Ari Moskowitz

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

Objective:To determine if intravenous thiamine would reduce lactate in patients with septic shock. Design:Randomized, double-blind, placebo-controlled trial. Setting:Two US hospitals. Patients:Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014. Interventions:Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. Measurements and Main Results:The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). Conclusion:Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.

The prevalence and significance of abnormal vital signs prior to in-hospital cardiac arrest

BACKGROUND Patients suffering in-hospital cardiac arrest often show signs of physiological deterioration before the event. The purpose of this study was to determine the prevalence of abnormal vital signs 1-4h before cardiac arrest, and to evaluate the association between these vital sign abnormalities and in-hospital mortality. METHODS We included adults from the Get With the Guidelines(®)- Resuscitation registry with an in-hospital cardiac arrest. We used two a priori definitions for vital signs: abnormal (heart rate (HR) ≤ 60 or ≥ 100 min(-1), respiratory rate (RR) ≤ 10 or >20 min(-1) and systolic blood pressure (SBP) ≤ 90 mm Hg) and severely abnormal (HR ≤ 50 or ≥ 130 min(-1), RR ≤ 8 or ≥ 30 min(-1) and SBP ≤ 80 mm Hg). We evaluated the association between the number of abnormal vital signs and in-hospital mortality using a multivariable logistic regression model. RESULTS 7851 patients were included. Individual vital signs were associated with in-hospital mortality. The majority of patients (59.4%) had at least one abnormal vital sign 1-4h before the arrest and 13.4% had at least one severely abnormal sign. We found a step-wise increase in mortality with increasing number of abnormal vital signs within the abnormal (odds ratio (OR) 1.53 (CI: 1.42-1.64) and severely abnormal groups (OR 1.62 (CI: 1.38-1.90)). This remained in multivariable analysis (abnormal: OR 1.38 (CI: 1.28-1.48), and severely abnormal: OR 1.40 (CI: 1.18-1.65)). CONCLUSION Abnormal vital signs are prevalent 1-4h before in-hospital cardiac arrest on hospital wards. In-hospital mortality increases with increasing number of pre-arrest abnormal vital signs as well as increased severity of vital sign derangements.

The Misapplication of Severity-of-Illness Scores toward Clinical Decision Making

Affiliations: 1 Massachusetts General Hospital, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Boston, MA 2 Research Center for Emergency Medicine, Aarhus University Hospital, Aarhus, Denmark 3 Beth Israel Deaconess Medical Center, Department of Anesthesia, Division of Critical Care, Boston MA 4 Beth Israel Deaconess Medical Center, Department of Emergency Medicine, Boston MA 5 Beth Israel Deaconess Medical Center, Department of Medicine, Division Pulmonary, Critical Care, and Sleep Medicine Boston MA

The relationship between lactate and thiamine levels in patients with diabetic ketoacidosis

PURPOSE Thiamine functions as an important cofactor in aerobic metabolism and thiamine deficiency can contribute to lactic acidosis. Although increased rates of thiamine deficiency have been described in diabetic outpatients, this phenomenon has not been studied in relation to diabetic ketoacidosis (DKA). In the present study, we hypothesize that thiamine deficiency is associated with elevated lactate in patients with DKA. MATERIALS AND METHODS This was a prospective observational study of patients presenting to a tertiary care center with DKA. Patient demographics, laboratory results, and outcomes were recorded. A one-time blood draw was performed and analyzed for plasma thiamine levels. RESULTS Thirty-two patients were enrolled. Eight patients (25%) were thiamine deficient, with levels lower than 9 nmol/L. A negative correlation between lactic acid and plasma thiamine levels was found (r = -0.56, P = .002). This relationship remained significant after adjustment for APACHE II scores (P = .009). Thiamine levels were directly related to admission serum bicarbonate (r = 0.44, P = .019), and patients with thiamine deficiency maintained lower bicarbonate levels over the first 24 hours (slopes parallel with a difference of 4.083, P = .002). CONCLUSIONS Patients with DKA had a high prevalence of thiamine deficiency. Thiamine levels were inversely related to lactate levels among patients with DKA. A study of thiamine supplementation in DKA is warranted.

