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      Hypermetabolism in Critically Ill Patients with COVID-19 and the Effects of Hypothermia: A Case Series

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          Abstract

          Background

          We have observed that critically ill patients with COVID-19 are in an extreme hypermetabolic state. This may be a major contributing factor to the extraordinary ventilatory and oxygenation demands seen in these patients. We aimed to quantify the extent of the hypermetabolic state and report the clinical effect of the use of hypothermia to decrease the metabolic demand in these patients.

          Methods

          Mild hypothermia was applied on four critically ill patients with COVID-19 for 48 hours. Metabolic rates, carbon dioxide production and oxygen consumption were measured by indirect calorimetry.

          Results

          The average resting energy expenditure (REE) was 299% of predicted. Mild hypothermia decreased the REE on average of 27.0% with resultant declines in CO 2 production (VCO 2) and oxygen consumption (VO 2) by 29.2% and 25.7%, respectively. This decrease in VCO 2 and VO 2 was clinically manifested as improvements in hypercapnia (average of 19.1% decrease in pCO 2 levels) and oxygenation (average of 50.4% increase in pO 2).

          Conclusion

          Our case series demonstrates the extent of hypermetabolism in COVID-19 critical illness and suggests that mild hypothermia reduces the metabolic rate, improves hypercapnia and hypoxia in critically ill patients with COVID-19.

          Highlights

          • COVID-19 critical illness induces an extreme hypermetabolic state.

          • Hypothermia attenuates the hypermetabolic response seen in patients with COVID-19.

          • Hypothermia in patients with COVID-19 may improve carbon dioxide and oxygen levels.

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          Most cited references 10

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          Temperature management in cardiac surgery

