Muscle Protein Synthesis after Protein Administration in Critical Illness.

Rationale: Dietary protein may attenuate the muscle atrophy experienced by patients in the ICU, yet protein handling is poorly understood. Objectives: To quantify protein digestion and amino acid absorption and fasting and postprandial myofibrillar protein synthesis during critical illness. Methods: Fifteen mechanically ventilated adults (12 male; aged 50 ± 17 yr; body mass index, 27 ± 5 kg⋅m-2) and 10 healthy control subjects (6 male; 54 ± 23 yr; body mass index, 27 ± 4 kg⋅m-2) received a primed intravenous L-[ring-2H5]-phenylalanine, L-[3,5-2H2]-tyrosine, and L-[1-13C]-leucine infusion over 9.5 hours and a duodenal bolus of intrinsically labeled (L-[1-13C]-phenylalanine and L-[1-13C]-leucine) intact milk protein (20 g protein) over 60 minutes. Arterial blood and muscle samples were taken at baseline (fasting) and for 6 hours following duodenal protein administration. Data are mean ± SD, analyzed with two-way repeated measures ANOVA and independent samples t test. Measurements and Main Results: Fasting myofibrillar protein synthesis rates did not differ between ICU patients and healthy control subjects (0.023 ± 0.013% h-1 vs. 0.034 ± 0.016% h-1; P = 0.077). After protein administration, plasma amino acid availability did not differ between groups (ICU patients, 54.2 ± 9.1%, vs. healthy control subjects, 61.8 ± 13.1%; P = 0.12), and myofibrillar protein synthesis rates increased in both groups (0.028 ± 0.010% h-1 vs. 0.043 ± 0.018% h-1; main time effect P = 0.046; P-interaction = 0.584) with lower rates in ICU patients than in healthy control subjects (main group effect P = 0.001). Incorporation of protein-derived phenylalanine into myofibrillar protein was ∼60% lower in ICU patients (0.007 ± 0.007 mol percent excess vs. 0.017 ± 0.009 mol percent excess; P = 0.007). Conclusions: The capacity for critically ill patients to use ingested protein for muscle protein synthesis is markedly blunted despite relatively normal protein digestion and amino acid absorption.

Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit.

Importance: The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition. Objective: Externally validate and assess the discriminatory capacities of an increase in SOFA score by 2 or more points, 2 or more SIRS criteria, or a qSOFA score of 2 or more points for outcomes among patients who are critically ill with suspected infection. Design, Setting, and Participants: Retrospective cohort analysis of 184 875 patients with an infection-related primary admission diagnosis in 182 Australian and New Zealand intensive care units (ICUs) from 2000 through 2015. Exposures: SOFA, qSOFA, and SIRS criteria applied to data collected within 24 hours of ICU admission. Main Outcomes and Measures: The primary outcome was in-hospital mortality. In-hospital mortality or ICU length of stay (LOS) of 3 days or more was a composite secondary outcome. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC). Adjusted analyses were performed using a model of baseline risk determined using variables independent of the scoring systems. Results: Among 184 875 patients (mean age, 62.9 years [SD, 17.4]; women, 82 540 [44.6%]; most common diagnosis bacterial pneumonia, 32 634 [17.7%]), a total of 34 578 patients (18.7%) died in the hospital, and 102 976 patients (55.7%) died or experienced an ICU LOS of 3 days or more. SOFA score increased by 2 or more points in 90.1%; 86.7% manifested 2 or more SIRS criteria, and 54.4% had a qSOFA score of 2 or more points. SOFA demonstrated significantly greater discrimination for in-hospital mortality (crude AUROC, 0.753 [99% CI, 0.750-0.757]) than SIRS criteria (crude AUROC, 0.589 [99% CI, 0.585-0.593]) or qSOFA (crude AUROC, 0.607 [99% CI, 0.603-0.611]). Incremental improvements were 0.164 (99% CI, 0.159-0.169) for SOFA vs SIRS criteria and 0.146 (99% CI, 0.142-0.151) for SOFA vs qSOFA (P <.001). SOFA (AUROC, 0.736 [99% CI, 0.733-0.739]) outperformed the other scores for the secondary end point (SIRS criteria: AUROC, 0.609 [99% CI, 0.606-0.612]; qSOFA: AUROC, 0.606 [99% CI, 0.602-0.609]). Incremental improvements were 0.127 (99% CI, 0.123-0.131) for SOFA vs SIRS criteria and 0.131 (99% CI, 0.127-0.134) for SOFA vs qSOFA (P <.001). Findings were consistent for both outcomes in multiple sensitivity analyses. Conclusions and Relevance: Among adults with suspected infection admitted to an ICU, an increase in SOFA score of 2 or more had greater prognostic accuracy for in-hospital mortality than SIRS criteria or the qSOFA score. These findings suggest that SIRS criteria and qSOFA may have limited utility for predicting mortality in an ICU setting.

Disseminated Aspergillosis with Mediastinal Invasion Causing Fatal Stroke in an Immunocompetent Young Man.

