Volume 16 Supplement 2
Is therapeutic hypothermia immunosuppressive?
- Kees H Polderman1
© Polderman; licensee BioMed Central Ltd. 2012
Published: 7 June 2012
The answer to the question in the title of this article would appear obvious. Even the term 'to catch a cold' is partly based on the widely-held assumption that lower temperatures or a chill can decrease the resistance to certain viral infections such as the common cold . Furthermore, a number of studies have clearly demonstrated that inadvertent decreases in temperature in the perioperative setting, and in some other situations, can significantly increase infection risk.
However, the question is not as easy to answer in cases where hypothermia is applied deliberately and with various precautions, which is the case in therapeutic cooling. In these cases potentially harmful responses such as shivering and tachycardia are carefully controlled, body temperatures are not allowed to drop below a predefined setpoint, and every effort is made to prevent side effects [2, 3]. Moreover, even the evidence that hypothermia plays a role in the development of the common cold is mixed, and the few studies performed to address this issue did not support the popular belief that colds are associated with exposure to a cold environment [1, 4].
The relationship between hypothermia and immune function are briefly discussed below.
In vitro studies and animal experiments
In most types of acute brain injury there is a significant and protracted inflammatory response in the hours following the acute event, whether this is ischemic, traumatic, or a combination of both. Proinflammatory mediators such as TNFα and IL-1 are released in large quantities by astrocytes, microglia, and endothelial cells following an episode of ischemia and reperfusion . The levels of these mediators begin to rise around 1 hour after injury and remain elevated for up to 5 days [2, 5, 6]. This in turn stimulates the chemotaxis of activated leucocytes across the blood-brain barrier and leads to an accumulation of inflammatory cells in the injured brain, as well as the emergence of adhesion molecules on leukocytes and endothelial cells. Simultaneously activation of the complement system occurs, beginning in the very early stages after brain injury. This further stimulates the passage of neutrophils and (in later stages) monocytes/macrophages . These inflammatory and immunological responses occur especially during reperfusion and are accompanied by free radical production (see below). These inflammatory responses can cause significant (additional) injury through the phagocytic actions of macrophages, synthesis of toxic products, and further stimulation of immune reactions in a vicious cycle.
Thus it can be argued that, at least in the initial stages of acute brain injury, a hyperinflammatory state exists. As explained in some more detail below hypothermia attenuates this proinflammatory state, but this in itself does not constitute immune suppression. On the other hand, it should be realized that the proinflammatory response outlined above is to some extent physiological; there is evidence suggesting that some inflammatory mediators have neuroprotective properties, although many others are neurotoxic [6–9]. Thus attenuating the response could have protective effects, but also some detrimental ones [2, 8, 9].
On balance there is persuasive evidence suggesting that the production of cytokines and leukocyte infiltration is disproportionate and harmful, and can significantly increase the risk and extent of brain cell injury and infarction [6–15]. Especially, the IL-1 family appears to be important in this regard . The destructive aspects of inflammation appear to outweigh the potential benefits especially in the later stages of injury [2, 6–9]. Thus there is a potential time window for therapeutic interventions to block or mitigate this process before it causes permanent injury.
Many animal experiments and in vitro studies have shown that mild hypothermia can suppress harmful inflammatory reactions that damage potentially viable nerve cells and astrocytes [10–12]. Hypothermia can also decrease production of leukotrienes and nitric oxide, prevent reperfusion-related DNA injury and lipid peroxidation, and impair neutrophil and macrophage function [2, 3]. Thus on balance the protective effects of cooling are likely to outweigh the potential negative effects. However, this does not mean that there are no negative effects, especially if the temperature drops below 32°C. It should be kept in mind that the suppression of inflammatory responses will occur in all organs, not just the injured ones; this is one of the reasons why inhibition of the immune response can lead to increased infection risk. Moreover, the effect is present regardless of whether a local or general hyperinflammatory state exists.