          Introduction Maintaining a constant core body temperature of 37°C is essential for survival, through maintaining optimal organ, tissue and cellular function. Tight temperature regulation is achieved through a complex, integrated system of thermogenesis and heat loss. Different levels of hypothermia for defined periods of time can be protective. Temperature management during and after cardiac surgery, as well as after accidental hypothermia can have major effects on both immediate and long-term outcome. Through knowledge of the mechanisms of temperature regulation, we can understand its influence of on different vital organ functions in modern cardiac anaesthesia. We here describe mechanisms of thermoregulation, the protective effect of induced hypothermia, detailed techniques and risks of temperature changes during cardiac surgeries . Thermoregulation Thermoregulation involves an extremely sophisticated system of balancing heat production by several organs, and heat loss. Heat production may be classified into shivering and non-shivering components, with each component playing a more dominant role during different physiological and pathological conditions. The different mechanisms of thermoregulation are summarized in Table 1. Heat loss occurs primarily from the skin of a patient to the environment through several processes, including; radiation, conduction, convection and evaporation. Of these processes, radiation is the most significant and accounts for approximately 60% of total heat loss. Radiation is emitted in the form of infrared rays. Heat from core body tissues is transported in blood to subcutaneous vessels, where heat is lost to the environment through radiation. Radiation is the major source of heat loss in most surgical patients. Conduction refers to loss of kinetic energy from molecular motion in skin tissues to surrounding air. Water absorbs far more conducted heat than air, and this accounts for more rapid hypothermia during accidental drowning, as well as the efficacy of water baths to cool hyperthermic patients. For this to be effective, warmed air or water must be moved away from the skin surface by currents in a process called convection. This accounts for the cooling effect of wind and laminar air flow in many surgical suites. Conduction and convection account for ∼15% of body heat loss. Approximately 22% of heat loss occurs by evaporation, as energy in the form of heat is consumed during the vaporization of water. Water evaporates from the body even when the body is not sweating, but mechanisms that enhance sweating increase evaporation. As long as the skin temperature is greater than its surroundings, radiation and conduction provide heat loss. At very high environmental temperatures, these processes cannot work and evaporation is the only manner in which heat can be dissipated. This generally is not the case in clinical settings. Skin temperature rises and falls with the temperature of a patient's surroundings. However, the core temperature remains relatively constant. This is due to a remarkable thermoregulatory system that is conventionally organized into three components: afferent sensing, central control and efferent responses (Figure 2). 1 Afferent sensing and central control: Some integration and temperature regulation may occur at the spinal cord level. However, the hypothalamus is the primary control center for thermoregulatory as it integrates most afferent input and coordinates the various efferent outputs required to maintain a normothermic level. Efferent response: As temperature receptors transmit information to the hypothalamus, this information is integrated and compared with threshold settings. Values above or below these thresholds determine the generated efferent response. Efferent outputs from the hypothalamus regulate body temperature by altering subcutaneous blood flows, sweating, skeletal muscle tone and overall metabolic activity. Heat loss is promoted by vasodilatation and sweating, while heat is conserved by inhibiting these processes. Production of heat (thermogenesis) is promoted by shivering and increases the overall metabolic rate (Figure 3). Temperature inputs to the hypothalamus are integrated and compared with threshold temperatures that trigger appropriate thermoregulatory responses. Normally these responses are initiated at as little as 0.1°C above and below normal body temperature of 37 °C. Therefore, the difference between temperatures that initiate sweating versus those initiating vasoconstriction is only 0.2°C. This is defined as the ‘interthreshold range’ and represents the narrow range at which the body does not initiate thermoregulatory efforts. General anesthesia and thermogenesis: Causes for inadvertent hypothermia include patients' exposure to a cold environment and the inability to initiate behavior responses. Volatile anesthetics, propofol, and older opioids such as morphine and meperidine promote heat loss through vasodilation. This process is compounded further by the fact that these drugs, as well as fentanyl and its derivatives, directly impair hypothalamic thermoregulation in a dose-dependent manner. Opioids also depress overall sympathetic outflow, which further inhibits any attempts at thermoregulation. The depressant effect on the hypothalamus results in an elevated threshold for heat response, along with a diminished threshold for cold response such as vasoconstriction and shivering. Therefore, opioids widen the normal interthreshold range from ∼0.2°C to as much as 4°C, 2 and patients are unable to adjust to cold environments and heat loss resulting from vasodilation. 1 It is notable that nitrous oxide depresses thermoregulation to a lesser extent than equipotent concentrations of the volatiles, and midazolam has minimal or no influence. 3 This should be true for other benzodiazepines as well. 2,3 Following induction of general anesthesia, the decline in body temperature occurs in three phases. The greatest decline occurs during the first half hour or phase 1. Normally body heat is maintained in an unevenly distributed manner; the temperature of core tissues is 2°C to 4°C greater than skin temperature. Following anesthesia induction, however, vasodilation combined with a lowered cold threshold in the hypothalamus allows a redistribution of body heat from core tissues to skin, where heat is lost primarily through radiation. Phase 2 commences after approximately 1 h, as core temperature decreases at a slower rate and proceeds in a linear manner as heat lost from the body exceeds heat production. Finally, after 3 to 5 h, phase 3 commences, as equilibrium is reached where heat loss is matched by heat production and thermoregulated vasoconstriction commences to function (Figure 4). 