Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation-A protocol for a randomized controlled pilot study

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, is spreading rapidly across the globe, with little proven effective therapy. Fever is seen in most cases of COVID-19, at least at the initial stages of illness. Although fever is typically treated (with antipyretics or directly with ice or other mechanical means), increasing data suggest that fever is a protective adaptive response that facilitates recovery from infectious illness. OBJECTIVE: To describe a randomized controlled pilot study of core warming patients with COVID-19 undergoing mechanical ventilation. METHODS: This prospective single-site randomized controlled pilot study will enroll 20 patients undergoing mechanical ventilation for respiratory failure due to COVID-19. Patients will be randomized 1:1 to standard-of-care or to receive core warming via an esophageal heat exchanger commonly utilized in critical care and surgical patients. The primary outcome is patient viral load measured by lower respiratory tract sample. Secondary outcomes include severity of acute respiratory distress syndrome (as measured by PaO2/FiO2 ratio) 24, 48, and 72 hours after initiation of treatment, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality. RESULTS: Resulting data will provide effect size estimates to guide a definitive multi-center randomized clinical trial. ClinicalTrials.gov registration number: NCT04426344. CONCLUSIONS: With growing data to support clinical benefits of elevated temperature in infectious illness, this study will provide data to guide further understanding of the role of active temperature management in COVID-19 treatment and provide effect size estimates to power larger studies

Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial

Objective To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. Methods This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. Results We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). Conclusions In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography

Core warming of coronavirus disease 2019 patients undergoing mechanical ventilation: A pilot study

Fever is a recognized protective factor in patients with sepsis, and growing data suggest beneficial effects on outcomes in sepsis with elevated temperature, with a recent pilot randomized controlled trial (RCT) showing lower mortality by warming afebrile sepsis patients in the intensive care unit (ICU). The objective of this prospective single-site RCT was to determine if core warming improves respiratory physiology of mechanically ventilated patients with coronavirus disease 2019 (COVID-19), allowing earlier weaning from ventilation, and greater overall survival. A total of 19 patients with mean age of 60.5 (±12.5) years, 37% female, mean weight 95.1 (±18.6) kg, and mean body mass index 34.5 (±5.9) kg/

The Use of Core Warming as a Treatment for Coronavirus Disease 2019 (COVID-19): an Initial Mathematical Model

Background: Increasing data suggest that elevated body temperature may be helpful in resolving a variety of diseases, including sepsis, acute respiratory distress syndrome (ARDS), and viral illnesses. SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), may be more temperature sensitive than other coronaviruses, particularly with respect to the binding affinity of its viral entry via the ACE2 receptor. A mechanical provision of elevated temperature focused in a body region of high viral activity in patients undergoing mechanical ventilation may offer a therapeutic option that avoids arrhythmias seen with some pharmaceutical treatments.  We investigated the potential to actively provide core warming to the lungs of patients with a commercially available heat transfer device via mathematical modeling, and examine the influence of blood perfusion on temperature using this approach.  Methods: Using the software Comsol Multiphysics, we modeled and simulated heat transfer in the body from an intraesophageal warming device, taking into account the airflow from patient ventilation. The simulation was focused on heat transfer and warming of the lungs and performed on  a simplified geometry of an adult human body and airway from the pharynx to the lungs.  Results: The simulations were run over a range of values for blood perfusion rate, which was a parameter expected to have high influence in overall heat transfer, since the heat capacity and density remain almost constant. The simulation results show a temperature distribution which agrees with the expected clinical experience, with the skin surface at a lower temperature than the rest of the body due to convective cooling in a typical hospital environment.  The highest temperature in this case is the device warming water temperature, and that heat diffuses by conduction to the nearby tissues, including the air flowing in the airways. At the range of blood perfusion investigated, maximum lung temperature ranged from 37.6°C to 38.6°C. Conclusions: The provision of core warming via commercially available technology currently utilized in the intensive care unit, emergency department, and operating room can increase regional temperature of lung tissue and airway passages. This warming may offer an innovative approach to treating infectious diseases from viral illnesses such as COVID-19, while avoiding the arrhythmogenic complications of currently used pharmaceutical treatments.  

The Use of Core Warming as a Treatment for Coronavirus Disease 2019 (COVID-19): an Initial Mathematical Model

Background: Increasing data suggest that elevated body temperature may be helpful in resolving a variety of diseases, including sepsis, acute respiratory distress syndrome (ARDS), and viral illnesses. SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), may be more temperature sensitive than other coronaviruses, particularly with respect to the binding affinity of its viral entry via the ACE2 receptor. A mechanical provision of elevated temperature focused in a body region of high viral activity in patients undergoing mechanical ventilation may offer a therapeutic option that avoids arrhythmias seen with some pharmaceutical treatments.  We investigated the potential to actively provide core warming to the lungs of patients with a commercially available heat transfer device via mathematical modeling, and examine the influence of blood perfusion on temperature using this approach.  Methods: Using the software Comsol Multiphysics, we modeled and simulated heat transfer in the body from an intraesophageal warming device, taking into account the airflow from patient ventilation. The simulation was focused on heat transfer and warming of the lungs and performed on  a simplified geometry of an adult human body and airway from the pharynx to the lungs.  Results: The simulations were run over a range of values for blood perfusion rate, which was a parameter expected to have high influence in overall heat transfer, since the heat capacity and density remain almost constant. The simulation results show a temperature distribution which agrees with the expected clinical experience, with the skin surface at a lower temperature than the rest of the body due to convective cooling in a typical hospital environment.  The highest temperature in this case is the device warming water temperature, and that heat diffuses by conduction to the nearby tissues, including the air flowing in the airways. At the range of blood perfusion investigated, maximum lung temperature ranged from 37.6°C to 38.6°C. Conclusions: The provision of core warming via commercially available technology currently utilized in the intensive care unit, emergency department, and operating room can increase regional temperature of lung tissue and airway passages. This warming may offer an innovative approach to treating infectious diseases from viral illnesses such as COVID-19, while avoiding the arrhythmogenic complications of currently used pharmaceutical treatments.  

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD &gt; 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene