Escalation to Barbiturate-Induced Coma for Refractory Seizures after Liver Transplantation

Seizures after liver transplantation were previously thought to be a reliable harbinger of catastrophe, but more recent studies have found seizure activity to be relatively common, and most cases do not result in a poor outcome. Generalized seizures are the most common, and they typically occur de novo within the first two weeks after transplantation. The underlying cause for seizure activity in these patients may be complex, with potential etiologies including metabolic, infectious, cerebrovascular, and medication-induced causes. Identification of the underlying cause and the use of antiepileptic drugs (AEDs) is crucial for minimizing risk to the patient’s neurologic and overall health. In this report, we present the case of a patient with refractory seizures unresponsive to conventional treatment, requiring prolonged barbiturate burst suppression with ventilator support. Seizure activity eventually ceased, and the patient made a full recovery.

SARS CoV-2 Genomic Characteristics and Clinical Impact of SARS-CoV-2 Viral Diversity in Critically Ill COVID-19 Patients: A Prospective Multicenter Cohort Study

Background: SARS-CoV-2 variant of concern (VOC) α spread worldwide, including in France, at the beginning of 2021. This variant was suggested to be associated with a higher risk of mortality than other variants. Little information is available in the subset of patients with severe disease admitted in the intensive care unit (ICU). We aimed to characterize the genetic diversity of SARS-CoV-2 variants isolated from patients with severe COVID-19 in order to unravel the relationships between specific viral mutations/mutational patterns and clinical outcomes.Methods: Prospective multicentre observational cohort study. Patients aged ≥18 years admitted in 11 ICUs from Great Paris area hospitals between October 1, 2020, and May 30, 2021 (before the introduction of VOC δ (B.617.2) in France) for acute respiratory failure (SpO2≤90% and need for supplemental oxygen or ventilator support) were included. SARS-CoV-2 infection, determined by RT-PCR testing. The primary clinical endpoint was day-28 mortality. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing (Illumina COVIDSeq).Results: 413 patients were included, 183 (44.3%) had been infected with pre-existing variants, 197 (47.7%) with variant α (B.1.1.7), and 33 (8.0%) with other variants. Patients infected with pre-existing variants were significantly older (64.9±11.9 vs 60.5±11.8 years; p=0.0005); they had significantly more frequent COPD (11.5% (n=21/183) vs 4.1% (n=8/197); p=0.009), and higher SOFA score (4 [3-8] vs 3 [2-4]; 0.0002). Day-28 mortality was not different between patients infected with pre-existing, α (B.1.1.7) or other variants (31.1% (n=57/183) vs 26.2% (n=51/197) vs 30.3% (n=10/33), respectively; p=0.550). There was no association between day-28 mortality with a specific variant or the presence of specific mutations in SARS CoV-2 genome, including 17 mutations selected in the spike protein and all 1017 non-synonymous mutations detected throughout the entire viral genome.Conclusions: At ICU admission, patients infected with pre-existing variants had a different clinical presentation from those infected with variant α (B.1.1.7) and other variants later in the course of the pandemic, but mortality did not differ between these groups. There was no association between a specific variant or SARS CoV-2 genome mutational pattern and day-28 mortality.

Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study

Background Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. Methods In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. Results Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0–121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09–0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10–0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08–7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. Conclusions In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

ERS Statement on pediatric long term noninvasive respiratory support

Long term noninvasive respiratory support, comprising continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV), in children is expanding worldwide, with increasing complexities of children being considered for this type of ventilator support and expanding indications such as palliative care. There have been improvements in equipment and interfaces. Despite growing experience, there are still gaps in a significant number of areas: there is a lack of validated criteria for CPAP/NIV initiation, optimal follow-up and monitoring; weaning and long term benefits have not been evaluated. Therapeutic education of the caregivers and the patient is of paramount importance, as well as continuous support and assistance, in order to achieve optimal adherence. The preservation or improvement of the quality of life of the patient and caregivers should be a concern for all children treated with long term CPAP/NIV. As NIV is a highly specialised treatment, patients are usually managed by an experienced pediatric multidisciplinary team. This Statement written by experts in the field of pediatric long term CPAP/NIV aims to emphasize on the most recent scientific input and should open up to new perspectives and research areas.

