The Inter-Rater Reliability of Pediatric Point-of-Care Lung Ultrasound Interpretation in Children With Acute Respiratory Failure.

OBJECTIVES: Use of point-of-care lung ultrasound (POC-LUS) has increased significantly in pediatrics yet it remains under-studied in the pediatric intensive care unit (PICU). No studies explicitly evaluate the reliability of POC-LUS artifact interpretation among critically ill children with acute respiratory failure (ARF) in the PICU. We thus designed this study to determine the inter-rater reliability of POC-LUS interpretation in pediatric ARF among pediatric intensivists trained in POC-LUS and an expert intensivist. METHODS: We compared the interpretation of lung sliding, pleural line characteristics, ultrasound artifacts, and POC-LUS diagnoses among pediatric intensivists and an expert intensivist in a cohort of children admitted to the PICU for ARF. Kappa statistics (k) adjusted for maximum attainable agreement (k/kmax ) were used to quantify chance-correct agreement between the pediatric intensivist and expert physician. RESULTS: We enrolled 88 patients, evaluating 3 zones per hemithorax (anterior, lateral, and posterior) for lung sliding, pleural line characteristics, ultrasound artifacts, and diagnosis. There was moderate agreement between the PICU intensivist and expert-derived diagnoses with 56% observed agreement (k/kmax  = 0.46, 95% confidence interval [CI] 0.31-0.65). Agreement in identification of lung sliding (k = 0.19, 95% CI -0.17 to 0.56) and pleural line characteristics (k = 0.24, 95% CI 0.08-0.40) was slight and fair, respectively, while agreement in the interpretation of ultrasound artifacts ranged from moderate to substantial. CONCLUSIONS: Evidence supporting the evaluation of neonatal and adult patients with POC-LUS should not be extrapolated to critically ill pediatric patients. This study adds to the evidence supporting use of POC-LUS in the PICU by demonstrating moderate agreement between PICU intensivist and expert-derived POC-LUS diagnoses.

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19.

BACKGROUND: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. AREAS OF UNCERTAINTY: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. DATA SOURCES: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. THERAPEUTIC ADVANCES: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. CONCLUSIONS: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

Clinical and Scientific Rationale for the "MATH+" Hospital Treatment Protocol for COVID-19.

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies' recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working," the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.

Point-of-Care Lung Ultrasound to Diagnose the Etiology of Acute Respiratory Failure at Admission to the PICU.

OBJECTIVES: Determine the sensitivity and specificity of point-of-care lung ultrasound in identifying the etiology of acute respiratory failure at admission to the PICU. DESIGN: Prospective observational study. SETTING: Tertiary PICU. PATIENTS: Children older than 37 weeks gestational age and less than or equal to 18 years old admitted to the PICU with acute respiratory failure from December 2018 to February 2020. INTERVENTION: Point-of-care lung ultrasound performed within 14 hours of admission to the PICU by physicians blinded to patient history and clinical course. Two physicians, blinded to all clinical information, independently interpreted the point-of-care lung ultrasound and then established a consensus diagnosis (ultrasound diagnosis). The ultrasound diagnosis was compared with an independent, standardized review of the medical record following hospital discharge (final diagnosis). MEASUREMENTS AND RESULTS: Eighty-eight patients were enrolled in the study. Forty-eight patients had a final diagnosis of bronchiolitis/viral pneumonitis (55%), 29 had pneumonia (33%), 10 had status asthmaticus (11%), and one was excluded because of an inability to differentiate the final diagnosis. Point-of-care lung ultrasound correctly identified the etiology of acute respiratory failure in 56% of patients (49/87; 95% CI, 46-66%). It identified bronchiolitis/viral pneumonitis with 44% sensitivity (95% CI, 0.31-0.58) and 74% specificity (95% CI, 0.59-0.85), pneumonia with 76% sensitivity (95% CI, 0.58-0.88) and 67% specificity (95% CI 0.54-0.78), and status asthmaticus with 60% sensitivity (95% CI, 0.31-0.83) and 88% specificity (95% CI, 0.79-0.94). CONCLUSIONS: In contrast to literature demonstrating high utility differentiating the cause of acute respiratory failure in adults, blinded point-of-care lung ultrasound demonstrates moderate sensitivity and specificity in identifying the etiology of pediatric acute respiratory failure at admission to the PICU among children with bronchiolitis, pneumonia, and status asthmaticus.