1–3 Perioperative temperature monitoring: Temperature monitoring devices vary according to the type of transducer used and the site to be monitored. The most commonly used transducers are thermistors and thermocouples. A more recent development is the use of monitors that emit infrared to measure temperature; these monitors are commonly found in aural canal thermometers, which are often referred to as tympanic membrane thermometers. Liquid crystal sensors also can be used to measure skin temperature. Core temperature is the best single indicator of body temperature. Therefore, all noncore temperature-monitoring sites need to be judged by their ability to accurately assess core temperature. Core temperature monitoring is appropriate for most patients undergoing general anesthesia, to facilitate detection and treatment of fever, malignant hyperthermia, and hypothermia. Monitoring sites: 1- Pulmonary artery catheter (PAC): PAC thermistor is located at the tip of the distal end allowing measurement of central blood temperature. Although it is the gold standard for core temperature measurement, 4 it is not used routinely due to numerous drawbacks including invasiveness and cost effectiveness. 2- Oesophageal temperature: This is usually monitored with a thermistor or thermocouple that is incorporated into an esophageal stethoscope. Oesophageal temperature accurately reflects core temperature in almost all conditions. These readings, however, can be artificially affected during general anesthesia by the use of humidified gases if the probe is not inserted far enough. 5,6 The optimal position for the sensor in adults is approximately 45 cm from the nose, which is 12 to 16 cm distal from where the heart and breath sounds are heard best. 7 More proximal positioning can result in falsely decreased temperatures as a result of the proximity to the trachea and the impact of cold, dry gases on the site. 6 Esophageal temperature probes are used frequently for their ease of placement and relatively minimal risk, and because the site is reliable. 3- Nasopharyngeal temperature: Nasopharyngeal temperature can be measured with an esophageal probe positioned above the palate, and it is close to brain and core temperature. 8 4- Tympanic membrane temperature: Because the eardrum is close to the carotid artery and the hypothalamus, tympanic membrane temperature is a reliable measure of core temperature and often is used as a reference for other sites. This measurement requires that a transducer be placed in contact with the tympanic membrane. 5- Bladder temperature: Bladder temperature is measured with a Foley catheter and attached temperature thermistor or thermocouple. Although bladder temperature is a close approximation of core temperature, the accuracy of this site decreases with low urine output and during surgical procedures of the lower abdomen. 9 6- Rectal temperature: Rectal temperature measurement is another site that approximates core temperature, but these readings may be affected by the presence of stool and of bacteria that generate heat. 10 Consequently, rectal temperature tends to exceed core temperature. Rectal and bladder temperatures lag behind other central monitoring sites during conditions in which the temperature changes rapidly such as cardiopulmonary bypass surgery. 7- Skin temperature: Intraoperative skin temperature monitoring is confounded by several factors; Core-to-peripheral redistribution which may be seen on anesthetic induction, thermoregulatory changes in vasomotor tone triggered when sufficient core hypothermia initiates intraoperative cutaneous vasoconstriction which can lead to a reduction in skin blood flow and temperature, and finally changes in ambient temperature. 8- Axillary temperature: Axillary temperatures are relatively close to core temperature and may be a reasonable choice in selected patients. However, its accuracy is questionable unless the probe is positioned carefully over the axillary artery and the arms positioned at the patient's side. 11 Hypothermia as a cytoprotective strategy Hypothermia had demonstrated potential benefits in myocardial infarction, organ transplantation, cardiopulmonary bypass (CPB), spinal cord injury (SCI), intestinal ischemia, and neonatal hypoxic ischemia. 12 Understanding how hypothermia can be of benefit is not simple as its action is mediated through complex systemic and cellular changes; moreover, such changes can vary widely depending on underlying pathological and metabolic condition. However, examples from nature have indicated that physiological hypothermia could be observed in species that normally hibernate. In these animals, body temperature and metabolism drops in a manner as that observed when intentional hypothermia is applied. 12 Hypothermia can be classified based on the depth of cooling from a normal body temperature of 37-38°C: mild hypothermia (32-35°C), moderate hypothermia (28-32°C) and deep hypothermia (  36°C). Hypothermic versus normothermic CPB: Hypothermic CPB had become an established practice for adult cardiac surgery by the late 1960s, and constituted the largest part of the surgical practice at most institutions until the reintroduction of warm CPB in early 1990s. 108 A systematic review of benefits and risks of maintaining normothermia during CPB among adults undergoing cardiac surgery had been published 109 and demonstrated no benefit of hypothermia during CPB in regard to mortality, risk of stroke, cognitive decline, atrial fibrillation, use of inotropic support or intra-aortic balloon pump, myocardial infarction, all cause infections, and acute kidney injury after cardiac surgery were comparable. Moreover, hypothermic bypass was associated with an increased risk of allogeneic red blood cells, fresh frozen plasma, and platelet transfusion. The authors concluded that “maintaining normothermia during cardiopulmonary bypass in adult cardiac surgery is as safe as that of hypothermic surgery, and associated with a reduced risk of allogeneic blood transfusion”. 109 This systemic review supports earlier trials in such field where normothermic CPB and warm cardioplegia were concomitantly used during adult cardiac surgery. 