The systemic effect on the immune system can be enhanced by a decrease in the white blood cell count, which can begin at temperatures below 32 to 33°C (although major decreases usually occur only at temperatures below 30 to 31°C). Biggar and coworkers reported a drop in WBC count from 6.0 ± 0.6 to 2.3 ± 0.3 when hypothermia of 29°C was induced in pigs . They did not observe significant changes in the number of circulating mature or immature neutrophils, and reported that neutrophil demargination after administration of intravenous catecholamines was similar at 37°C and 29°C. However, they also observed that administration of corticosteroids and, importantly, of endotoxins failed to stimulate the normal release of neutrophils from the bone marrow . Failure of this response could significantly impact infection risks .
Most of these observations were made in animal experiments, but the hypothermia-induced suppression of the hyperinflammatory responses and decrease in WBC count have been confirmed in clinical reports in humans with traumatic brain injury [10, 11, 17].
Thus the very mechanisms that provide tissue protection could simultaneously impair the patients' ability to fight infections. In addition, lowering body temperature can lead to a decrease in insulin secretion and to induction of insulin resistance [2, 3]. This can lead to hyperglycaemia, which can in turn impair leucocyte function and further increase infection risks. Finally, hypothermia can cause vasoconstriction in the skin, which could increase the risk for bedsores and surgical wound infections.
In summary, based on the in vitro evidence we would expect hypothermia to inhibit the mostly harmful neuroinflammatory response and ameliorate the hyperinflammatory state that occurs after acute injury, but at the price of increasing infection risk.
Clinical studies reporting the infection risks associated with therapeutic cooling in different categories of patients with acute brain injury have produced divergent results; studies in patients who develop accidental hypothermia have mostly reported higher infection risks.
The link between accidental hypothermia in the perioperative setting and a higher incidence of surgical wound infections was first demonstrated by Kurz and coworkers in 1996 , and has since been confirmed in numerous studies in various categories of surgical patients [19–26]. The most recent example is a study by Seamon and coworkers, who found that intraoperative hypothermia (below 35°C) was independently associated with surgical site infection rates after trauma laparotomy . Local factors such as hypothermia-induced vasoconstriction in the skin may add to the underlying immunosuppressive effect to further increase the rate of wound infections. Recently, Laupland and colleagues reported that severe hypothermia (<32°C, but not 32 to 35.9°C) was associated with significant increases in risk for infections acquired in ICU .
The link between hypothermia and infections is far less clear when mild hypothermia is induced under controlled circumstances. Numerous studies in patients with post-hypoxic brain injury following cardiac arrest have not reported significant increases in rates of infections, although some have reported trends in that direction . Seven multicentered trials in newborn babies treated with neonatal asphyxia for 48 to 72 hours also did not report consistent increases in infection risks .
In contrast, clinical studies in patients with ischemic stroke and TBI have tended to find higher risks of infection, especially pneumonia, in patients treated with hypothermia. For example, Hemmen and coworkers reported a rate of pneumonia of 50% in patients with ischemic stroke treated with hypothermia and thrombolysis, compared to 10% in controls . Although the overall outcome was better in hypothermia patients in spite of the high infection rate, this indicates that use of hypothermia in these patients may present significant difficulties.
Some studies using hypothermia in patients with severe traumatic brain injury have also reported high infection rates . There is evidence that this can be prevented by a combination of preventive measures, perhaps including use of antibiotic prophylaxis such as selective decontamination of the digestive tract (SDD) [28, 30, 31].
In one example, Kamps and coworkers reported on their use of prolonged therapeutic cooling to control intracranial pressure in patients with severe traumatic brain injury, in a setting where SDD was routinely used, and reported that infection rates were 20% in patients treated with hypothermia and 34.4% for matched controls . Most notably, the risk of ventilator-associated pneumonia was the same in patients treated with hypothermia compared with matched controls.
Hypothermia impairs immune function and inhibits various inflammatory responses. This is inherent to the treatment, and impairment of harmful inflammatory reactions in the brain may be one of the mechanisms through which hypothermia can exert protective effects. Hypothermia-induced insulin resistance and hyperglycemia may further increase infection risks. In clinical studies, hypothermia has been most clearly linked to infection risk in the context of accidental hypothermia; controlled therapeutic cooling appears to carry a lower risk, especially if hypothermia is used for limited periods of time (<48 hours). The risk appears to increase with prolonged use, and careful monitoring is required in these patients. Prophylactic antibiotics may be considered in high-risk patients who are cooled for prolonged periods.
