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.
Mohr NM, Doerschug KC: Point: Should antipyretic therapy be given routinely to febrile patients in septic shock? Yes. Chest 2013, 144(4):1096-1098.
Ray JJ, Schulman CI: Fever: suppress or let it ride? Journal of thoracic disease 2015, 7(12):E633-E636.
Drewry AM, Hotchkiss RS: Counterpoint: Should antipyretic therapy be given routinely to febrile patients in septic shock? No. Chest 2013, 144(4):1098-1101.
O'Grady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC, Linden P, Maki DG, Nierman D, Pasculle W et al: Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Critical Care Medicine 2008, 36(4):1330-1349.
Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, Dellamonica J, Bouadma L, Cook F, Beji O et al: Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med 2012, 185(10):1088-1095.
Saxena M, Young P, Pilcher D, Bailey M, Harrison D, Bellomo R, Finfer S, Beasley R, Hyam J, Menon D et al: Early temperature and mortality in critically ill patients with acute neurological diseases: trauma and stroke differ from infection. Intensive Care Med 2015, 41(5):823-832.
Young PJ, Saxena M, Beasley R, Bellomo R, Bailey M, Pilcher D, Finfer S, Harrison D, Myburgh J, Rowan K: Early peak temperature and mortality in critically ill patients with or without infection. Intensive Care Med 2012.
Berman JD, Neva FA: Effect of temperature on multiplication of Leishmania amastigotes within human monocyte-derived macrophages in vitro. Am J Trop Med Hyg 1981, 30(2):318-321.
Mace TA, Zhong L, Kilpatrick C, Zynda E, Lee C-T, Capitano M, Minderman H, Repasky EA: Differentiation of CD8+ T cells into effector cells is enhanced by physiological range hyperthermia. Journal of Leukocyte Biology 2011, 90(5):951-962.
Chu CM, Tian SF, Ren GF, Zhang YM, Zhang LX, Liu GQ: Occurrence of temperature-sensitive influenza A viruses in nature. J Virol 1982, 41(2):353-359.
Moench LM: A Study of the Heat Sensitivity of the Meningoeoecus in Vitro within the Range of Therapeutic Temperatures. Journal of Laboratory and Clinical Medicine 1937, 22:665-676.
Small PM, Tauber MG, Hackbarth CJ, Sande MA: Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infection and immunity 1986, 52(2):484-487.
Mackowiak PA, Ruderman AE, Martin RM, Many WJ, Smith JW, Luby JP: Effects of physiologic variations in temperature on the rate of antibiotic-induced bacterial killing. American journal of clinical pathology 1981, 76(1):57-62.
Launey Y, Nesseler N, Mallédant Y, Seguin P: Clinical review: fever in septic ICU patients--friend or foe? Critical care (London, England) 2011, 15(3):222-222.
Doran TF, De Angelis C, Baumgardner RA, Mellits ED: Acetaminophen: more harm than good for chickenpox? J Pediatr 1989, 114(6):1045-1048.
Brandts CH, Ndjave M, Graninger W, Kremsner PG: Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria. Lancet 1997, 350(9079):704-709.
Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V: Increased virus shedding with aspirin treatment of rhinovirus infection. Jama 1975, 231(12):1248-1251.
Peters MJ, Woolfall K, Khan I, Deja E, Mouncey PR, Wulff J, Mason A, Agbeko RS, Draper ES, Fenn B et al: Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial. Critical care (London, England) 2019, 23(1):69-69.
Evans SS, Repasky EA, Fisher DT: Fever and the thermal regulation of immunity: the immune system feels the heat. Nature reviews Immunology 2015, 15(6):335-349.
Lee CT, Zhong L, Mace TA, Repasky EA: Elevation in body temperature to fever range enhances and prolongs subsequent responsiveness of macrophages to endotoxin challenge. PLoS One 2012, 7(1):e30077.
van der Zee J: Heating the patient: a promising approach? Annals of Oncology 2002, 13(8):1173-1184.
Bull JMC: Clinical Practice of Whole-Body Hyperthermia: New Directions. In: Thermoradiotherapy and Thermochemotherapy. Medical Radiology (Diagnostic Imaging and Radiation Oncology). Berlin, Heidelberg: Springer; 1996.
Westermann AM, Grosen EA, Katschinski DM, Jäger D, Rietbroek R, Schink JC, Tiggelaar CL, Jäger E, Zum Vörde sive Vörding P, Neuman A et al: A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer. European Journal of Cancer 2001, 37(9):1111-1117.
Robins HI, Dennis WH, Neville AJ, Shecterle LM, Martin PA, Grossman J, Davis TE, Neville SR, Gillis WK, Rusy BF: A nontoxic system for 41.8 degrees C whole-body hyperthermia: results of a Phase I study using a radiant heat device. Cancer research 1985, 45(8):3937-3944.
Shi H, Cao T, Connolly JE, Monnet L, Bennett L, Chapel S, Bagnis C, Mannoni P, Davoust J, Palucka AK et al: Hyperthermia Enhances CTL Cross-Priming. The Journal of Immunology 2006, 176(4):2134-2141.
Basu S, Srivastava PK: Fever‐like temperature induces maturation of dendritic cells through induction of hsp90. International Immunology 2003, 15(9):1053-1061.
Tsan M-F, Gao B: Heat shock proteins and immune system. Journal of Leukocyte Biology 2009, 85(6):905-910.
Raju TN: Hot brains: manipulating body heat to save the brain. Pediatrics 2006, 117(2):e320-321.
Epstein NN: Artificial Fever as a Therapeutic Procedure. Cal West Med 1936, 44(5):357-358.
Goury A, Poirson F, Chaput U, Voicu S, Garcon P, Beeken T, Malissin I, Kerdjana L, Chelly J, Vodovar D et al: Targeted Temperature Management Using The "Esophageal Cooling Device" After Cardiac Arrest (The COOL Study): A feasibility and safety study. Resuscitation 2017, 121:54-61.
Hegazy AF, Lapierre DM, Butler R, Martin J, Althenayan E: The esophageal cooling device: A new temperature control tool in the intensivist's arsenal. Heart & Lung: The Journal of Acute and Critical Care 2017, 46(3):143-148.
Markota A, Fluher J, Kit B, Balazic P, Sinkovic A: The introduction of an esophageal heat transfer device into a therapeutic hypothermia protocol: A prospective evaluation. Am J Emerg Med 2016, 34(4):741-745.
Khan I, Haymore J, Barnaba B, Armahizer M, Melinosky C, Bautista MA, Blaber B, Chang WT, Parikh G, Motta M et al: Esophageal Cooling Device Versus Other Temperature Modulation Devices for Therapeutic Normothermia in Subarachnoid and Intracranial Hemorrhage. Ther Hypothermia Temp Manag 2018, 8(1):53-58.
Williams D, Leslie G, Kyriazis D, O'Donovan B, Bowes J, Dingley J: Use of an Esophageal Heat Exchanger to Maintain Core Temperature during Burn Excisions and to Attenuate Pyrexia on the Burns Intensive Care Unit. Case Reports in Anesthesiology 2016, 2016:6.
Kalasbail P, Makarova N, Garrett F, Sessler DI: Heating and Cooling Rates With an Esophageal Heat Exchange System. Anesth Analg 2018, 126(4):1190-1195.
Bhatti F, Naiman M, Tsarev A, Kulstad E: Esophageal Temperature Management in Patients Suffering from Traumatic Brain Injury. Ther Hypothermia Temp Manag 2019.
Martin KR, Naiman M, Espinoza M: Using Esophageal Temperature Management to Treat Severe Heat Stroke: A Case Report. J Neurosci Nurs 2019.
Hegazy AF, Lapierre DM, Butler R, Althenayan E: Temperature control in critically ill patients with a novel esophageal cooling device: a case series. BMC anesthesiology 2015, 15:152.
Markota A, Košir AS, Balažič P, Živko I, Sinkovič A: A Novel Esophageal Heat Transfer Device for Temperature Management in an Adult Patient with Severe Meningitis. Journal of Emergency Medicine 2017, 52(1):e27-e28.
Roden DM, Harrington RA, Poppas A, Russo AM: Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment. Heart Rhythm 2020.