110–112 On the other hand, arguments for hypothermic CPB techniques are still favored due to its effectiveness in reducing O2 demand and in increasing ischemic tolerance: these arguments have been established a long time ago. 62,113 Moreover, other argued that the reduction in metabolic rate associated with hypothermia would also allow for the use of reduced CPB flows. 51 Finally, as hypothermia requires haemodilution as hypothermia with whole blood prime results in hypertension during CPB, the introduction of hypothermia is of crucial importance in decreasing strain on blood bank resources. 114 Total aortic arch replacement (TARCH) is generally performed with hypothermic circulatory arrest (HCA) at 15-22°C plus selective cerebral perfusion (SCP) in an attempt to minimize neuropsychological morbidities associated with this type of surgery. However, the cooling and rewarming phases of HCA are time-consuming, and the complications due to prolonged cardiopulmonary bypass (CPB) remain a serious problem. Moreover, there is great controversy regarding optimal perfusion temperature and flow for SCP and the safe time limit for HCA. In a recent trial, the safety and efficacy of TARCH with deep HCA (at the lowest rectal temperatures of 20-25°C) was compared with TARCH with tepid HCA (32 °C), retrospectively. Twenty-seven patients (group C) who underwent TARCH with deep hypothermia at the lowest rectal temperatures of 20-25°C were compared with 23 patients (group W), who underwent TARCH with 32°C tepid hypothermia. Circulatory arrest time, cardiopulmonary bypass time, operating time, amount of blood transfused and postoperative neurological complications were significantly reduced in group W compared with group C. 115 Temperature management during off pump surgeries: In OPCAB surgery, a patient's temperature is influenced by the same environmental sources of heat loss that many other non-CPB surgical patients encounter. Additionally, because of an open thorax and extremities exposed for vascular conduit harvest, maintaining normothermia can be difficult. Although the optimal temperature during OPCAB is not clearly known, efforts to maintain normothermia are generally instituted and normothermia has been considered a goal, particularly to aid in the timely extubation of these patients. These efforts include maintaining an elevated ambient operating room temperature, warming ventilated gases and intravenous fluids, water blankets, and forcing warm convective air over non exposed portions of the body. Potential benefits of maintaining normothermia had been thoroughly discussed and can be summarized as: maintenance of normothermia, rather than hypothermia, may facilitate early tracheal extubation. Hypothermia alters the distribution and decreases the metabolism of most drugs, including anesthetic drugs and muscle relaxants, thus prolonging recovery. Postoperative shivering increases metabolic rate and potentially lead to myocardial ischemia; coagulopathies, increased incidence of surgical wound infection, and perioperative cardiac morbidity are other potential risk factors. 116 Normothermia is proved to be associated with better cardiac and vascular conditions, a lower cardiac injury rate, and a lower inflammatory response. The close correlation between the increased interleukin-6 and troponin-I levels indicates a potential deleterious effect of lowered temperature on the patient's outcome. 117 During off-pump coronary artery bypass grafting, hypothermia increases vasoconstriction, myocardial after load, coagulopathy and postoperative bleeding. 118 Woo and colleagues 118 demonstrated that during off-pump coronary artery bypass grafting, hypothermia increases vasoconstriction, myocardial after load, coagulopathy and postoperative bleeding. On the other hand, a prospective randomized study to evaluate the effect of fluid warming using Hotline™ system during off-pump coronary artery bypass (OPCAB) surgery demonstrated no significant differences between the 2 thermal management groups in hemodynamic parameters, serum catecholamine concentrations, duration of intensive care unit stay, or duration of ward stay though warming IV fluids with Hotline™ system was capable in preventing hypothermia. 119 Again, it is obvious that the optimal temperature during OPCAB is not known. Efforts to maintain normothermia are generally appreciated, however no insights regarding whether temperature management during such procedure can positively influence patient outcome. Active thermal manipulations It is well known that initial 0.5–1.5°C reduction in core temperature is difficult to prevent because it results from redistribution of heat from the central thermal compartment to cooler peripheral tissues. 120 Even the most effective clinical warmers do not prevent hypothermia during the first hour of anesthesia. 120,121 Although redistribution cannot effectively be treated, it can be prevented. Redistribution results when anesthetic induced vasodilatation allows heat to flow peripherally down the normal temperature gradient. Skin surface warming before induction of anesthesia does not significantly alter core temperature (which remains well regulated), but it does increase body heat content. When peripheral tissue temperature is sufficiently increased, little redistribution hypothermia occurs. 122,123 Airway heating and humidification: Simple thermodynamic calculations indicate that less than 10% of metabolic heat production is lost via the respiratory tract. Because little heat is lost via respiration, even active airway heating and humidification minimally influence core temperature. 