Introduction: Aspergillus flavus is a common cause of aspergillosis. Case Presentation: A previously fit and well, immunocompetent 27-year-old male living in Australia developed disseminated A. flavus complex infection with mediastinal and cardiac invasion, superior vena cava obstruction and stroke, with fatal haemorrhagic transformation. Conclusion: Aspergillus Flavus is a rare but important cause of serious disease in the immunocompetent.

Defining the correlates of lymphopenia and independent predictors of poor clinical outcome in adults hospitalized with COVID-19 in Australia.

Lymphopenia is a common feature of acute COVID-19 and is associated with increased disease severity and 30-day mortality. Here we aim to define the demographic and clinical characteristics that correlate with lymphopenia in COVID-19 and determine if lymphopenia is an independent predictor of poor clinical outcome. We analysed the ENTER-COVID (Epidemiology of hospitalized in-patient admissions following planned introduction of Epidemic SARS-CoV-2 to highly vaccinated COVID-19 naïve population) dataset of adults (N = 811) admitted for COVID-19 treatment in South Australia in a retrospective registry study, categorizing them as (a) lymphopenic (lymphocyte count < 1 × 109/L) or (b) non-lymphopenic at hospital admission. Comorbidities and laboratory parameters were compared between groups. Multiple regression analysis was performed using a linear or logistic model. Intensive care unit (ICU) patients and non-survivors exhibited lower median lymphocyte counts than non-ICU patients and survivors respectively. Univariate analysis revealed that low lymphocyte counts associated with hypertension and correlated with haemoglobin, platelet count and negatively correlated with urea, creatinine, bilirubin, and aspartate aminotransferase (AST). Multivariate analysis identified age, male, haemoglobin, platelet count, diabetes, creatinine, bilirubin, alanine transaminase, c-reactive protein (CRP) and lactate dehydrogenase (LDH) as independent predictors of poor clinical outcome in COVID-19, while lymphopenia did not emerge as a significant predictor.

Pfizer BNT 162b2 COVID-19 vaccine-induced fulminant myopericarditis: A case study.

The use of mRNA COVID-19 vaccine can on rare occasions cause life-threatening, fulminant myopericarditis. This case report demonstrates previously reported benefit of early use of venoarterial extracorporeal membrane oxygenation mechanical assistance and supports the use of intravenous highly purified immunoglobulin pharmacotherapy to help achieve a good clinical outcome.

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Repurposing a Neurocritical Care Unit for the Management of Severely Ill Patients With COVID-19: A Retrospective Evaluation.

BACKGROUND: The World Health Organisation declared a coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Following activation of the UK pandemic response, our institution began planning for admission of COVID-19 patients to the neurointensive care unit (neuro-ICU) to support the local critical care network which risked being rapidly overwhelmed by the high number of cases. This report will detail our experience of repurposing a neuro-ICU for the management of severely ill patients with COVID-19 while retaining capacity for urgent neurosurgical and neurology admissions. METHODS: We conducted a retrospective process analysis of the repurposing of a quaternary level neuro-ICU during the early stages of the COVID-19 pandemic in the United Kingdom. We retrieved demographic data, diagnosis, and outcomes from the electronic health care records of all patients admitted to the ICU between March 1, 2020 and April 30, 2020. Processes for increase in surge capacity, reduction in ICU demand, and staff redeployment and rapid training are reported. RESULTS: Over a 10-day period, total ICU capacity was increased by 21.7% (from 23 to 28 beds) while the capacity to provide mechanical ventilation was increased by 77% (from 13 to 23 beds). There were 30 ICU admissions of 29 COVID-19 patients between March 1 and April 30, 2020; median (range) length of ICU stay was 9.9 (1.3 to 32) days, duration of mechanical ventilation 11 (1 to 27) days, and ICU mortality rate 41.4%. There was a 44% reduction in urgent neurosurgical and neurology admissions compared with the same period in 2019. CONCLUSIONS: It is possible to repurpose a dedicated neuro-ICU for the management of critically ill non-neurological patients during a pandemic response, while maintaining access for urgent neuroscience referrals.

Plasma exchange for COVID-19 thrombo-inflammatory disease.

Severe COVID-19 disease is a hyperinflammatory, pro-thrombotic state. We undertook plasma exchange (PEX) to determine its effects on organ function and thrombo-inflammatory markers. Seven critically ill adults with severe COVID-19 respiratory failure (PaO2:FiO2 ratio < 200 mm Hg) requiring invasive or noninvasive ventilatory support and elevated thrombo-inflammatory markers (LDH >800 IU/L and D-dimer >1000 µg/L (or doubling from baseline) received PEX, daily, for a minimum of 5 days. No other immunomodulatory medications were initiated during this period. Seven patients matched for age and baseline biochemistry were a comparator group. Coagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen: ADAMTS13 ratio, Factor VIII and D-dimers were all elevated. Following 5 days of PEX, plasma levels of all the above, and ferritin levels, were significantly reduced (P < .05) while lymphocyte counts normalized (P < .05). The PaO2:FiO2 ratio increased from a median interquartile range (IQR) of 11.6 (10.8-19.7) kPa to 18.1 (16.0-25.9) kPa (P < .05). Similar improvements were not observed in controls. Acute kidney injury (AKI) occurred among five patients in the control arm but not in patients receiving PEX. PEX improved oxygenation, decreased the incidence of AKI, normalized lymphocyte counts and reduced circulating thrombo-inflammatory markers including D-Dimer and VWF Ag:ADAMTS13 ratio.

Dysnatremia and 6-Month Functional Outcomes in Critically Ill Patients With Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study.

OBJECTIVES: To investigate the association between plasma sodium concentrations and 6-month neurologic outcome in critically ill patients with aneurysmal subarachnoid hemorrhage. DESIGN: Prospective cohort study. SETTING: Eleven ICUs in Australia and New Zealand. PARTICIPANTS: Three-hundred fifty-six aneurysmal subarachnoid hemorrhage patients admitted to ICU between March 2016 and June 2018. The exposure variable was daily measured plasma sodium. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six-month neurologic outcome as measured by the modified Rankin Scale. A poor outcome was defined as a modified Rankin Scale greater than or equal to 4. The mean age was 57 years (± 12.6 yr), 68% were female, and 32% (n = 113) had a poor outcome. In multivariable analysis, including age, illness severity, and process of care measures as covariates, higher mean sodium concentrations (odds ratio, 1.17; 95% CI, 1.05-1.29), and greater overall variability-as measured by the sd (odds ratio, 1.53; 95% CI, 1.17-1.99)-were associated with a greater likelihood of a poor outcome. Multivariable generalized additive modeling demonstrated, specifically, that a high initial sodium concentration, followed by a gradual decline from day 3 onwards, was also associated with a poor outcome. Finally, greater variability in sodium concentrations was associated with a longer ICU and hospital length of stay: mean ICU length of stay ratio (1.13; 95% CI, 1.07-1.20) and mean hospital length of stay ratio (1.08; 95% CI, 1.01-1.15). CONCLUSIONS: In critically ill aneurysmal subarachnoid hemorrhage patients, higher mean sodium concentrations and greater variability were associated with worse neurologic outcomes at 6 months, despite adjustment for known confounders. Interventional studies would be required to demonstrate a causal relationship.

Outcomes following grade V subarachnoid haemorrhage: A single-centre retrospective study.

SummaryGrade V subarachnoid haemorrhage is associated with high mortality and morbidity, yet there are few contemporary reports on the treatment provided and outcomes of these patients. In this single-centre retrospective cohort study, we primarily sought to determine the 12-month mortality of patients admitted to the Royal Adelaide Hospital intensive care unit between 2006 and 2016 with grade V subarachnoid haemorrhage. Secondary objectives were to describe treatments provided, patient destination following hospital discharge, organ donation and hospital financial costs. Over the 11-year study period, there were 139 patients admitted with grade V subarachnoid haemorrhage. The annual number of admissions did not change over time. The median age was 56 (interquartile range 48-70) years, 88 (63%) were female and 77 (55%) had a procedure to isolate an aneurysm. There were 77 (55%) patients who died in the intensive care unit, 87 (63%) died in hospital and 89 (64%) had died at 12 months. Of the 52 patients who survived to hospital discharge, 33 (63%) were transferred to a rehabilitation facility, 17 (33%) to another acute care hospital and two (4%) were discharged. Of the 87 patients who died in hospital, 45 (52%) donated organs. The total hospital cost of managing this cohort was A$8.3 million, with a median cost of A$41,824 (interquartile range A$9,933-A$97,332) per patient. Grade V subarachnoid haemorrhage has a high mortality rate, with one-third of patients alive after one year.

Severe meningococcal serogroup W sepsis presenting as myocarditis: A case report and review of literature.

The global incidence of invasive meningococcal disease due to serogroup W (MenW) has risen over the last decade. The following case emphasises the atypical features of MenW meningococcaemia, which included myocarditis, a rare but important complication. It also highlights the potential novel role that cardiac magnetic resonance imaging can provide in the diagnosis of MenW myocarditis. Complications of these infections can be avoided with early recognition and susceptibility testing to prevent the use of inappropriate antibiotics and treatment failure.

Idiopathic systemic capillary leak syndrome presenting as septic shock: A case report.

BACKGROUND: Idiopathic capillary leak syndrome (Clarkson's Disease) is a rare angiopathy with a heterogenous phenotype that may present as distributive shock refractory to resuscitative management. OBJECTIVE: We report a case of idiopathic systemic capillary leak syndrome presenting as septic shock. METHODS: Structured case report and review of the literature. RESULTS: A 27-year old man admitted to our institution with coryzal symptoms rapidly deteriorated with presumed sepsis, leading to intensive care unit admission. Following further deterioration, Idiopathic systemic capillary leak syndrome was considered and intravenous immunoglobulin administered, resulting in rapid improvement in the patient's clinical status. CONCLUSIONS: Idiopathic systemic capillary leak syndrome is a rare and potentially life-threatening angiopathy that may present as, and should be considered in, refractory distributive shock. Administration of intravenous immunglobulin resulted in rapid recovery in this patient, and has been associated with positive outcomes in previous cases.