Sapp JL, Alqarawi W, MacIntyre CJ, Tadros R, Steinberg C, Roberts JD, Laksman Z, Healey JS, Krahn AD: Guidance On Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society. Can J Cardiol 2020.
IT’IS Database for thermal and electromagnetic parameters of biological tissues [itis.swiss/database]
Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L et al: The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt) 2005, 6(4):369-375.
Gozzoli V, Schottker P, Suter PM, Ricou B: Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med 2001, 161(1):121-123.
Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, Mackle D, McArthur C et al: Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. New England Journal of Medicine 2015, 373(23):2215-2224.
Zhang Z: Antipyretic therapy in critically ill patients with established sepsis: a trial sequential analysis. PLoS One 2015, 10(2):e0117279.
Dallimore J, Ebmeier S, Thayabaran D, Bellomo R, Bernard G, Schortgen F, Saxena M, Beasley R, Weatherall M, Young P: Effect of active temperature management on mortality in intensive care unit patients. Crit Care Resusc 2018, 20(2):150-163.
Drewry AM, Ablordeppey EA, Murray ET, Stoll CRT, Izadi SR, Dalton CM, Hardi AC, Fowler SA, Fuller BM, Colditz GA: Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis. Critical care medicine 2017, 45(5):806-813.
Niven DJ, Stelfox HT, Laupland KB: Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. J Crit Care 2013, 28(3):303-310.
Schell-Chaple HM, Puntillo KA, Matthay MA, Liu KD, National Heart L, Blood Institute Acute Respiratory Distress Syndrome N: Body temperature and mortality in patients with acute respiratory distress syndrome. American journal of critical care : an official publication, American Association of Critical-Care Nurses 2015, 24(1):15-23.
Evans EM, Doctor RJ, Gage BF, Hotchkiss RS, Fuller BM, Drewry AM: The Association of Fever and Antipyretic Medication With Outcomes in Mechanically Ventilated Patients: A Cohort Study. Shock 2019, 52(2):152-159.
Davis T: NICE guideline: feverish illness in children--assessment and initial management in children younger than 5 years. Archives of disease in childhood Education and practice edition 2013, 98(6):232-235.
Baud D, Qi X, Nielsen-Saines K, Musso D, Pomar L, Favre G: Real estimates of mortality following COVID-19 infection. The Lancet Infectious Diseases.
Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG: Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms. J Virol 2013, 87(14):8017-8028.
Aquino RS, Park PW: Glycosaminoglycans and infection. Front Biosci (Landmark Ed) 2016, 21:1260-1277.
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R et al: A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9. Circulation Research 2000, 87(5):e1-e9.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC et al: Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003, 426(6965):450-454.
Foxman EF, Storer JA, Fitzgerald ME, Wasik BR, Hou L, Zhao H, Turner PE, Pyle AM, Iwasaki A: Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells. Proceedings of the National Academy of Sciences 2015, 112(3):827-832.
Laporte M, Stevaert A, Raeymaekers V, Boogaerts T, Nehlmeier I, Chiu W, Benkheil M, Vanaudenaerde B, Pöhlmann S, Naesens L: Hemagglutinin Cleavability, Acid Stability, and Temperature Dependence Optimize Influenza B Virus for Replication in Human Airways. Journal of Virology 2019, 94(1):e01430-01419.
He J, Tao H, Yan Y, Huang S-Y, Xiao Y: Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV). bioRxiv 2020:2020.2002.2017.952903.
Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W: Detection of SARS-CoV-2 in Different Types of Clinical Specimens. Jama 2020.
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J et al: SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med 2020, 382(12):1177-1179.
Chan KH, Peiris JS, Lam SY, Poon LL, Yuen KY, Seto WH: The Effects of Temperature and Relative Humidity on the Viability of the SARS Coronavirus. Advances in virology 2011, 2011:734690.
Bonfanti N, Gundert E, Goff K, Drewry A, Bedimo R, Kulstad E: Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study. medRxiv 2020:2020.2004.2003.20052001.
Copyright (c) 2020 Marcela Mercado-Montoya, Nathaniel Bonfanti, Anne Drewry, Emily Gundert, Roger Bedimo, Victor Kostov, Konstantin Kostov, Shailee Shah, Erik Kulstad
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