Thiamine as a metabolic resuscitator after out-of-hospital cardiac arrest.

INTRODUCTION: Thiamine is a key cofactor for aerobic metabolism, previously shown to improve mortality and neurological outcomes in a mouse model of cardiac arrest. We hypothesized that thiamine would decrease lactate and improve outcomes in post-arrest patients. METHODS: Single center, randomized, blinded, placebo-controlled, Phase II trial of thiamine in adults within 4.5 hours of return of spontaneous circulation after out-of-hospital cardiac arrest (OHCA), with coma and lactate ≥ 3 mmol/L. Participants received 500 mg IV thiamine or placebo twice daily for 2 days. Randomization was stratified by lactate > 5 or ≤ 5 mmol/L. The primary outcome of lactate was checked at baseline, 6, 12, and 24 hours, and compared using a linear mixed model to account for repeated measures. Secondary outcomes included SOFA score, pyruvate dehydrogenase, renal injury, neurological outcome, and mortality. RESULTS: Of 93 randomized patients, 76 were enrolled and included in the analysis. There was no difference in lactate over 24 hours (mean difference 0.34 mmol/L (95% CI: -1.82, 2.50), p = 0.43). There was a significant interaction between randomization lactate subgroup and the effect of the intervention on mortality (p = 0.01) such that mortality was higher with thiamine in the lactate > 5 mmol/L group and lower with thiamine in the < 5 mmol/L group. This subgroup difference prompted the Data and Safety Monitoring Board to recommend the study be terminated early. PDH activity increased over 72 hours in the thiamine group. There were no differences in other secondary outcomes. CONCLUSION: In this single-center randomized trial, thiamine did not affect lactate over 24 hours after OHCA.

Thiamine as a metabolic resuscitator after in-hospital cardiac arrest.

INTRODUCTION: Elevated lactate is associated with mortality after cardiac arrest. Thiamine, a cofactor of pyruvate dehydrogenase, is necessary for aerobic metabolism. In a mouse model of cardiac arrest, thiamine improved pyruvate dehydrogenase activity, survival and neurologic outcome. AIM: To determine if thiamine would decrease lactate and increase oxygen consumption after in-hospital cardiac arrest. METHODS: Randomized, double-blind, placebo-controlled phase II trial. Adult patients with arrest within 12 hours, mechanically ventilated, with lactate ≥ 3 mmol/L were included. Randomization was stratified by lactate > 5 or ≤ 5 mmol/L. Thiamine 500 mg or placebo was administered every 12 hours for 3 days. The primary outcome of lactate was checked at baseline, 6, 12, 24, and 48 hours, and compared using a linear mixed model, accounting for repeated measures. Secondary outcomes included oxygen consumption, pyruvate dehydrogenase, and mortality. RESULTS: Enrollments stopped after 36 patients due Data Safety and Monitoring Board concern about potential harm in an unplanned subgroup analysis. There was no overall difference in lactate (mean difference at 48 hours 1.5 mmol/L [95% CI -3.1-6.1], global p = 0.88) or any secondary outcomes. In those with randomization lactate > 5 mmol/L, mortality was 92% (11/12) with thiamine and 67% (8/12) with placebo (p = 0.32). In those with randomization lactate ≤ 5 mmol/L mortality was 17% (1/6) with thiamine and 67% (4/6) with placebo (p = 0.24). There was a significant interaction between randomization lactate and the effect of thiamine on survival (p = 0.03). CONCLUSIONS: In this single center trial thiamine had no overall effect on lactate after in-hospital cardiac arrest.

Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomized, placebo controlled clinical trial.

INTRODUCTION: Acute pancreatitis is a common disease which, in its severe form, is associated with significant morbidity and mortality. Currently, there is no specific therapy known to attenuate organ failure in severe pancreatitis and treatment consists primarily of supportive care. Corticosteroids have been shown to be beneficial in disease processes associated with systemic inflammation and could potentially improve outcomes in severe acute pancreatitis. METHODS: The Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) trial is a multi-centre, double-blind, randomized, placebo-controlled clinical trial that aims to determine the impact of corticosteroids versus placebo on organ injury in patients with severe acute pancreatitis. Patients are randomized to receive 100 mg of hydrocortisone parenterally versus matching placebo every 8 h for 3 days. Clinical and laboratory data are collected at the time of study enrollment, at 24, 48 and 72 h. The primary end-point for the trial is the difference in 72-h change in the Sequential Organ Failure Assessment (SOFA) score between hydrocortisone and placebo groups. Additional key secondary outcomes include ventilator free days and 28-day mortality. DISCUSSION: This study will add to the evidence base in the treatment of severe acute pancreatitis. The results will inform clinical practice and future studies in the field. Trial registration number The trial is registered on clinicaltrials.gov (NCT05160506). It was posted on December 16th, 2021. The study protocol was approved by the Beth Israel Deaconess Medical Center Committee on Clinical Investigation (CCI) (protocol 2021 P-000803).