The Association Between Admission Magnesium Concentrations and Lactic Acidosis in Critical Illness

Introduction: Although magnesium plays an important role in aerobic metabolism and magnesium deficiency is a common phenomenon in critical illness, the association between magnesium deficiency and lactic acidosis in the intensive care unit (ICU) has not been defined. Methods: This was a retrospective, cross-sectional study conducted at a 77 ICU bed tertiary medical center. Data pertaining to the first unique admission of any ICU patient between 2001 and 2008 were extracted from the Multiparameter Intelligent Monitoring in Intensive Care database. Hypomagnesemia was defined as serum magnesium <1.6 mg/dL. Mild and severe lactic acidosis were defined as lactate concentrations of >2 and > 4 mmol/L, respectively. Multivariate modeling was used to explore the association between magnesium and lactate concentrations. Results: Of 8922 critically ill patients, 22.6% were hypomagnesemic. Hypomagnesemia was associated with an increased adjusted risk of mild lactic acidosis (odds ratio [OR] 1.71, 95% confidence interval [95%CI] 1.51-1.94, P < .001) and severe lactic acidosis (OR 1.56, 95%CI 1.32-1.84, P < .001) than the reference quartile. The association between hypomagnesemia and mild lactic acidosis was stronger in those at risk of magnesium deficiency, including diabetics (OR 2.02, 95%CI 1.51-2.72, P < .001) and alcoholics (OR 1.92, 95%CI 1.16-3.19, P = .01). As an internal model control, hypokalemia was not associated with an increased risk of lactic acidosis. Conclusions: Magnesium deficiency is a common finding in patients admitted to the ICU and is associated with lactic acidosis. Our findings support the biologic role of magnesium in metabolism and raise the possibility that hypomagnesemia is a correctable risk factor for lactic acidosis in critical illness.

Quick Sequential Organ Failure Assessment and Systemic Inflammatory Response Syndrome Criteria as Predictors of Critical Care Intervention Among Patients With Suspected Infection

Objectives: The Sepsis III clinical criteria for the diagnosis of sepsis rely on scores derived to predict inhospital mortality. In this study, we introduce the novel outcome of “received critical care intervention” and investigate the related predictive performance of both the quick Sequential Organ Failure Assessment and the Systemic Inflammatory Response Syndrome criteria. Design: This was a single-center, retrospective analysis of electronic health records. Setting: Tertiary care hospital in the United States. Patients: Patients with suspected infection who presented to the emergency department and were admitted to the hospital between January 2010 and December 2014. Interventions: Systemic Inflammatory Response Syndrome and quick Sequential Organ Failure Assessment scores were calculated, and their relationships to the receipt of critical care intervention and inhospital mortality were determined. Measurement and Main Results: A total of 24,164 patients were included of whom 6,693 (27.7%) were admitted to an ICU within 48 hours; 4,453 (66.5%) patients admitted to the ICU received a critical care intervention. Among those with quick Sequential Organ Failure Assessment less than 2, 13.4% received a critical care intervention and 3.5% died compared with 48.2% and 13.4%, respectively, for quick Sequential Organ Failure Assessment greater than or equal to 2. The area under the receiver operating characteristic was similar whether quick Sequential Organ Failure Assessment was used to predict receipt of critical care intervention or inhospital mortality (0.74 [95% CI, 0.73–0.74] vs 0.71 [0.69–0.72]). The area under the receiver operating characteristic of Systemic Inflammatory Response Syndrome for critical care intervention (0.69) and mortality (0.66) was lower than that for quick Sequential Organ Failure Assessment (p < 0.001 for both outcomes). The sensitivity of quick Sequential Organ Failure Assessment for predicting critical care intervention was 38%. Conclusions: Emergency department patients with suspected infection and low quick Sequential Organ Failure Assessment scores frequently receive critical care interventions. The misclassification of these patients as “low risk,” in combination with the low sensitivity of quick Sequential Organ Failure Assessment greater than or equal to 2, may diminish the clinical utility of the quick Sequential Organ Failure Assessment score for patients with suspected infection in the emergency department.

Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a Randomized, Double-Blind, Placebo-controlled Trial

Rationale: Acute kidney injury (AKI) is common in patients with sepsis and has been associated with high mortality rates. The provision of thiamine to patients with sepsis may reduce the incidence and severity of sepsis‐related AKI and thereby prevent renal failure requiring renal replacement therapy (RRT). Objectives: To test the hypothesis that thiamine supplementation mitigates kidney injury in septic shock. Methods: This was a secondary analysis of a single‐center, randomized, double‐blind trial comparing thiamine to placebo in patients with septic shock. Renal function, need for RRT, timing of hemodialysis catheter placement, and timing of RRT initiation were abstracted. The baseline creatinine and worst creatinine values between 3 and 24 hours, 24 and 48 hours, and 48 and 72 hours were likewise abstracted. Results: There were 70 patients eligible for analysis after excluding 10 patients in whom hemodialysis was initiated before study drug administration. Baseline serum creatinine in the thiamine group was 1.2 mg/dl (interquartile range, 0.8‐2.5) as compared with 1.8 mg/dl (interquartile range, 1.3‐2.7) in the placebo group (P = 0.3). After initiation of the study drug, more patients in the placebo group than in the thiamine group were started on RRT (eight [21%] vs. one [3%]; P = 0.04). In the repeated measures analysis adjusting for the baseline creatinine level, the worst creatinine levels were higher in the placebo group than in the thiamine group (P = 0.05). Conclusions: In this post hoc analysis of a randomized controlled trial, patients with septic shock randomized to receive thiamine had lower serum creatinine levels and a lower rate of progression to RRT than patients randomized to placebo. These findings should be considered hypothesis generating and can be used as a foundation for further, prospective investigation in this area.