MANAGEMENT OF MEDICAL COMPLICATIONS ASSOCIATED WITH A PRESUMED TETANUS INFECTION IN A NORTHWEST BORNEAN ORANGUTAN (PONGO PYGMAEUS PYGMAEUS).

An 18-yr-old female orangutan (Pongo pygmaeus pygmaeus) developed opisthotonus after sustaining conspecific bite wounds 3 wk earlier. The orangutan developed progressive tetraparesis and dysphagia, despite normal mentation, suggestive of tetanus. A tetanus vaccine had been administered at 2 yr of age, but none since. Brain magnetic resonance imaging, computed tomography, cerebral spinal fluid tap, and bloodwork were unremarkable. Viral, Baylisascaris, and tetanus toxin testing were negative. A femoral central venous catheter (CVC) was placed to provide medications, fluids, and parenteral nutrition. The orangutan received human tetanus immunoglobulin, tetanus toxoid, penicillin, methocarbamol, and analgesia. After 1 wk, the catheterized limb became edematous; a deep vein thrombosis (DVT) was diagnosed ultrasonographically. A cephalic CVC was placed, the limb casted, intravenous therapy reinitiated, and enoxaparin started. The orangutan became mobile days later, and progressively improved. Despite no compliance with enoxaparin, the DVT resolved without residual signs. This is the first reported case of presumptive tetanus and DVT in a great ape.

Effectiveness of a Transesophageal Echocardiography Course.

BACKGROUND: Transesophageal echocardiography has important applications for the management of the critically ill patient. There is a need to develop effective training programs for the critical care community in acquiring skill at critical care transesophageal echocardiography. OBJECTIVE: We studied the effectiveness of a 1-day simulation-based course that focused on the acquisition of skill in the performance of critical care transesophageal echocardiography. METHODS: Learners received training in image acquisition with a transesophageal simulator and training in image interpretation in small group sessions. Skill at image acquisition and image interpretation was assessed at the beginning and at the completion of the course. RESULTS: There were 27 learners who attended the course. Pre and post knowledge scores were 55 (19; mean [SD]) and 88 (9; P < .0005), respectively. Pre and post image acquisition scores were 3.6 (3.7) and 9.9 (0.3; P < .0001), respectively. CONCLUSIONS: A 1-day course in critical care transesophageal echocardiography that combined case-based image interpretation with image acquisition training using a simulator improved technical skills and knowledge base.

Assessment of dynamic changes in cardiac function during resuscitation of patients with suspected septic shock: A prospective, observational, cohort study.

STUDY OBJECTIVE: To describe changes in cardiac function throughout the course of resuscitation of patients with suspected septic shock. METHODS: Prospective observational cohort study of Point-of-Care Transthoracic Echocardiograms (TTE) obtained in Emergency Department (ED) patients with a presumed infectious cause of hypotension within one hour of initiating IV fluid resuscitation. Findings of this pre-resuscitation TTE were compared to mid-resuscitation TTE (obtained upon disposition from the ED), and post-resuscitation TTE (obtained after admission to hospital). RESULTS: 22 enrolled patients had a second TTE available for comparison to the initial, pre-resuscitation TTE. 12 patients had a mid-resuscitation TTE and 16 patients had a post-resuscitation TTE. We observed a high incidence of changes on TTE during the clinical course of resuscitation (14/22 [64%]). Patients who developed LV or RV dysfunction during resuscitation were more likely to require vasopressor infusion and ICU admission (Spearman's coefficients [95% CI] of 0.68 [0.36-0.86] and 0.47 [0.04;0.75] respectively). Development of RV dysfunction alone was associated with increased use of positive pressure ventilation and vasopressor infusion (Spearman's coefficients [95% CI] of 0.43 [0;0.72] and 0.47 [0.05,0.75] respectively). CONCLUSIONS: Cardiac function changes assessed by TTE are common during the resuscitation of patients with septic shock. These changes likely reflect the underlying physiology of patients with septic shock and correlate with need for interventions and higher level of care. Further work is required to characterize these changes and to elucidate how to use these physiologic data to guide management.

Influence of head-of-bed elevation on the measurement of inferior vena cava diameter and collapsibility.

