 in the placebo group and 19 in the thiamine group). There was a significant difference in post-operative relative maximal oxygen consumption between the thiamine and placebo group (107%, vs. 90%, p = 0.02).

There were no significant differences in any measured clinical outcomes between groups.  One patient died in the placebo group and none in the thiamine group. No side effects of the study supplement were reported in either group.

Author’s Conclusions:

“In this randomized, placebo-controlled, double-blind, phase II trial, we found no difference in post-operative lactate levels or clinical outcomes between patients receiving thiamine or placebo. We found a significant increase in post-operative oxygen consumption in patients receiving thiamine.”

Evaluation:

This was a small size randomized study with adequate power only for analysis of lab values, and did not have enough patients to allow meaningful evaluation of any clinical outcomes. The primary outcome of serum lactic acid that was not significantly different between groups suggests that thiamine availability is not a rate-limiting step in lactate clearance in patients with normal thiamine status on admission.

The result that relative PDH activity was decreased in the thiamine group was the opposite of what the investigators anticipated. Since they could not explain this result and suggested that it could be a chance finding or related to the assay used, this result raises questions about other possible chance or spurious findings.

The finding of significantly improved oxygen consumption after thiamine administration does carry potentially clinically relevant implications.  Although thiamine availability may not routinely be rate limiting for lactate clearance, this does not exclude the possibility that supplemental thiamine may have beneficial effects post-cardiac surgery or for other critically ill patients.  However, the small number of patients that had measurements of oxygen consumption increases the possibility of a chance occurrence.  Ultimately, there is a need for much larger studies to determine if thiamine supplementation provides meaningful improvements in oxygen consumption and (most importantly) patient outcome.

One of the more interesting tidbits of this study was the information that operative stress appears to acutely lower serum thiamine into the deficient range in 15% of patients at 6 hours post-op.  It would be interesting to know if this is a transient effect, if it represents increased need for thiamine that exceeds stores, or if greater numbers of patients would demonstrate decreased serum thiamine decreases over time.  It should be remembered that decreased serum levels of some nutrients under metabolic stress may be part of a protective mechanism or stress response that is beneficial.  It would be folly to assume that supplementation is always indicated in the setting of decreased serum nutrient levels under stress.

Our Take Home Message(s)

1. Thiamine supplementation before and after CABG does not alter postoperative serum lactic acid.
2. High dose intravenous thiamine pre and post CABG with cardiopulmonary bypass may decrease pyruvate dehydrogenase activity and increase oxygen consumption.
3. CABG with cardiopulmonary bypass decreases serum thiamine into the deficient range in 15% of patients without pre-existing thiamine deficiency, but further study is needed to assess the significance of surgical stress on serum thiamine levels.
4. There is a need for larger studies to investigate the effect of supplemental thiamine on patient outcomes in cardiac surgery and critical illness in general, especially in the setting of marginal hemodynamics and perfusion.

Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):

Having trouble seeing any of the resources on our page?  Retype www.GInutrition.virginia.edu into your browser to reach our newly updated page

Upcoming Webinars 2016:

Tuesday, May 24 at 1:00 PM (ET):  Meeting Full Calorie Needs in the ICU:  Should We?

June 21 at 1:00 PM (ET) :  Micronutrient Deficiencies after Gastric Bypass Surgery

Latest Practical Gastroenterology article:

Nanavati AJ, Prabhakar S. Enhanced Recovery After Surgery: If You Are Not Implementing It, Why Not?  Practical Gastroenterology 2016;XXXX(4):46.

Joe Krenitsky MS, RDN

PS – Please feel free to forward on to friends and colleagues.