Shenfu injection as treatment for critical illness: a narrative review of clinical trials.

Background and Objective: Shenfu injection (SFI) is a traditional herbal medicine derived from components of ginseng and aconite and is commonly used in China to treat a variety of conditions. Shenfu has been suggested to have beneficial effects in various critical illnesses, including heart failure, cardiac arrest, and septic shock. In recent years, there have been a number of studies reporting that SFI improves patient outcomes when used concurrently with other treatments, but its use has not been adopted outside of China. This narrative review explored the results of clinical trials that have tested SFI's efficacy in various critical illnesses. Methods: PubMed was searched for clinical trials, systematic reviews and meta-analyses published between 1990 and July 2022 relating to clinical trials using SFI in various critical illnesses. Systematic reviews and meta-analyses were included to enable inclusion of data from trials originally not published in English. The selected articles were then summarized in the following disease categories: heart failure, cardiac arrest, sepsis, and severe pulmonary disease. Key Content and Findings: Clinical trials testing SFI in heart failure, cardiac arrest, sepsis, and pulmonary disease were reviewed. The design, methodology, and key findings of each trial or meta-analysis are summarized and discussed. Key limitations were also highlighted and discussed. Overall, several clinical trials suggest SFI may hold therapeutic potential for the treatment of critical illness, however, additional research is likely still needed. Conclusions: Based on the current body of literature, further research-especially multi-center randomized, double-blind trials with detailed reporting of all methods and results according to international guidelines-is needed to evaluate whether SFI is a useful addition to existing treatments for these conditions.

Thiamine as adjunctive therapy for diabetic ketoacidosis (DKAT) trial protocol and statistical analysis plan: a prospective, single-centre, double-blind, randomised, placebo-controlled clinical trial in the USA.

INTRODUCTION: Diabetic ketoacidosis (DKA) is a potentially life-threatening diabetic complication. Despite the high prevalence of DKA and the substantial associated healthcare burden, limited research on strategies to improve outcomes currently exists.Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase, which plays a key role in aerobic glucose metabolism. Thiamine deficiency is common in patients with DKA, resulting in a shift to anaerobic metabolism and hyperlactatemia, which can prolong and complicate recovery. Therefore, we hypothesise that thiamine administration will improve aerobic metabolism and lead to faster resolution of acidemia in patients with DKA. METHODS AND ANALYSIS: In this single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial, 100 patients admitted to the hospital with DKA will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) or placebo (0.9% saline identical in appearance and volume) two times per day for 2 days. The primary outcome will be the change in bicarbonate level over 24 hours as compared between the two treatment groups. Additional secondary outcomes include the change over time in anion gap, lactate levels, oxygen consumption by circulating mononuclear cells, intensive care unit and hospital length-of-stay and hospital resource usage when comparing the two study arms. ETHICS AND DISSEMINATION: This trial was approved by the Committee on Clinical Investigations, the institutional review board of Beth Israel Deaconess Medical Center (protocol number 2018P000475). Findings will be disseminated through peer-reviewed publications and professional conference presentations. TRIAL REGISTRATION NUMBER: NCT03717896; clinicaltrials.gov.

Thiamine administration in septic shock: a post hoc analysis of two randomized trials.