Hemophagocytosis, hyper-inflammatory responses, and multiple organ damages in COVID-19-associated hyperferritinemia

Hyperferritinemia comes to light frequently in general practice. However, the characteristics of COVID-19-associated hyperferritinemia and the relationship with the prognosis were not well described. The retrospective study included 268 documented COVID-19 patients. They were divided into the hyperferritinemia group (≥ 500 µg/L) and the non-hyperferritinemia group (< 500 µg/L). The prevalence of fever and thrombocytopenia and the proportion of patients with mechanical ventilator support and in-hospital death were much higher in the hyperferritinemia group (P < 0.001). The hyperferritinemia patients showed higher median IL-6, D-dimer, and hsCRP (P < 0.001) and lowered FIB level (P = 0.036). The hyperferritinemia group had a higher proportion of patients with AKI, ARDS, and CSAC (P < 0.001). According to the multivariate analysis, age, chronic pulmonary disease, and hyperferritinemia were found to be significant independent predictors for in-hospital mortality [HR 1.041 (95% CI 1.015–1.068), P = 0.002; HR 0.427 (95% CI 0.206–0.882), P = 0.022; HR 6.176 (95% CI 2.447–15.587), P < 0.001, respectively]. The AUROC curve was 0.88, with a cut-off value of ≥ 971 µg/L. COVID-19 patients with hyperferritinemia had a high proportion of organ dysfunction, were more likely to show hyper-inflammation, progressed to hemophagocytic lymphohistiocytosis, and indicated a higher proportion of death.

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs

A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019, with disease pathology ranging from asymptomatic to severe respiratory distress with multi-organ failure requiring mechanical ventilator support. It has been found that SARS-CoV-2 infection drives intracellular complement activation in lung cells that tracks with disease severity. However, the cellular and molecular mechanisms responsible remain unclear. To shed light on the potential mechanisms, we examined publicly available RNA-Sequencing data using CIBERSORTx and conducted a Ingenuity Pathway Analysis to address this knowledge gap. In complement to these findings, we used bioinformatics tools to analyze publicly available RNA sequencing data and found that upregulation of complement may be leading to a downregulation of T-cell activity in lungs of severe COVID-19 patients. Thus, targeting treatments aimed at the modulation of classical complement and T-cell activity may help alleviate the proinflammatory effects of COVID-19, reduce lung pathology, and increase the survival of COVID-19 patients.

Study of effect of serum magnesium concentration on clinical outcome of critically sick patients in medical intensive care unit

Background: Deficiency of magnesium is common and often ignored. It is associated with cardiac irregularity, cardiac insufficiency, seizure and electrolyte imbalance. As this element has multiple functions in our body it is important in the pathophysiology of several critical illnesses in intensive care unit (ICU). Hence the present study was undertaken to determine the usefulness of admission serum magnesium levels with regards to patient outcome considering mortality, need and duration of ventilator support, and acute physiologic assessment and chronic health evaluation 2 (APACHE 2) score.Methods: Demographic data such as age and sex were recorded. Patients were assessed for presenting complaints, history of other diseases and habits through an interview with the patients or care giver. These findings were recorded on a predesigned proforma patients was followed up for the outcomes such as mortality, need of ventilator support, duration of ICU stay and APACHE 2 score.Results: Regarding comparison between outcome of patients between two groups, 44% patients with magnesium level <1.7 mg/dl have improved and 72% patient didn’t improve. 44% patients with magnesium level >1.7 mg/dl have improved and 28% patient didn’t improve.Conclusions: From present observational study we can conclude that hypomagnesaemia is more common in patients more than 50 years of age and with male predominance. Pneumonia with septicaemia and cerebrovascular accident (CVA) was commonly associated with hypomagnesaemia. In present study we have observed that hypomagnesaemia is associated with high APACHE 2 score, poor outcome and more requirement of ventilatory support.

Epidemiological Study of Patients Admitted in Intensive Care Unit with Severe Acute Respiratory Illness with a Possible Diagnosis of COVID19 (EPIC19), a Multicentre Study.

BackgroundGlobal pandemic of COVID 19 has affected many countries. The initial epicenter was in China with gradual spread to various countries including India.For a developing country like India with limited resources and high population, it is worthwhile to know how these patients requiring intensive care admission were managed and the outcome of these patients. To address these issues, a prospective observational study was planned.Methods A multicenter study was conducted from June 2020 to December 2020 including 4 centers across India. Patients > 18 years of age admitted in the intensive care unit (ICU), with the diagnosis of COVID 19 pneumonia confirmed by reverse transcriptase –polymerase chain reaction (RT-PCR) or rapid antigen test (RAT) as applicable were included. Factors associated with ICU mortality were examined using multivariable logistic regression analysis and Cox proportional hazard model. ResultsOf 667 patients were included in the study. ICU mortality was 60 %. In multivariable analysis, history of cerebral vascular accident (CVA), day 1 acute physiology and chronic health evaluation (APACHE II) score, need for invasive ventilator support, minimum PO2, fluid balance and complications such as pneumothorax and arrhythmia during ICU admission were associated with mortality. Among these parameters, day 1 need for invasive ventilator support (odds ratio OR: 3.01(1.81, 5.00) and development of arrhythmia (OR 3.85 [1.56, 8.06]) had higher odds of mortality. Cox proportional hazard analysis showed, history of ischemic heart disease (IHD) (Hazard Ratio, HR 1.64, 95% CI:1.13, 2.38), day1 APACHE II (HR 1.03, 95% CI:1.00, 1.07), arterial blood gas (ABG) pH (HR 0.14, 95% CI:0.03, 0.56) and use of therapeutic anticoagulation (HR 0.42,95% CI:0.29, 0.61) as a predictor of 7 days ICU mortality. Daywise trend of ventilator parameters showed dynamic compliance was higher on day3 and 4 in survivors.ConclusionIn this cohort of ICU patients, ICU mortality was 60%. The reason for higher mortality could be the severity of illness as suggested by the day 1 PF ratio (109.31 [77.79-187.26]).Trial Registration-(IEC131/2020, CTRI/2020/06/025858).

Endotracheal tube mal-insertion via Zenker’s diverticulum to trachea

An 86-year-old woman with chronic respiratory failure was under endotracheal tube insertion and mechanical ventilator support for 2 months due to previous intra-cranial hemorrhage. She presented with difficult nasogastric (NG) tube insertion after changing endotracheal tube and was transferred to our emergency room. The initial vital signs were blood pressure: 136/85 mmHg, heart rate: 100 bpm, respiratory rate: 20 cpm, body temperature: 36.5o c, and SpO2 : 100% under ventilator support, and stupor consciousness was remained as usual. The physical examination showed bilateral clear breath sound. We tried the NG tube insertion again but in vain; therefore, the esophagogastroduodenoscopy (EGD) was performed for NG tube insertion and revealed malposition of the endotracheal tube over upper esophagus and Zenker’s diverticulum with ulcerations (Panel A). Endotracheal tube was inserted to the esophagus, via the Zenker’s diverticulum, and then to the trachea. The neck CT confirmed the diagnosis (Panel B). After endotracheal tube replacement via bronchoscopy and supportive care with antibiotics treatment, the patient was discharged after admission for two weeks.