Reasons for death in patients with sepsis and septic shock

Purpose: Understanding the underlying cause of mortality in sepsis has broad implications for both clinical care and interventional trial design. However, reasons for death in sepsis remain poorly understood. We sought to characterize reasons for in‐hospital mortality in a population of patients with sepsis or septic shock. Materials and methods: We performed a retrospective review of patients admitted to the intensive care unit with sepsis or septic shock who died during their index admission. Reasons for death were classified into 6 categories determined a priori by group consensus. Interrater reliability was calculated and Fleiss &kgr; reported. The associations between selected patient characteristics (eg, serum lactate) and reason for death were also assessed. Results: One hundred fifteen patients were included. Refractory shock (40%) and comorbid withdrawal of care (44%) were the most common reasons for death. Overall interrater agreement was substantial (&kgr; = 0.61, P < .01). Lactate was higher in patients who died because of refractory shock as compared with those who died for other reasons (4.7 vs 2.8 mmol/L, P < .01). Conclusion: In this retrospective cohort, refractory shock and comorbid withdrawal of care were the most common reasons for death. Following prospective validation, the classification methodology presented here may be useful in the design/interpretation of trials in sepsis. HighlightsReasons for death in sepsis have been incompletely characterized.We present a method for classifying reasons for death among patients with sepsis and septic shock.The most common reasons for death in sepsis were refractory shock and comorbid withdrawal of care.Initial serum lactate may be a useful predictor of death from refractory shock in sepsis.

Disease heterogeneity and risk stratification in sepsis-related occult hypoperfusion: A retrospective cohort study

PURPOSE Occult hypoperfusion is associated with increased mortality in patients with sepsis. We sought to determine the practice patterns and outcomes of patients with sepsis-related occult hypoperfusion and introduce a potential method for risk stratification. MATERIALS AND METHODS Single-center retrospective study of normotensive patients presenting to an urban tertiary care emergency department with lactate greater than or equal to 4 mmol/L and suspected infection. χ(2) Testing, Spearman, and Wilcoxon coefficients were used to compare binary, parametric, and nonparametric data, respectively. Patients were divided into 4 groups based on lactate clearance (<4 mmol/L) and the presence of respiratory distress while in the emergency department; outcomes were compared using χ(2) test and analysis of variance. RESULTS Median initial lactate was 4.7 mmol/L (interquartile range, 4.2-6.4), and 34 (45.2%) of 73 exhibited respiratory distress. Hyperlactatemia resolved in 67.1% (49/73) of patients. Mortality was 23.3% (17/73), and 19.1% (14/73) required vasopressors. In patients with lactate clearance and without respiratory distress (n = 27), mortality was 0%, and none required vasopressors. In patients with persistent hyperlactatemia and/or respiratory distress (n = 46), 30.4% required vasopressors, and the mortality was 37.0% (P < .01 and P < .01, respectively). CONCLUSIONS Patients defined as having occult hypoperfusion comprise a heterogeneous group with a varied degree of illness severity. Identifying those with low risk of clinical deterioration may be important for titration of care.

Thiamine in septic shock patients with alcohol use disorders: An observational pilot study

Purpose: Alcohol‐use disorders (AUDs) have been associated with increased sepsis‐related mortality. As patients with AUDs are often thiamine deficient, we investigated practice patterns relating to thiamine administration in patients with AUDs presenting with septic shock and explored the association between receipt of thiamine and mortality. Materials: We performed a retrospective cohort study of patients presenting with septic shock between 2008 and 2014 at a single tertiary care center. We identified patients with an AUD diagnosis, orders for microbial cultures and use of antibiotics, vasopressor dependency, and lactate levels ≥ 4 mmol/L. We excluded those who received thiamine later than 48 h of sepsis onset. Results: We included 53 patients. Thirty‐four (64%) patients received thiamine. Five patients (15%) received their first thiamine dose in the emergency department. The median time to thiamine administration was 9 (quartiles: 4, 18) hours. The first thiamine dose was most often given parenterally (68%) and for 100 mg (88%). In those receiving thiamine, 15/34 (44%) died, compared to 15/19 (79%) of those not receiving thiamine, p = 0.02. Conclusions: A considerable proportion of patients with AUDs admitted for septic shock do not receive thiamine. Thiamine administration in this patient population was associated with decreased mortality. Highlights:Many patients with alcohol‐use‐disorders and septic shock do not receive thiamine.Thiamine was most often given in the ICU, rather than the emergency department.Failure to receive thiamine may be associated with increased mortality.