Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial.

PURPOSE: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness. METHODS: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation. RESULTS: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019). CONCLUSION: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot randomised controlled trial.

BACKGROUND: Self-reported penicillin allergies are highly prevalent in hospitalised patients and are associated with poor health and health service outcomes. Critically ill patients have historically been underrepresented in prospective delabelling studies in part due to concerns around clinical stability and reliability of penicillin skin testing. Allergy assessment tools exist to identify low-risk penicillin allergy phenotypes and facilitate direct oral challenge delabelling. PEN-FAST is a clinical decision rule that has been validated to predict true penicillin allergy in a cohort of non-critically ill patients. There is however limited evidence regarding the feasibility, safety and efficacy of direct oral challenges and the use of delabelling clinical decisions rules in the intensive care setting. METHODS: Critically ill patients in the intensive care unit (ICU) with low-risk penicillin allergy phenotypes (PEN-FAST score < 3) will be randomised 1:1 to direct oral penicillin challenge (single dose 250 mg oral amoxicillin or implicated penicillin) or routine care, followed by a 2-h observation period. Patients will receive a second oral challenge/observation prior to hospital discharge (with subsequent observation for 2 h). An assessment for antibiotic-associated adverse events will also be undertaken at 24 h and 5 days post each challenge/observation and again at 90 days post-randomisation. The primary outcome measures are feasibility (proportion of eligible patients recruited and protocol compliance) and safety (proportion of patients who experience an antibiotic-associated immune-mediated adverse event or serious adverse event). DISCUSSION: We will report the feasibility and safety of point-of-care penicillin direct oral challenge in this first randomised controlled trial of low-risk penicillin allergy in critically ill hospitalised patients. Upon completion of the project, important findings will inform the design of planned large prospective multi-centre clinical trials in Australian and international ICUs, further examining safety and efficacy and exploring antimicrobial prescribing-related outcomes following penicillin oral challenge. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Registration Number: ACTRN12621000051842 Date registered: 20/01/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379735&isReview=true.

High-Dose Hydroxocobalamin for Refractory Vasoplegia Post Cardiac Surgery.

Administration of high-dose hydroxocobalamin, or vitamin B12, is an emerging, targeted rescue therapy for the treatment of refractory vasoplegic shock. This is an uncommon but potentially life-threatening complication following cardiac surgery and carries a poor prognosis, particularly when patients fail to respond to first-line therapy with catecholamine vasopressors. This study describes our experience in treating refractory vasodilatory shock following cardiac surgery with high-dose hydroxocobalamin. Administration of hydroxocobalamin in seven patients was associated with an improvement in mean arterial blood pressure or reduction in vasopressor requirements, which were both immediate and sustained throughout our observational period. No deaths or adverse effects attributable to hydroxocobalamin administration occurred in our cohort. Our observations show that high-dose hydroxocobalamin is a safe and effective rescue therapy in refractory vasoplegic shock post cardiopulmonary bypass (CPB).

Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Assessment of Substrate for Ventricular Tachycardia With Hemodynamic Compromise.

Background: The majority of data regarding tissue substrate for post myocardial infarction (MI) VT has been collected during hemodynamically tolerated VT, which may be distinct from the substrate responsible for VT with hemodynamic compromise (VT-HC). This study aimed to characterize tissue at diastolic locations of VT-HC in a porcine model. Methods: Late Gadolinium Enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging was performed in eight pigs with healed antero-septal infarcts. Seven pigs underwent electrophysiology study with venous arterial-extra corporeal membrane oxygenation (VA-ECMO) support. Tissue thickness, scar and heterogeneous tissue (HT) transmurality were calculated at the location of the diastolic electrograms of mapped VT-HC. Results: Diastolic locations had median scar transmurality of 33.1% and a median HT transmurality 7.6%. Diastolic activation was found within areas of non-transmural scar in 80.1% of cases. Tissue activated during the diastolic component of VT circuits was thinner than healthy tissue (median thickness: 5.5 mm vs. 8.2 mm healthy tissue, p < 0.0001) and closer to HT (median distance diastolic tissue: 2.8 mm vs. 11.4 mm healthy tissue, p < 0.0001). Non-scarred regions with diastolic activation were closer to steep gradients in thickness than non-scarred locations with normal EGMs (diastolic locations distance = 1.19 mm vs. 9.67 mm for non-diastolic locations, p < 0.0001). Sites activated late in diastole were closest to steep gradients in tissue thickness. Conclusions: Non-transmural scar, mildly decreased tissue thickness, and steep gradients in tissue thickness represent the structural characteristics of the diastolic component of reentrant circuits in VT-HC in this porcine model and could form the basis for imaging criteria to define ablation targets in future trials.

Optimal Sedation and Pain Management: A Patient- and Symptom-Oriented Paradigm.

In the critically ill patient, optimal pain and sedation management remains the cornerstone of achieving comfort, safety, and to facilitate complex life support interventions. Pain relief, using multimodal analgesia, is an integral component of any orchestrated approach to achieve clinically appropriate goals in critically ill patients. Sedative management, however, remains a significant challenge. Subsequent studies including most recent randomized trials have failed to provide strong evidence in favor of a sedative agent, a mode of sedation or ancillary protocols such as sedative interruption and sedative minimization. In addition, clinical practice guidelines, despite a comprehensive evaluation of relevant literature, have limitations when applied to individual patients. These limitations have been most apparent during the coronavirus disease 2019 pandemic. As such, there is a need for a mindset shift to a practical and achievable sedation strategy, driven by patients' characteristics and individual patient needs, rather than one cocktail for all patients. In this review, we present key principles to achieve patient-and symptom-oriented optimal analgesia and sedation in the critically ill patients. Sedative intensity should be proportionate to care complexity with due consideration to an individual patient's modifiers. The use of multimodal analgesics, sedatives, and antipsychotics agents-that are easily titratable-reduces the overall quantum of sedatives and opioids, and reduces the risk of adverse events while maximizing clinical benefits. In addition, critical considerations regarding the choice of sedative agents should be given to factors such as age, medical versus operative diagnosis, and cardiovascular status. Specific populations such as trauma, neurological injury, and pregnancy should also be taken into account to maximize efficacy and reduce adverse events.

Tocilizumab for severe COVID-19 pneumonia: Case series of 5 Australian patients.

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.

Sedation and Delirium in the Intensive Care Unit-A Practice-Based Approach.

INTRODUCTION: Critically ill patients often require sedation for comfort and to facilitate therapeutic interventions. Sedation practice guidelines provide an evidence-based framework with recommendations that can help improve key sedation-related outcomes. MATERIALS AND METHODS: We conducted a narrative review of current guidelines and recent trials on sedation. RESULTS: From a practice perspective, current guidelines share many limitations including lack of consensus on the definition of light sedation, optimal frequency of sedation assessment, optimal timing for light sedation and consideration of combinations of sedatives. We proposed several strategies to address these limitations and improve outcomes: 1) early light sedation within the first 48 hours with time-weighted monitoring (overall time spent in light sedation in the first 48 hours-sedation intensity-has a dose-dependent relationship with mortality risk, delirium and time to extubation); 2) provision of analgesia with minimal or no sedation where possible; 3) a goal-directed and balanced multimodal approach that combines the benefits of different agents and minimise their side effects; 4) use of dexmedetomidine and atypical antipsychotics as a sedative-sparing strategy to reduce weaning-related agitation, shorten ventilation time and accelerate physical and cognitive rehabilitation; and 5) a bundled approach to sedation that provides a framework to improve relevant clinical outcomes. CONCLUSION: More effort is required to develop a practical, time-weighted sedation scoring system. Emphasis on a balanced, multimodal appraoch that targets light sedation from the early phase of acute critical illness is important to achieve optimal sedation, lower mortality, shorten time on ventilator and reduce delirium.