Observational study of the effect of ketamine infusions on sedation depth, inflammation, and clinical outcomes in mechanically ventilated patients with SARS-CoV-2.

Severely ill patients with COVID-19 are challenging to sedate and often require high-dose sedation and analgesic regimens. Ketamine can be an effective adjunct to facilitate sedation of critically ill patients but its effects on sedation level and inflammation in COVID-19 patients have not been studied. This retrospective, observational cohort study evaluated the effect of ketamine infusions on inflammatory biomarkers and clinical outcomes in mechanically ventilated patients with SARS-CoV-2 infection. A total of 186 patients were identified (47 received ketamine, 139 did not). Patients who received ketamine were significantly younger than those who did not (mean (standard deviation) 59.2 (14.2) years versus 66.3 (14.4) years; P = 0.004), but there was no statistically significant difference in body mass index (P = 0.25) or sex distribution (P = 0.91) between groups. Mechanically ventilated patients who received ketamine infusions had a statistically significant reduction in Richmond Agitation-Sedation Scale score (-3.0 versus -2.0, P < 0.001). Regarding inflammatory biomarkers, ketamine was associated with a reduction in ferritin (P = 0.02) and lactate (P = 0.01), but no such association was observed for C-reactive protein (P = 0.27), lactate dehydrogenase (P = 0.64) or interleukin-6 (P = 0.87). No significant association was observed between ketamine administration and mortality (odds ratio 0.971; 95% confidence interval 0.501 to 1.882; P = 0.93). Ketamine infusion was associated with improved sedation depth in mechanically ventilated COVID-19 patients and provided a modest anti-inflammatory benefit but did not confer benefit with respect to mortality or intensive care unit length of stay.

Systemic Inflammatory Response Syndrome After Extracorporeal Membrane Oxygenation Decannulation in COVID-19 Patients.

INTRODUCTION: Systemic inflammatory response syndrome (SIRS) is frequently observed following decannulation from extracorporeal membrane oxygenation (ECMO). Differentiating cytokine release due to infection from endothelial injury from cannula removal and/or discontinuation from the ECMO circuit has been shown to impact treatment and outcomes. This response, however, may be complicated in COVID-19 patients due to prevalent glucocorticoid and immune modulator use. It remains unclear whether COVID-19 infection and/or associated immune modulator use impact the incidence of SIRS following decannulation. OBJECTIVES: The aim of this study is to investigate the incidence of the SIRS phenomenon and associated outcomes in patients with COVID-19 after ECMO decannulation. METHODS: An IRB-approved retrospective chart review of all patients who survived ECMO between June 31, 2010 and July 7, 2021 was done to identify patients who experienced SIRS within 48 hours of decannulation from ECMO support. Patients with COVID-19 were confirmed by a positive reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV2. SIRS was confirmed when two out of three of the following criteria were met: fever, leukocytosis, and/or initiation/escalation of vasopressors. Patients who developed post-ECMO SIRS were then distinguished based on the presence of infection. Infection was defined by the presence of either a new or positive culture following decannulation. We compared the incidence of SIRS and infection within 48 hours of decannulation in patients with and without COVID-19. RESULTS: We identified 227 eligible patients who survived ECMO. Twenty-eight patients (12%) had COVID-19. Of these patients, ten patients with COVID-19 (36%) experienced post-ECMO SIRS, including those with true SIRS (n=3) and associated infections (n=7). Five of the ten patients with COVID-19 who experienced post-ECMO SIRS were exposed to immune modulators within two weeks of decannulation. Ninety-five (42%) patients without COVID-19 developed post-ECMO SIRS. Thirty-day survival in COVID patients who experienced post-ECMO SIRS compared to COVID patients who did not experience post-ECMO SIRS was 73% vs. 94%. (p=0.11). CONCLUSION: Post-ECMO SIRS is common. The incidence of SIRS following decannulation was similar when historically compared to non-COVID patients who survived ECMO in a previously reported cohort from our institution. Immune-modulation exposure within two weeks of decannulation did not affect the incidence of SIRS in patients with COVID-19.

Perfusion-Dependent Focal Neurologic Deficits in a Critically Ill Heart Transplant Recipient: A Case of Tacrolimus-Associated Reversible Cerebral Vasospasm Syndrome?

TACROLIMUS, a mainstay of immunosuppression after orthotopic heart transplantation (OHT), is associated with a broad range of side effects. Vasoconstriction caused by tacrolimus has been proposed as a mechanism underlying common side effects such as hypertension and renal injury. Neurologic side effects attributed to tacrolimus include headaches, posterior reversible encephalopathy syndrome (PRES), or reversible cerebral vasospasm syndrome (RCVS). Six case reports have been published describing RCVS in the setting of tacrolimus administration after OHT. The authors report a case of perfusion-dependent focal neurologic deficits attributed to tacrolimus-induced RCVS in an OHT recipient.