PURPOSE: Inferior vena cava (IVC) diameter and variation are commonly measured in the supine position to estimate intravascular volume status of critically ill patients. Many scientific societies describe the measurement of IVC diameter in the supine position. However, critically ill patients are rarely placed supine due to concerns for aspiration risk, worsened respiratory mechanics, increases in intracranial pressure, and the time it takes to change patient position. We assessed the influence of head-of-bed (HOB) elevation on IVC measurements. METHODS: We conducted a prospective observational study of critically ill patients undergoing critical care ultrasound. With HOB at 0°, IVC maximum (IVCmax0°) and minimum (IVCmin0°) diameters were measured. Measurements were then repeated with HOB elevated to 30° and 45°. Collapsibility index (CI), defined as (IVCmax - IVCmin)/IVCmax, was calculated for each HOB elevation. Mean differences were then compared. RESULTS: A convenience sample of 95 patients was studied, of whom 45% were on vasopressors and 44% were spontaneously breathing. The CI did not significantly differ between the three positions. We found a significant difference (P ≤ .0001) between IVCmax at 45° (2.09 cm) and 0° (1.96 cm), IVCmin at 45° (1.75 cm) and 0° (1.59 cm), IVCmax at 45° (2.09 cm) and 30° (1.97 cm), and IVCmin at 45° (1.75 cm) and 30° (1.61 cm). CONCLUSIONS: In a population of critically ill patients undergoing goal-directed ultrasound examinations, elevating HOB to 30° did not significantly alter IVC measurements or CI. At 45°, however, IVCmax and IVCmin diameters increased significantly, albeit with no significant change in CI. Performing ultrasound measurements of the IVC with HOB elevated to 30° is unlikely to produce clinically meaningful changes.

Right Heart Thrombi: Patient Outcomes by Treatment Modality and Predictors of Mortality: A Pooled Analysis.

RATIONALE: Right heart thrombi (RiHT) is characterized by the presence of thrombus within the right atrium or right ventricle (RV). Current literature suggests pulmonary embolism (PE) with RiHT carries a high mortality. Guidelines lack recommendations in managing RiHT. We created a pooled analysis on RiHT and report on our institutional experience in managing RiHT. We aimed to evaluate whether patient characteristics and differing treatment modalities predict mortality. METHODS: We created a pooled analysis of case reports and series of patients with RiHT and PE between January 1956 and 2017. We also reviewed a series of consecutive patients with RiHT identified from our institutional PE registry. Age, shock, RV dysfunction, clot mobility, treatment modality, and hospital outcome had to be reported. RESULTS: We identified 316 patients in our pooled analysis. Patients received the following therapies: no treatment 15 (5%), systemic anticoagulation 73 (23%), systemic thrombolysis 108 (34%), surgical embolectomy 101 (32%), catheter-directed therapy 11 (3%), and systemic thrombolysis with surgery 8 (3%). In-hospital mortality was 18.7%. Univariate analysis showed age and shock reduced odds of survival. Multivariate analysis showed shock reduced odds of survival (odds ratios [OR] 0.36, 95% confidence interval [CI]: 0.19-0.72, P ≤ .01) while age, RV dysfunction, and clot-mobility did not affect mortality. In a reduced multivariate analysis adjusting for shock, treatment modality, and clot location alone, systemic thrombolysis increased odds of survival when compared to systemic anticoagulation (OR 2.72, 95% CI: 1.11-6.64, P = .02). Our institutional series identified 18 patients, where in-hospital mortality was 22.2%, 18 (100%) had RV dysfunction, and 5 (28%) had shock. Patients received the following therapies: systemic anticoagulation 8 (44.4%), systemic thrombolysis 4 (22.2%), surgical embolectomy 4 (22.2%), and catheter-directed thrombolysis 2 (11.1%). CONCLUSION: Presence of shock in RiHT is an independent predictor of mortality. Systemic thrombolysis may offer increased odds of survival when compared to systemic anticoagulation. Our findings should be interpreted with caution as they derive from retrospective reports and subject to publication bias.

Expert Agreement in the Interpretation of Lung Ultrasound Studies Performed on Mechanically Ventilated Patients.

OBJECTIVES: Although lung ultrasound (US) has been shown to have high diagnostic accuracy in patients presenting with acute dyspnea, its precision in critically ill patients is unknown. We investigated common areas of agreement and disagreement by studying 6 experts as they interpreted lung US studies in a cohort of intensive care unit (ICU) patients. METHODS: A previous study by our group asked experts to rate the quality of 150 lung US studies performed by 10 novices in a population of mechanically ventilated patients. For this study, experts were asked to interpret them without the clinical context, reporting the presence of pneumothorax, interstitial syndrome, consolidation, atelectasis, or pleural effusion. RESULTS: The rate of expert agreement depended on how it was defined, ranging from 51% (with a strict definition of agreement) to 57% (with a more liberal definition). Removing cases involving lung consolidation (the most common source of disagreement) improved the rates of agreement to 69% and 86%, respectively. CONCLUSIONS: The frequency of agreement was lower than might have been expected in this study. Several potential reasons are identified, chief among them the fact that ICU patients often develop multiple pulmonary insults, making agreement on a specific primary diagnosis challenging. This finding suggests that the utility of lung US in identifying the main contributing lung condition in ICU patients may be lower than in dyspneic patients encountered in the emergency department. It also raises the possibility that the clinical context is more important for lung US than other imaging modalities.