BACKGROUND: This is a post hoc analysis of combined cohorts from two previous Phase II clinical trials to assess the effect of thiamine administration on kidney protection and mortality in patients with septic shock. METHODS: Patient-level data from the Thiamine in Septic Shock Trial (NCT01070810) and the Thiamine for Renal Protection in Septic Shock Trial (NCT03550794) were combined in this analysis. The primary outcome for the current study was survival without the receipt of renal replacement therapy (RRT). Analyses were performed on the overall cohort and the thiamine-deficient cohort (thiamine < 8 nmol/L). RESULTS: Totally, 158 patients were included. Overall, thiamine administration was associated with higher odds of being alive and RRT-free (adjusted odds ratio [aOR]: 2.05 [95% confidence interval (CI) 1.08-3.90]) and not needing RRT (aOR: 2.59 [95% CI 1.01-6.62]). In the thiamine-deficient group, thiamine administration was associated with higher odds of being alive and RRT-free (aOR: 8.17 [95% CI 1.79-37.22]) and surviving to hospital discharge (aOR: 6.84 [95% CI 1.54-30.36]). There was a significant effect modification by baseline thiamine deficiency for alive and RRT-free (interaction, p = 0.016) and surviving to hospital discharge (p = 0.019). CONCLUSION: In the combined analysis of two previous randomized trials, thiamine administration was associated with higher odds of being alive and RRT-free at hospital discharge in patients with septic shock. This signal was stronger in patients with thiamine deficiency.

Establishment of a reference interval for thiamine concentrations in healthy dogs and evaluation of the prevalence of absolute thiamine deficiency in critically ill dogs with and without sepsis using high-performance liquid chromatography.

OBJECTIVE: To determine the normal reference interval (RI) for thiamine concentrations in healthy dogs and investigate the prevalence of thiamine deficiency in critically ill dogs with and without sepsis. DESIGN: Prospective, observational, multicenter study, conducted between 2019 and 2021. SETTING: Two veterinary university teaching hospitals. ANIMALS: A total of 109 dogs were enrolled into 3 groups: 40 healthy dogs, 33 dogs with suspected or confirmed sepsis and evidence of tissue hypoperfusion (Doppler blood pressure ≤90 mm Hg or plasma lactate ≥3 mmol/L), and 36 dogs with other critical illnesses and evidence of tissue hypoperfusion. INTERVENTIONS: For each dog, CBC, serum biochemistry, plasma lactate concentration, whole-blood thiamine concentration, blood pressure, vital parameters, Acute Patient Physiologic and Laboratory Evaluation (APPLE)fast score, and clinical outcomes were recorded, alongside basic patient parameters and dietary history. Whole-blood thiamine pyrophosphate (TPP) concentrations were measured using high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The RI for whole-blood TPP in healthy dogs was 70.9-135.3 µg/L. Median TPP concentrations were significantly lower in septic dogs compared to healthy controls (P = 0.036). No significant difference in median TPP concentrations was found between septic dogs and nonseptic critically ill dogs, or between healthy dogs and nonseptic critically ill dogs. TPP concentrations were below the normal RI in 27.3% of septic dogs, compared to 19.4% of nonseptic critically ill dogs (P = 0.57). No correlations were found between TPP concentrations and lactate concentrations, age, body condition scores, time since last meal, RBC count, serum alanine aminotransferase, APPLEfast scores, or patient outcomes. CONCLUSIONS: TPP concentrations were significantly lower in septic dogs compared to healthy controls, with an absolute thiamine deficiency found in 27.3% of septic dogs. The established TPP RI allows for further investigation of thiamine deficiency in critically ill dogs.

Kidney-specific biomarkers for predicting acute kidney injury following cardiac arrest.

AIM: To evaluate the performance of kidney-specific biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and cystatin-C) in early detection of acute kidney injury (AKI) following cardiac arrest (CA) when compared to serum creatinine. METHODS: Adult CA patients who had kidney-specific biomarkers of AKI collected within 12 h of return of spontaneous circulation (ROSC) were included. The association between renal biomarker levels post-ROSC and the development of KDIGO stage III AKI within 7 days of enrollment were assessed as well as their predictive value of future AKI development, neurological outcomes, and survival to discharge. RESULTS: Of 153 patients, 54 (35%) developed stage III AKI within 7 days, and 98 (64%) died prior to hospital discharge. Patients who developed stage III AKI, compared to those who did not, had higher median levels of creatinine, NGAL, and cystatin-C (p < 0.001 for all). There was no statistically significant difference in KIM-1 between groups. No biomarker outperformed creatinine in the ability to predict stage III AKI, neurological outcomes, or survival outcomes (p > 0.05 for all). However, NGAL, cystatin-C, and creatinine all performed better than KIM-1 in their ability to predict AKI development (p < 0.01 for all). CONCLUSION: In post-CA patients, creatinine, NGAL, and cystatin-C (but not KIM-1) measured shortly after ROSC were higher in patients who subsequently developed AKI. No biomarker was statistically superior to creatinine on its own for predicting the development of post-arrest AKI.

Thiamine for Renal Protection in Septic Shock (TRPSS): A Randomized, Placebo-controlled, Clinical Trial.