Health and Well-Being of Intensive Care Unit Physicians: How to Ensure the Longevity of a Critical Specialty.

A second epidemic of burnout, fatigue, anxiety, and moral distress has emerged concurrently with the coronavirus disease 2019 (COVID-19) pandemic, and critical care physicians are especially affected. This article reviews the history of burnout in health care workers, presents the signs and symptoms, discusses the specific impact of the COVID-19 pandemic on intensive care unit caregivers, and attempts to identify potential strategies to combat the Great Resignation disproportionately affecting health care workers. The article also focuses on how the specialty can amplify the voices and highlight the leadership potential of underrepresented minorities, physicians with disabilities, and the aging physician population.

Outcomes of extracorporeal membrane oxygenation in immunosuppressed vs. Immunocompetent patients.

INTRODUCTION: Immunosuppressed hosts represent a growing group of patients who suffer acute respiratory failure and may be considered for therapies such as extracorporeal membrane oxygenation (ECMO). OBJECTIVES: We conducted this retrospective study to determine whether acutely or chronically immunosuppressed patients placed on ECMO for cardiac and/or respiratory failure in our institution have different outcomes than immunocompetent patients placed on ECMO in our institution. METHODS: Adult patients placed on ECMO between June 31, 2010 and July 7, 2021 were identified within an IRB-approved database. Data was retrospectively extracted from the database and patients' medical records. Patients who survived ECMO decannulation were sub-grouped by the presence of acute or chronic immunosuppression, defined by the use of high-dose steroids or immunosuppressive agents for greater than four weeks prior to ECMO initiation. We analyzed and compared baseline characteristics and clinical outcomes using chi-squared tests for categorical variables and a one-way analysis of variance (ANOVA) for continuous variables. RESULTS: 385 patients were included in this study, with 39 identified as chronically immunosuppressed, 49 as acutely immunosuppressed, and 297 as immunocompetent. There was no statistical difference in ECMO survival (respectively 54%, 59%, 65% p = 0.359) or 30-day survival (33%, 51%, 48% p = 0.149) for chronically immunosuppressed, acutely immunosuppressed, and immunocompetent, respectively. There were significant differences in rates of pre-ECMO COVID infection (p<0.001), coronary artery disease (p<0.001), smoking (p = 0.003), and acute kidney injury (p = 0.032). Acutely immunosuppressed patients had the highest rates of new infections during ECMO (p = 0.006). CONCLUSION: When compared to immunocompetent patients, both acutely and chronically immunosuppressed patients had no significant difference in ECMO survival or 30-day survival. Acutely immunosuppressed patients had less comorbidities than chronically immunosuppressed patients, but they were more commonly infected during ECMO. ECMO may still be a valuable tool in appropriately selected patients with refractory respiratory or cardiac failure.

Non-competitive Inhibition of Nicotinic Acetylcholine Receptors by Ladybird Beetle Alkaloids.

Ladybird beetles (Family Coccinellidae) secrete an alkaloid rich venom from their leg joints that protects them from predators. Coccinellines, the major venom constituents, are alkaloids composed of three fused piperidine rings that share a common nitrogen atom. Although many coccinellines have been isolated and chemically characterized, their pharmacological properties are essentially unknown. Using radioligand binding and functional assays we investigated the actions of several coccinellines on skeletal muscle and α7 nicotinic acetylcholine receptors (nAChRs). The alkaloids were shown to displace the specific binding of tritiated piperidyl-N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]-TCP), which has been shown to bind deep within the ion channel of the electric fish (Torpedo) muscle nAChR. The stereoisomers precoccinelline and hippodamine (whose nitrogens are predicted to be ionized at physiological pH) and their respective analogs N-methyl-precoccinelline and N-methyl-hippodamine (whose quaternary nitrogens are permanently charged) displayed similar IC50s for inhibition of [(3)H]-TCP binding. However, the corresponding precoccinelline and hippodamine N-oxides, coccinelline and convergine (which have an electronegative oxygen bonded to an electropositive nitrogen) displayed significantly higher binding IC50s. Finally, exochomine, a dimeric coccinelline containing the hippodamine structure, displayed the highest IC50 (lowest affinity) for displacing specific [(3)H]-TCP binding. The presence of a desensitizing concentration (10(-3) M) of carbachol (CCh) had little or no effect on the affinity of the Torpedo nAChR for the three coccinellines tested. High concentrations of the coccinellid alkaloids did not affect binding of [(3)H]-cytisine to Torpedo receptor ACh binding sites. Inhibition of the alpha7 nAChR with pre-equilibrated precoccinelline was insurmountable with respect to ACh concentration. We conclude that the coccinellines bind to one or more allosteric sites rather than to the ACh binding sites, and inhibit nAChR responses to ACh through a non-competitive mechanism. Future chemical and pharmacological investigations of other ladybird beetle alkaloids are likely to reveal other interesting alkaloids affecting ligand-gated receptors.