The Rapid Assessment of Competency in Echocardiography Scale: Validation of a Tool for Point-of-Care Ultrasound.

OBJECTIVES: Increased use of point-of-care ultrasound (US) requires the development of assessment tools that measure the competency of learners. In this study, we developed and tested a tool to assess the quality of point-of-care cardiac US studies performed by novices. METHODS: In phase 1, the Rapid Assessment of Competency in Echocardiography (RACE) scale was developed on the basis of structured interviews with subject matter experts; the tool was then piloted on a small series of US studies in phase 2. In phase 3, the tool was applied to a sample of 154 point-of-care US studies performed by 12 learners; each study was independently rated by 2 experts, with quantitative analysis subsequently performed. RESULTS: Evidence of the content validity of the RACE scale was supported by a consensus exercise, wherein experts agreed on the assessment dimensions and specific items that made up the RACE scale. The tool showed good inter-rater reliability. An analysis of inter-item correlations provided support for the internal structure of the scale, and the tool was able to discriminate between learners early in their point-of-care US learning and those who were more advanced in their training. CONCLUSIONS: The RACE scale provides a straightforward means to assess learner performance with minimal requirements for evaluator training. Our results support the conclusion that the tool is an effective means of making valid judgments regarding competency in point-of-care cardiac US.

Comparison of video laryngoscopy versus direct laryngoscopy during urgent endotracheal intubation: a randomized controlled trial.

OBJECTIVES: In the critically ill undergoing urgent endotracheal intubation by direct laryngoscopy, multiple attempts are often required with a higher complication rate due to the urgency, uncontrolled setting, comorbidities, and variability in expertise of operators. We hypothesized that Glidescope video laryngoscopy would be superior to direct laryngoscopy during urgent endotracheal intubation. DESIGN: Single-center prospective randomized controlled trial. SETTING: Beth Israel Medical Center, an 856-bed urban teaching hospital with a 16-bed closed medical ICU. PATIENTS: Of 153 consecutive patients undergoing urgent endotracheal intubation by pulmonary and critical care medicine fellows, 117 met inclusion criteria. INTERVENTIONS: Patients undergoing urgent endotracheal intubation were randomized to Glidescope video laryngoscopy or direct laryngoscopy as the primary intubation device. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was the rate of first-attempt success. Acute Physiology and Chronic Health Evaluation II scores were similar between groups (20.9 ± 8.2 vs 19.9 ± 7.9). First-attempt success was achieved in 74% of the Glidescope video laryngoscopy group compared with 40% in the direct laryngoscopy group (p < 0.001). All unsuccessful direct laryngoscopy patients were successfully intubated with Glidescope video laryngoscopy, 82% on the first attempt. There was no significant difference in rates of complications between direct laryngoscopy and Glidescope video laryngoscopy: esophageal intubations (7% vs 0%; p = 0.05), aspiration events (7% vs 9%; p = 0.69), desaturation (8% vs 4%; p = 0.27), and hypotension (13% vs 11%; p = 0.64). CONCLUSIONS: Glidescope video laryngoscopy improves the first-attempt success rate during urgent endotracheal intubation performed by pulmonary and critical care medicine fellows when compared with direct laryngoscopy.

The impact of video laryngoscopy use during urgent endotracheal intubation in the critically ill.