Risk Factors and Outcomes of ICU Admission Following Allogeneic Hematopoietic Stem Cell Transplantation

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct) can develop complications such as life-threatening infections, multi-system organ failure, ICU admission and ventilator support in the immediate post-transplant period. Whereas outcomes of these complications, particularly ICU admission and ventilator support, are known to be poor, little is known about the risk factors leading to them. Methods: We conducted a retrospective study to analyze the impact of pre-transplant risk factors on acute inpatient complications, focusing on ICU admission, ventilator support and multi-system organ failure, following allo-hsct at the University of Alabama at Birmingham (UAB) between 2008 and 2016. Mortality rates and survival outcomes of patients admitted to the ICU were also analyzed. Pre-transplant individual comorbidities were defined as per Sorror's HCT-CI. Results: There were 304 patients included with a median age of 52y (18-72y). There were 51% male and 82% Non-Hispanic white patients. The most common indication for transplant was AML (45%). Donor type was matched-unrelated, haploidentical and matched-related in 53%, 35% and 12% of cases, respectively. Majority of the patients received myeloablative conditioning (74%). The prevalence of health behaviors and comorbidities at the time of transplant is shown in Table 1. There were 39% patients with HCT-CI score of ≥3, 23% with moderate pulmonary compromise, 22% with a psychiatric disorder, 13% with severe pulmonary compromise, 13% with diabetes mellitus (DM), 10% with cardiac abnormalities and 6% with infection at the time of transplant. During the initial hospitalization, 33 (11%) patients required ICU admission, 29 (10%) required ventilator support, 33 (11%) developed multi-system organ failure, 79 (26%) developed bacterial infections and 15 (5%) developed fungal infections. The median time to neutrophil engraftment was 13 days (7-48 days). In multivariable analysis (Table 2), risk factors for ICU admission included pre-transplant infection (HR 6.50, 95% CI 1.82-23.26, p=0.004), pre-transplant DM (HR 4.14, 95% CI 1.56-10.97, p=0.004), time to neutrophil engraftment (HR 1.13, 95% CI 1.05-1.21, p=0.0007), donor type (ref: matched related donor; haplo: HR 0.24 95% CI 0.07-0.82, p=0.02) and HSCT era (ref: 2008-2010; 2010-2013: HR 0.18 95% CI 0.04-0.88, p=0.03; 2014-2016: HR 0.12 95% CI 0.03-0.4, p=0.0006). Risk factors for ventilator support included pre-transplant infection (HR 10.09, 95% CI 2.44-41.64, p=0.001), pre-transplant DM (HR 3.61, 95% CI 1.31-9.91, p=0.01), time to neutrophil engraftment (HR 1.17, 95% CI 1.11-1.23, p&lt;0.0001) and HSCT era (ref: 2008-2010; 2010-2013: HR 0.21 95% CI 0.06-0.81, p=0.02; 2014-2016: HR 0.07 95% CI 0.02-0.31, p=0.0005). Risk factors for multi-system organ failure included pre-transplant DM (HR 4.38, 95% CI 1.64-11.74, p=0.003), time to neutrophil engraftment (HR 1.13, 95% CI 1.08-1.19, p&lt;0.0001) and HSCT era (ref: 2008-2010; 2010-2013: HR 0.21 95% CI 0.05-0.80, p=0.003; 2014-2016: HR 0.16 95% CI 0.05-0.48, p=0.001).Risk factor for bacterial infection included HSCT era (ref: 2008-2010; 2010-2013: HR 0.30 95% CI 0.14-0.65, p=0.002; 2014-2016: HR 0.24 95% CI 0.12-0.49, p&lt;0.0001) and for fungal infection included pre-transplant pulmonary compromise (ref: no compromise; severe pulmonary compromise HR 5.16, 95% CI 1.05-25.4, p=0.04). For patients admitted to the ICU, the 60-day and 6-month mortality was 58% and 67%, respectively. No deaths were attributed to relapse disease. The median overall survival for patients admitted to the ICU was 1.4 months (Figure 1). Conclusion: Patients with DM and infection at the time of HSCT and delayed neutrophil engraftment during transplant are at an increased risk for ICU admission, ventilator support and multi-system organ failure following allo-hsct. Patients admitted to the ICU are also at a high risk for early mortality leading to poor survival. Optimizing glycemic control and delaying transplant until resolution of infection, if the underlying disease would allow, may help improve both morbidity and mortality in transplant recipients. Figure 1 Figure 1. Disclosures Di Stasi: Syndax Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Alabama at Birmingham: Current Employment.