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

Nathaniel Bonfanti; Emily Gundert; Kristina Goff; Anne Drewry; Roger Bedimo; Erik Kulstad

Traditionally, fever has been treated because its metabolic costs were felt to outweigh its potential physiologic benefit in an already stressed host. [1] However, increasing data suggest that fever may be a protective adaptive response that should be allowed to run its course under most circumstances. [2, 3] Higher early fever is associated with a lower risk of death among patients with an ICU admission diagnosis of infection. [4, 5] Fever may enhance immune-cell function, [6, 7] inhibit pathogen growth, [8] [9] [10] and increase the activity of antimicrobial drugs. [11] Fever potentially benefits infected patients via multiple mechanisms; in vitro and animal studies have shown that elevated temperatures augment immune function, increase production of protective heat shock proteins, directly inhibit microorganism growth, reduce viral replication, and enhance antibiotic effectiveness. [3, 12] More rapid recoveries are observed from chickenpox, [13] malaria, [14] and rhinovirus [15] infections with avoidance of antipyretic medication, and many innate and adaptive immunological processes are accelerated by fever. [16] [17] [18] Randomized controlled trials have consistently failed to find benefits to treating fever of infectious etiology. [16, [19] [20] [21] [22] [23] [24] A retrospective cohort study evaluating 1,264 patients requiring mechanical ventilation found that high fever (≥39.5°C) was associated with increased risk for mortality in mechanically ventilated patients; however, in patients with sepsis, moderate fever (38.3°C-39.4°C) was protective, and antipyretic medication was not associated with changes in outcome. [25] As recently as the 1910's, the "malaria fever cure" (inducing fever to treat a range of conditions, an approach known as "pyrotherapy") was widespread, with the originator of the idea receiving the Nobel Prize in Medicine or Physiology in 1927. [26, 27] Currently, the UK National Institute for Health and Care Excellence (NICE) recommend not using antipyretic agents "with the sole aim of reducing body temperature in children with fever." [16, 28] Actively inducing hyperthermia by directly heating the body has been used in cancer treatment, with minimal adverse effects. [29] [30] [31] [32] Hyperthermia has been found to have positive impacts on the immune system, causing increased levels of heat-shock proteins, [33, 34] which are directly related to antigen presentation and cross-presentation, activation of macrophages and lymphocytes, and activation and maturation of dendritic cells. [35] A pilot study of external warming of septic patients (ClinicalTrials.gov Identifier: NCT02706275) has recently been completed.