124 Consequently, airway heating and humidification are even less effective than usual in patients in most need of effective warming. Airway heating and humidification are more effective in infants and children than in adults, 125 but cutaneous warming also is more effective in these patients and transfers more than ten times as much heat. Hygroscopic condenser humidifiers and heat-and-moisture exchanging filters (“artificial noses”) retain substantial amounts of moisture and heat within the respiratory system. In terms of preventing heat loss, these passive devices are about half as good as active systems, however their costs are much affordable compared to other active systems. Warm intravenous fluids: It is not possible to warm patients by administering heated fluids, because the fluids cannot (much) exceed body temperature. On the other hand, heat loss resulting from cold IV fluids becomes significant when large amounts of crystalloid solution or blood are administered. One unit of refrigerated blood or one litre of crystalloid solution administered at room temperature decreases mean body temperature more than 0.25°C. Fluid warmers minimize these losses and should be used when large amounts of IV fluid or blood are administered. Most warmers allow fluid to warm in the tubing between the heater and the patient. Cutaneous warming: Operating room temperature is the most critical factor influencing heat loss, because it determines the rate at which metabolic heat is lost by radiation and convection from the skin and by evaporation from within surgical incisions. Consequently, increasing room temperature is one way to minimize heat loss. However, room temperatures exceeding 23°C are generally required to maintain normothermia in patients undergoing all but the smallest procedures 126 as most operating room personnel find such temperatures uncomfortably warm. Infants may require ambient temperatures exceeding 26°C to maintain normothermia. Such temperatures are sufficiently high to impair performance of operating room personnel. The easiest method of decreasing cutaneous heat loss is to apply passive insulation to the skin surface. Insulators readily available in most operating rooms include cotton blankets, surgical drapes, plastic sheeting, and reflective composites (space blankets). A single layer of insulators reduces heat loss by approximately 30 percent; moreover, there are no clinically important differences among the insulation types. 127 The reduction in heat loss from all commonly used passive insulators is similar because the layer of still air trapping beneath the covering provides most of the insulation. Consequently, adding additional layers of insulation further reduces heat loss only slightly. 128 These data indicate that simply adding additional layers of passive insulation or warming the insulation before application usually is insufficient in patients who become hypothermic while covered with a single layer of insulation. Cutaneous heat loss is roughly proportional to surface area throughout the body. 129 Consequently, the amount of skin covered is more important than which surfaces are insulated. Passive insulation alone rarely is sufficient to maintain normothermia in patients undergoing large operations. Active warming is required in those cases. Because about 90% of metabolic heat is lost via the skin surface, only cutaneous warming transfers sufficient heat to prevent hypothermia. Consequently, for intraoperative use, circulating-water and forced-air devices are the two major systems requiring consideration. Studies consistently report that circulating-water mattresses are nearly ineffective. 130 Circulating water is more effective, and safer, when placed over patients rather than under them, and in that position, it can almost completely eliminate metabolic heat loss. 131 The forced air warming device is the most effective method to maintain temperature during most surgical procedures. 120,132,133 These devices are able to maintain normothermia even in patients undergoing large surgical procedures, and if employed in the intraoperative period, they increase central temperature by almost 0.75°C/hour. 120 Malignant hyperthermia in cardiac surgery The underlying mechanism for malignant hyperthermia (MH) is uncontrolled release of calcium from the sarcoplasmic reticulum triggered by volatile anesthetics and depolarizing muscle relaxants. 134 This exaggerated intracellular calcium release in MH-susceptible skeletal muscle leads to large increases in aerobic and anaerobic metabolism as the muscle cells attempt to re-establish homeostasis by sequestering unbound calcium. 135 However, in MH-susceptible muscle, the rise in calcium caused by the triggering agents overwhelms the cellular capacity to re-establish homeostasis. The pathologically enhanced intracellular calcium rise eventually reaches the threshold levels for myofibrillar contraction and muscular rigidity begins. This leads to increased oxygen consumption and increased carbon dioxide production. Heat is generated with rising lactic acid levels. Rhabdomyolysis ensues with leakage of muscle cell contents into the circulation. 134–136 In case an MH episode is suspected, all triggering agents should be discontinued immediately and anesthesia should be changed to total intravenous anesthesia. 137 Help should be called as early as possible. Hyperventilation with a high fresh gas flow (>10 l/min) should be started and treatment with a bolus of dantrolene at 2.5 mg/kg initiated. 138 The initial bolus of dantrolene (2.5 mg/kg) should be repeated until clinical signs and acidosis subside. 139 Cooling measures need to be started (e.g., placing ice packs on the groin, axillae and neck) and maintained until the temperature of the patient is below 38.5°C. 135 Urine output of at least 2 ml/kg/h should be targeted. 136 There are only a few reports of surgery with CPB and MH. Those reports suggest the use of non-triggering agents and careful management of temperature changes in the intra- and postoperative period, specifically during rewarming. 140,141 In patients with a presumptive history of MH undergoing cardiac surgery, normothermic CPB and off-pump surgery are alternatives that should be considered individually. Conclusion: Temperature is a physiologic variable that can be manipulated to suit the requirements of a particular management strategy according to patients' preoperative risk factors. Because of its profound physiologic and pathophysiologic implications, temperature is a crucial homeostatic variable, particularly in the setting of cardiac surgery during which significant changes in temperature can occur. A debate has emerged in recently published studies about the optimum cardiopulmonary bypass temperature for good outcome (normothermic vs. hypothermic). The ideal temperature for CPB is probably an indeterminate value that varies with the physiological goals. The choice of CPB temperature will always be a compromise between competing goals. To date, there has been a lack of evidence regarding the optimal temperature management strategy during cardiopulmonary bypass. Thus, temperature management strategies during CPB rely primarily on personal or institutional preference, rather than a solid scientific basis.
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            Effects of induced hypothermia in patients with septic adult respiratory distress syndrome.