BACKGROUND: The video laryngoscope (VL) has been shown to improve laryngoscopic views and first-attempt success rates in elective operating room and simulated tracheal intubations compared with the direct laryngoscope (DL). However, there are limited data on the effectiveness of the VL compared with the DL in urgent endotracheal intubations (UEIs) in the critically ill. We assessed the effectiveness of using a VL as the primary intubating device during UEI in critically ill patients when performed by less experienced operators. METHODS: We compared success rates of UEIs performed by Pulmonary and Critical Care Medicine (PCCM) fellows in the medical intensive care unit and medical or surgical wards. A cohort of PCCM fellows using GlideScope VL as the primary intubating device was compared with a historical cohort of PCCM fellows using a traditional Macintosh or Miller blade DL. The primary measured outcome was first-attempt intubation success rate. Secondary outcomes included total number of attempts required for successful tracheal intubation, rate of esophageal intubation, need for supervising attending intervention, duration of intubation sequence, and incidence of hypoxemia and hypotension. RESULTS: There were 138 UEIs, with 78 using a VL and 50 using a DL as the primary intubating device. The rate of first-attempt success was superior with the VL as compared with the DL (91% vs 68%, P < 0.01). The rate of intubations requiring ≥3 attempts (4% vs 20%, P < 0.01), unintended esophageal intubations (0% vs 14%, P < 0.01), and the average number of attempts required for successful tracheal intubation (1.2 ± 0.56 vs 1.7 ± 1.1, P < 0.01) all improved significantly with use of the VL compared with the DL. CONCLUSIONS: UEI using a VL as the primary device improved intubation success and decreased complications compared with a DL when PCCM fellows were the primary operators. These data suggest that the VL should be used as the primary device when urgent intubations are performed by less experienced operators.

Comparison of chest radiograph and lung ultrasound in children with acute respiratory failure.

PURPOSE: Chest x-ray (CXR) is the standard imaging used to evaluate children in acute respiratory distress and failure. Our objective was to compare the lung-imaging techniques of CXR and lung ultrasound (LUS) in the evaluation of children with acute respiratory failure (ARF) to quantify agreement and to determine which technique identified a higher frequency of pulmonary abnormalities. METHODS: This was a secondary analysis of a prospective observational study evaluating the sensitivity and specificity of LUS in children with ARF from 12/2018 to 02/2020 completed at the University of Wisconsin-Madison (USA). Children > 37.0 weeks corrected gestational age and ≤ 18 years of age admitted to the PICU with ARF were evaluated with LUS. We compared CXR and LUS completed within 6 h of each other. Kappa statistics (k) adjusted for maximum attainable agreement (k/kmax) were used to quantify agreement between imaging techniques and descriptive statistics were used to describe the frequency of abnormalities. RESULTS: Eighty-eight children had LUS completed, 32 with concomitant imaging completed within 6 h are included. There was fair agreement between LUS and CXR derived diagnoses with 58% agreement (k/kmax = 0.36). Evaluation of imaging patterns included: normal, 57% agreement (k = 0.032); interstitial pattern, 47% agreement (k = 0.003); and consolidation, 65% agreement (k = 0.29). CXR identified more imaging abnormalities than LUS. CONCLUSIONS: There is fair agreement between CXR and LUS-derived diagnoses in children with ARF. Given this, clinicians should consider the benefits and limitations of specific imaging modalities when evaluating children with ARF. Additional studies are necessary to further define the role of LUS in pediatric ARF given the small sample size of our study.

Outcomes of mild therapeutic hypothermia after in-hospital cardiac arrest.

BACKGROUND: Although the benefits of mild therapeutic hypothermia (MTH) in selected patients after out-of-hospital cardiac arrest have been consistently demonstrated, no controlled trial of MTH in selected patients after in-hospital cardiac arrest (IHCA) has been published. We sought to assess the benefit of MTH after IHCA in patients meeting our institutions IHCA MTH inclusion criteria. METHODS: A retrospective, historical control study was performed. During the 3-year period before and after the 2006 MTH protocol implementation at our institution, we identified a total of 118 patients admitted to our Medical Intensive Care Unit after resuscitation from an IHCA. Two blinded investigators identified all patients meeting our institutions MTH protocol inclusion criteria and the patients in each time period were compared. The primary outcome was discharge with good neurological function. RESULTS: 33 IHCA patients met MTH protocol inclusion criteria; 16 patients were admitted prior to MTH protocol implementation and thus were not treated with MTH post arrest while 17 patients were admitted after implementation and were all treated with MTH post arrest. 91% of patients had an arrest rhythm of asystole or pulseless electrical activity. Good neurological function at discharge was found in 24% of MTH patients and 31% of controls (P = .62). CONCLUSIONS: No difference in neurological outcome at discharge was detected in predominantly non-shockable IHCA patients treated with MTH. This finding, if confirmed with further study, may define a population of patients for whom this costly and resource intensive therapy should be withheld.

"MATH+" Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale.

In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working", the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically.