Faculty Bibliography

INTRODUCTION: Thiamine (TH) is a co-factor for pyruvate dehydrogenase, an enzyme necessary for pyruvate entry into the Krebs cycle, and without this enzyme, pyruvate would be converted to lactate. Elevated lactate, which is often used as a marker of perfusion, is proportionally associated with increased mortality in septic shock. The few publications on TH in septic shock are inconclusive. This study aims to ascertain if there is benefit to adding TH to standard of care (SOC) in the management of septic shock.
METHOD(S): IRB-approved, multicenter, retrospective review from 2016 to 2021. Adult patients admitted to the ICU for septic shock and receiving >= 400 mg a day of IV TH (in divided doses) were included. Patients < 18, pregnant, admitted for SARS-COV-2, or whom received < 400 mg of TH daily were excluded. Two matched cohorts were evaluated, SOC plus TH versus SOC alone. The primary endpoint is time to shock reversal, defined as off vasopressors for at least 12 hrs and alive. Secondary endpoints include time to lactate clearance (< 2 mmol/L), lactate trends at 6, 12, 24, 48 hrs, and end of therapy, hospital and ICU lengths of stay, new end organ dysfunction, and in-hospital mortality.
RESULT(S): Data from 50 patients were analyzed: 25 in the SOC plus TH and 25 in the SOC arm. The TH arm had greater number of vasopressors (2 vs. 1, p=.019), and greater utilization of stress-dose steroids (72% vs. 8%, p<.001), however there was no difference in cumulative vasopressor dose in norepinephrine equivalents at baseline (BL) (30.1 vs. 25.8 mcg/min, p=.248). There was no difference in SOFA score at ICU admission (10 vs. 8.5, p=.106) or lactate level at ICU admission (5.9 vs. 3.9 mmol/L, p=.055). There was a longer time to shock reversal from vasopressor initiation time in the TH arm (93 vs. 37.1 hrs, p=.023). Lactate clearance was slower in the TH arm (44.75 vs. 15.8 hrs, p=.027), and there was increased in-hospital mortality in the TH arm (13 vs. 5, p=.018).
CONCLUSION(S): Compared to SOC alone, TH treated patients had longer times to shock reversal. However, this outcome may have been confounded by differences at BL with regard to number of vasopressors, and stress-dose steroid utilization, which indicate these patients were sicker at BL. Larger, prospective studies are required to confirm these findings

INTRODUCTION: Clostridium difficile infection (CDI) is associated with significant morbidity and mortality. Salvage therapy may include IVIG, fecal microbiota transplant (FMT) or colectomy. There is limited data regarding the effectiveness of IVIG for CDI (43-65%) or optimal dosing strategies.
METHOD(S): This is a retrospective review of critically ill patients who received IVIG (Gamunex-C) for severe or fulminant CDI at NYU Langone Health. The primary outcome was response to therapy, defined as hospital survival and complete resolution of CDI symptoms by the last day of CDI treatment without need for surgery or FMT.
RESULT(S): Fifteen patients received IVIG for severe (n=6) or fulminant (n=9) CDI, with the BI/NAP1/027 strain isolated in 27% of cases. Patients were primarily female (66%) with a median age of 62 years and had a SOFA score of 7 (IQR 4,8) at the time of IVIG administration. Twelve patients were immunosuppressed (e.g., transplant, malignancy) and nine had chronic kidney disease. There were five patients with recurrent CDI for the index infection, defined as CDI in the previous 8 weeks. Active anti-CDI therapies prior to IVIG administration included enteral vancomycin (93%), IV metronidazole (80%), rectal vancomycin (27%), fidaxomicin (7%), tigecycline (7%) and cholestyramine (7%). Median time to IVIG administration from the date of CDI positivity was 41 hours (21,75). The median total dose of IVIG administered per patient was 1.2 g/kg given over 2 days (1.5,3). Response to treatment was observed in 11 patients (73%); 4 required either colectomy (n=3) or FMT (n=1). Among the 5 patients with recurrent disease who received IVIG, response was observed in 4 cases (80%). Adverse events related to IVIG were not reported, and there were no cases of CDI recurrence within 6 months of CDI therapy completion. One in-hospital mortality was observed, which was unrelated to CDI.
CONCLUSION(S): For severe or fulminant CDI, IVIG pharmacotherapy was associated with a favorable treatment response in 73% of patients, possibly averting the need for care escalation to colectomy or FMT. Various dosing strategies were utilized, limiting assessment of a doseresponse relationship. Further data and a comparison to a cohort of critically ill patients who did not receive IVIG is needed to delineate place in therapy

OBJECTIVE:concentration after KCl administration) and assess the incidence of hyperkalemia. METHODS:This single-center, retrospective study evaluated infants and children who received parenteral KCl supplementation of 0.5 or 1 mEq/kg between January 2017 and December 2019. RESULTS:compared with those who had a concentration drawn after this time frame (0.8 vs 0.6 mEq/L; p < 0.01). CONCLUSIONS:of 0.8 and 0.5 mEq/L, respectively, in non-cardiac pediatric patients, with low observed incidence of hyperkalemia.

The oral factor Xa inhibitors (OFXAi) apixaban and rivaroxaban are increasingly utilized for the treatment of venous thromboembolism (VTE) with recommended initial higher dose 7- and 21-day lead-in regimens, respectively. In patients receiving initial parenteral anticoagulation, it remains unknown if the full recommended higher dose OFXAi lead-in regimens are warranted, or if days can be subtracted. We aimed to describe when clinicians may deviate from recommended lead-in durations and evaluate clinical outcomes in these scenarios. This is a retrospective, observational study of patients 18 years or older who were treated with rivaroxaban or apixaban for acute pulmonary embolism (PE) or symptomatic proximal deep vein thrombosis (DVT) that received parenteral anticoagulation for at least 24 h before transitioning to the OFXAi. Among our cohort of 171 patients with acute VTE who received parenteral anticoagulation for a median of 48 h, 134 (78%) were prescribed a full OFXAi lead-in and 37 (22%) were prescribed a reduced lead-in. Patients in the reduced lead-in group were older with more cardiac comorbidities and antiplatelet use. There were four recurrent thromboembolic events within 3 months, two in the reduced lead-in group and two in the full lead-in group (5% vs. 2%, p = 0.206). Bleeding within 3 months occurred in 9 (5%) patients, with 6 events occurring in the reduced lead-in group and 3 events in the full lead-in group (16% vs. 2%, p = 0.004). Prescribing patterns of OFXAi lead-in therapy duration are variable in patients receiving initial parenteral anticoagulation. Larger cohorts are needed to better define the safety and efficacy of lead-in reduction.

Nucleoside or nucleotide analogues (NAs) have the potential to cause lactic acidosis by inhibiting DNA polymerase-γ of human mitochondria and impairing aerobic metabolism. Patients may be asymptomatic, have mild non-specific symptoms, or present in multisystem organ failure. There is a paucity of data to guide management of life-threatening lactic acidosis due to NA therapy. Here we describe a case of a 60-year old critically ill male with decompensated cirrhosis secondary to hepatitis B virus (HBV) infection who developed severe lactic acidosis (13.8 mmol/L) 2 days after initiation of tenofovir alafenamide (TAF). All other possible etiologies for the elevated lactate were ruled out. Lactic acidosis resolved rapidly with TAF discontinuation and supplementation with cofactors supporting mitochondrial oxidative phosphorylation, including coenzyme Q10, levocarnitine, riboflavin, and thiamine. This case highlights the ability of TAF to cause lactic acidosis early after therapy initiation, especially in susceptible hosts, and reviews the potential role for cofactor supplementation for drug-induced mitochondrial injury.

BACKGROUND/UNASSIGNED:Corticosteroids and tocilizumab have been shown to improve survival in patients who require supplemental oxygen from coronavirus disease 2019 (COVID-19) pneumonia. The optimal dose of immunosuppression for the treatment of COVID-19 acute respiratory distress syndrome (ARDS) is still unknown. OBJECTIVE/UNASSIGNED:The objective of this study was to evaluate the effectiveness and safety of high- versus low-dose corticosteroids with or without tocilizumab for the treatment of COVID-19 ARDS. METHODS/UNASSIGNED:This was a retrospective study of patients admitted to the intensive care unit (ICU) requiring mechanical ventilation who received high- versus low-dose corticosteroids with or without tocilizumab. The primary outcome was survival to discharge. Safety outcomes included infections and incidence of hyperglycemia. RESULTS/UNASSIGNED:= 0.01). The highest rate of a bacterial pneumonia was in patients who received high-dose corticosteroids with tocilizumab. CONCLUSIONS/UNASSIGNED:In critically ill patients with COVID-19 ARDS requiring mechanical ventilation, we found no difference in high- versus low-dose corticosteroids with regard to survival to hospital discharge. However, patients receiving only low-dose corticosteroids without tocilizumab did worse than the other groups. Larger prospective studies are needed to determine the optimal immunosuppression dosing strategy in this patient population.

The use of acute mechanical circulatory support (MCS) has increased over the last decade. For patients with left-ventricular failure, an Impella^® (Abiomed, Danvers, MA) may be used to improve cardiac output. The purpose of this study is to describe Impella^® anticoagulation patterns and evaluate the safety and effectiveness of our protocol. This is a retrospective review of all adult patients who required at least 24 h of Impella^® support and received a heparin-based purge solution. In total, 109 patients were included in the final analysis. The most common indication for Impella^® device insertion was cardiogenic shock (76%) with the remaining patients receiving a device for a high-risk procedures; typically coronary artery bypass grafting or percutaneous coronary intervention. A total of 9 thrombotic events occurred among 8 (7%) patients and 50 bleeding events occurred among 43 (39%) patients, with the most common classification being BARC 3a (60%). A univariate analysis revealed that patients were more likely to bleed if they were less than 65 years old, had an indication of cardiogenic shock for Impella^®, inserted the device peripherally, were on dual antiplatelet therapy, or had an intra-aortic balloon pump prior to Impella^® insertion, the latter of which was confirmed with a multivariate analysis (OR 2.5 [1.072-5.830]; p = 0.034). For those monitored by anti-Xa, the presence of two or more values greater than 0.40 IU/mL was a risk factor for bleeding (p = 0.037). Our study identifies risk factors for bleeding in patients receiving temporary MCS with an Impella^®.

The backbone induction therapy for primary central nervous system lymphoma (PCNSL) is high dose methotrexate (HD-MTX) and rituximab, which can be combined with other chemotherapeutic agents. The optimal dose of HD-MTX remains unclear, as doses between 3 and 8 g/m² have been shown to be effective. In this retrospective study, HD-MTX dosed at 3-5 g/m² demonstrated an overall response of 81.8%, with 11 (50%) complete responses. The median overall survival was not met at 29 months and median progression free survival was 12.5 months.There were two discontinuations due to nephrotoxicity. The most common adverse event was hepatotoxicity (18.5%), with no treatment-related mortality events observed.Overall, HD-MTX dosed at 3-5 g/m² demonstrated similar efficacy and lower toxicity compared to higher doses in PCNSL patients. Reducing the initial HD-MTX dose may help ensure tolerability and completion of induction therapy, especially in patients with co-morbidities or older age who have poorer outcomes.

Cardiac arrest has many implications for morbidity and mortality. Few interventions have been shown to improve return of spontaneous circulation (ROSC) and long-term outcomes after cardiac arrest. Ischemic-reperfusion injury upon achieving ROSC creates an imbalance between oxygen supply and demand. Multiple events occur in the postcardiac arrest period, including excitotoxicity, mitochondrial dysfunction, and oxidative stress and inflammation, all of which contribute to ongoing brain injury and cellular death. Given that complex pathophysiology underlies global brain hypoxic ischemia, neuroprotective strategies targeting multiple stages of the neuropathologic cascade should be considered as a means of mitigating secondary neuronal injury and improving neurologic outcomes and survival in cardiac arrest victims. In this review article, we discuss a number of different pharmacologic agents that may have a potential role in targeting these injurious pathways following cardiac arrest. Pharmacologic therapies most relevant for discussion currently include memantine, perampanel, magnesium, propofol, thiamine, methylene blue, vitamin C, vitamin E, coenzyme Q₁₀ , minocycline, steroids, and aspirin.

INTRODUCTION: Vasodilatory shock may arise after cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) and can require salvage therapy with either hydroxocobalamin (HCB) or methylene blue (MB). Data is limited regarding the optimal agent and dosing strategy for each situation.
METHOD(S): This is a retrospective review of patients who received HCB or MB at NYU Langone Health for refractory vasodilatory shock that occurred within 48 hr after CPB or ECMO cannulation. The primary endpoint was the change in vasopressor requirement at 6, 12, 24, and 48 hr after intervention, characterized as both norepinephrine equivalents (NEE) and vasoactive inotropic score (VIS).
RESULT(S): Thirty patients were identified, of which 15 received HCB and 15 received MB. Patients were primarily male (70%) with a median age of 67 and SOFA score of 10. Indications for salvage therapy included postcardiotomy shock (70%) and ECMO cannulation (30%). Dosing strategies included bolus only (9 HCB; 6 MB) or bolus plus infusion (6 HCB; 9 MB), with infusions continuing for a median of 6 hr (5, 6) for HCB and 11 hr (6, 24) for MB. The median cumulative dose was 5000 mg (5000, 10000) for HCB and 5 mg/kg (1.75, 6.8) for MB. Baseline NEE prior to drug administration was 0.42 mcg/kg/min for HCB vs 0.5 mcg/kg/min for MB (p=0.98), and baseline VIS was 28 for HCB vs 23 for MB (p=0.44). Patients who received HCB had a greater percentage change in NEE compared to MB at 6 hr (-72% [-84, -40] vs 0% [-16, +29], p< 0.01) and 12 hr (-73% [-88, -55] vs -39% [-59, +8]; p< 0.01), as well as VIS at 6 hr (-42% [-56, -30] vs 0% [-10, +32]; p< 0.01) and 12 hr (-50% [-78, -32] vs -15% [-41, +17]; p< 0.01). No differences in NEE or VIS were observed at 24 or 48 hr. The bolus plus infusion dosing strategy led to a faster resolution of shock than bolus alone for HCB (27 hr [20, 37] vs 140 hr [98, 436]; p< 0.01) but not for MB (136 hr [30, 251] vs 233 hr [206, 260]; p=0.55). There were no differences in adverse drug events between groups.
CONCLUSION(S): We observed greater differences in change in NEE and VIS favoring the use of HCB over MB at 6 and 12 hr, but not at 24 or 48 hr. A HCB dosing strategy of bolus followed by infusion demonstrated a faster resolution of shock in comparison to bolus alone. Further research is required to confirm these results