- Heikkinen T, Järvinen A: The common cold. Lancet. 2003, 361: 51-59. 10.1016/S0140-6736(03)12162-9.View ArticlePubMedGoogle Scholar
- Polderman KH: Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009, 37: S186-S202. 10.1097/CCM.0b013e3181aa5241.View ArticlePubMedGoogle Scholar
- Polderman KH, Herold I: Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med. 2009, 37: 1101-1120. 10.1097/CCM.0b013e3181962ad5.View ArticlePubMedGoogle Scholar
- Douglas RG, Lindgren KM, Couch RB: Exposure to cold environment and rhinovirus common cold: failure to demonstrate effect. N Engl J Med. 1968, 279: 742-747. 10.1056/NEJM196810032791404.View ArticleGoogle Scholar
- Small DL, Morley P, Buchan AM: Biology of ischemic cerebral cell death. Prog Cardiovasc Dis. 1999, 42: 185-207. 10.1016/S0033-0620(99)70002-2.View ArticlePubMedGoogle Scholar
- Schmidt OI, Heyde CE, Ertel W, Stahel PF: Closed head injury - an inflammatory disease?. Brain Res Brain Res Rev. 2005, 48: 388-399.View ArticlePubMedGoogle Scholar
- Asensio VC, Campbell IL: Chemokines in the CNS: plurifunctional mediators in diverse states. Trends Neurosci. 1999, 22: 504-512. 10.1016/S0166-2236(99)01453-8.View ArticlePubMedGoogle Scholar
- Merrill JE, Benveniste EN: Cytokines in inflammatory brain lesions: helpful and harmful. Trends Neurosci. 1996, 19: 331-338. 10.1016/0166-2236(96)10047-3.View ArticlePubMedGoogle Scholar
- Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T: Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002, 8: 101-105. 10.1097/00075198-200204000-00002.View ArticlePubMedGoogle Scholar
- Aibiki M, Maekawa S, Ogura S, Kinoshita Y, Kawai N, Yokono S: Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans. J Neurotrauma. 1999, 16: 225-232. 10.1089/neu.1999.16.225.View ArticlePubMedGoogle Scholar
- Kimura A, Sakurada S, Ohkuni H, Todome Y, Kurata K: Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit Care Med. 2002, 30: 1499-1502. 10.1097/00003246-200207000-00017.View ArticlePubMedGoogle Scholar
- Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, Fujii M, Yamashita S, Maekawa T, Suzuki M: Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma. 2004, 21: 1706-1711. 10.1089/neu.2004.21.1706.View ArticlePubMedGoogle Scholar
- Dietrich WD, Chatzipanteli K, Vitarbo E, Wada K, Kinoshita K: The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma. Acta Neurochir Suppl. 2004, 89: 69-74. 10.1007/978-3-7091-0603-7_9.PubMedGoogle Scholar
- Schoettle RJ, Kochanek PM, Magargee MJ, Uhl MW, Nemoto EM: Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma. 1990, 7: 207-217. 10.1089/neu.1990.7.207.View ArticlePubMedGoogle Scholar
- Patel HC, Boutin H, Allan SM: Interleukin-1 in the brain: mechanisms of action in acute neurodegeneration. Ann NY Acad Sci. 2003, 992: 39-47. 10.1111/j.1749-6632.2003.tb03136.x.View ArticlePubMedGoogle Scholar
- Biggar WD, Bohn D, Kent G: Neutrophil circulation and release from bone marrow during hypothermia. Infect Immun. 1983, 40: 708-712.PubMed CentralPubMedGoogle Scholar
- Ishikawa K, Tanaka H, Shiozaki T, Takaoka M, Ogura H, Kishi M, Shimazu T, Sugimoto H: Characteristics of infection and leukocyte count in severely head-injured patients treated with mild hypothermia. J Trauma. 2000, 49: 912-922. 10.1097/00005373-200011000-00020.View ArticlePubMedGoogle Scholar