            To test the hypothesis that treatment with hypothermia affects the course of overwhelming acute respiratory failure associated with sepsis.
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              Is Open Access

              The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines for Cardiopulmonary Bypass—Temperature Management during Cardiopulmonary Bypass

              Abstract: To improve our understanding of the evidence-based literature supporting temperature management during adult cardiopulmonary bypass, The Society of Thoracic Surgeons, the Society of Cardiovascular Anesthesiology and the American Society of ExtraCorporeal Technology tasked the authors to conduct a review of the peer-reviewed literature, including 1) optimal site for temperature monitoring, 2) avoidance of hyperthermia, 3) peak cooling temperature gradient and cooling rate, and 4) peak warming temperature gradient and rewarming rate. Authors adopted the American College of Cardiology/American Heart Association method for development clinical practice guidelines, and arrived at the following recommendation.
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                Author and article information

                Contributors
                Journal
                Metabol Open
                Metabol Open
                Metabolism Open
                Published by Elsevier Inc.
                2589-9368
                26 July 2020
                26 July 2020
                Affiliations
                Division of Cardiovascular and Thoracic Surgery, North Shore University Hospital, Northwell Health, 300 Community Drive, 1DSU, Manhasset, NY, 11030
                Author notes
                []Corresponding author. Division of Cardiovascular and Thoracic Surgery North Shore University Hospital, 300 Community Drive, Manhasset, NY, 11030 Tel.: +1 (516) 562 4970; fax: +1 (516) 562 3786 pyu2@ 123456northwell.edu
                Article
                S2589-9368(20)30026-8 100046
                10.1016/j.metop.2020.100046
                7382710
                © 2020 Published by Elsevier Inc.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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