Rationale: Kidney injury is common and associated with worse outcomes in patients with septic shock. Mitochondrial resuscitation with thiamine (vitamin B1) may attenuate septic kidney injury. Objectives: To assess whether thiamine supplementation attenuates kidney injury in septic shock. Methods: The TRPSS (Thiamine for Renal Protection in Septic Shock) trial was a multicenter, randomized, placebo-controlled trial of thiamine versus placebo in septic shock. The primary outcome was change in serum creatinine between enrollment and 72 hours after enrollment. Measurements and Main Results: Eighty-eight patients were enrolled (42 patients received the intervention, and 46 received placebo). There was no significant between-groups difference in creatinine at 72 hours (mean difference, -0.57 mg/dl; 95% confidence interval, -1.18, 0.04; P = 0.07). There was no difference in receipt of kidney replacement therapy (14.3% vs. 21.7%, P = 0.34), acute kidney injury (as defined by stage 3 of the Kidney Disease: Improving Global Outcomes acute kidney injury scale; 54.7% vs. 73.9%, P = 0.07), or mortality (35.7% vs. 54.3%, P = 0.14) between the thiamine and placebo groups. Patients who received thiamine had more ICU-free days (median [interquartile range]: 22.5 [0.0-25.0] vs. 0.0 [0.0-23.0], P < 0.01). In the thiamine-deficient cohort (27.4% of patients), there was no difference in rates of kidney failure (57.1% thiamine vs. 81.5% placebo) or in-hospital mortality (28.6% vs. 68.8%) between groups. Conclusions: In the TRPSS trial, there was no statistically significant difference in the primary outcome of change in creatinine over time. Patients who received thiamine had more ICU-free days, but there was no difference in other secondary outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT03550794).

Successful management of ventricular fibrillation and ventricular tachycardia using defibrillation and intravenous amiodarone therapy in a cat.

OBJECTIVE: To describe the successful management of ventricular fibrillation (VF) and ventricular tachycardia (VT) using cardiopulmonary resuscitation, including defibrillation, followed by continuous rate infusion of IV amiodarone, in a cat with cardiac arrest secondary to tachyarrhythmia. CASE SUMMARY: A 12-year-old previously healthy neutered male Scottish Fold cat presented following an acute episode of collapse. Initial physical examination revealed severe tachycardia and cardiovascular collapse. Within a few minutes after arrival, the cat experienced cardiopulmonary arrest. Electrocardiographic assessment was suggestive of VF, and CPR was initiated, including 2 rounds of defibrillation (2 joule/kg each), resulting in return of spontaneous circulation with sustained VT. After procainamide and lidocaine failed to result in conversion to normal sinus rhythm (NSR), continuous IV amiodarone therapy was initiated, and NSR was achieved. Echocardiography demonstrated severe systolic dysfunction, and tachycardia-induced cardiomyopathy (TICM) secondary to chronic VT was suspected; however, dilated cardiomyopathy (DCM) or end-stage hypertrophic cardiomyopathy could not be ruled out. The patient was discharged the following day with oral amiodarone and pimobendan. During a recheck examination performed 7 months later the cat was in NSR, with no direct evidence of long-term amiodarone adverse effects. The cat died acutely at home 8 months after discharge. NEW OR UNIQUE INFORMATION PROVIDED: This report is the first to describe the successful use of IV amiodarone in a cat to manage sustained VT following CPR.

Assessment of the CoaguChek-XS portable prothrombin time point-of-care analyzer for horses.

Coagulopathies in horses are common and potentially life-threatening. In equine field medicine, a portable point-of-care (POC) prothrombin time (PT) testing device could be useful to identify early changes in extrinsic clotting. The CoaguChek-XS (Roche Diagnostics) is a small, portable POC PT analyzer used in human medicine. Our preliminary study assessed the suitability of CoaguChek-XS for testing PT in horses and established the PT reference interval (PT RI) in healthy horses using this instrument. Blood samples collected from 102 healthy and ill horses were analyzed with the CoaguChek-XS and compared to a semi-automated coagulometric analyzer (SACA) as the gold standard. There was a significant positive correlation between the 2 measurement methods ( r = 0.765, p < 0.01), and very good agreement, with 97% of the samples falling within limits of agreement. The mean CoaguChek-XS PT coefficient of variation was 0.8%, indicating high precision. With high precision and good agreement with the coagulometric PT, the CoaguChek-XS should be further validated for PT measurement in horses.