- Kurz A, Sessler DI, Lenhardt R, Study of Wound Infection and Temperature Group: Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med. 1996, 334: 1209-1215. 10.1056/NEJM199605093341901.View ArticlePubMedGoogle Scholar
- McAnally HB, Cutter GR, Ruttenber AJ, Clarke D, Todd JK: Hypothermia as a risk factor for pediatric cardiothoracic surgical site infection. Pediatr Infect Dis J. 2001, 20: 459-462. 10.1097/00006454-200104000-00023.View ArticlePubMedGoogle Scholar
- Melling AC, Ali B, Scott EM, Leaper DJ: Effects of preoperative warming on the incidence of would infection after clean surgery: a randomized controlled trial. Lancet. 2001, 358: 876-880. 10.1016/S0140-6736(01)06071-8.View ArticlePubMedGoogle Scholar
- Flores-Maldonado A, Medina-Escobedo CE, Ríos-Rodríguez HM, Fernández-Domínguez R: Mild perioperative hypothermia and risk of wound infection. Arch Med Res. 2001, 32: 227-231. 10.1016/S0188-4409(01)00272-7.View ArticlePubMedGoogle Scholar
- Hedrick TL, Heckman JA, Smith RL, Sawyer RG, Friel CM, Foley EF: Efficacy of protocol implementation on incidence of wound infection in colorectal operations. J Am Coll Surg. 2007, 205: 432-438. 10.1016/j.jamcollsurg.2007.04.042.View ArticlePubMedGoogle Scholar
- Wong PF, Kumar S, Bohra A, Whetter D, Leaper DJ: Randomized clinical trial of perioperative systemic warming in major elective abdominal surgery. Br J Surg. 2007, 94: 421-426. 10.1002/bjs.5631.View ArticlePubMedGoogle Scholar
- Moretti B, Larocca AM, Napoli C, Martinelli D, Paolillo L, Cassano M, Notarnicola A, Moretti L, Pesce V: Active warming systems to maintain perioperative normothermia in hip replacement surgery: a therapeutic aid or a vector of infection?. J Hosp Infect. 2009, 73: 58-63. 10.1016/j.jhin.2009.06.006.View ArticlePubMedGoogle Scholar
- Sumer BD, Myers LL, Leach J, Truelson JM: Correlation between intraoperative hypothermia and perioperative morbidity in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg. 2009, 135: 682-686. 10.1001/archoto.2009.65.View ArticlePubMedGoogle Scholar
- Seamon MJ, Wobb J, Gaughan JP, Kulp H, Kamel I, Dempsey DT: The effects of intraoperative hypothermia on surgical site infection: an analysis of 524 trauma laparotomies. Ann Surg. 2012, doi: 10.1097/SLA.0b013e31824b7e35Google Scholar
- Laupland KB, Zahar JR, Adrie C, Minet C, Vésin A, Goldgran-Toledano D, Azoulay E, Garrouste-Orgeas M, Cohen Y, Schwebel C, Jamali S, Darmon M, Dumenil AS, Kallel H, Souweine B, Timsit JF: Severe hypothermia increases the risk for intensive care unit-acquired infection. Clin Infect Dis. 2012, doi: 10.1093/cid/cir1033Google Scholar
- Polderman KH: Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet. 2008, 371: 1955-1969. 10.1016/S0140-6736(08)60837-5.View ArticlePubMedGoogle Scholar
- Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD, ICTuS-L Investigators: Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010, 41: 2265-2270. 10.1161/STROKEAHA.110.592295.PubMed CentralView ArticlePubMedGoogle Scholar
- Polderman KH, Tjong Tjin Joe R, Peerdeman SM, Girbes AR: Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Med. 2002, 28: 1563-1573. 10.1007/s00134-002-1511-3.View ArticlePubMedGoogle Scholar
- Kamps M, Bisschops LA, van der Hoeven JG, Hoedemaekers CW: Hypothermia does not increase the risk of infection: a case control study. Crit Care. 2011, 15: R48-10.1186/cc10012.PubMed CentralView ArticlePubMedGoogle Scholar
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