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Mechanisms of action, physiological effects, and complications ofhypothermia

Kees H. Polderman, MD

W hen applying hypother-mia in a clinical setting, itis important to be awareof the underlying mecha-

nisms through which the treatment ex-erts its effects. Understanding these is-sues can help guide clinical decisionsregarding the required depth and dura-tion of the treatment, and help in under-standing physiological changes and sideeffects occurring during mild (34°C–35.9°C), moderate (32°C–33.9°C), mod-

erate-deep (30°C–31.9°C), and deep(�30°C) hypothermia (1). Insufficientunderstanding of these mechanisms islikely to decrease therapeutic efficacy,and can at worst lead to treatment fail-ure. This is illustrated by early experi-ences with induced hypothermia in thetreatment of cardiac arrest and traumaticbrain injury (TBI), and other indicationsin the 1940s, 1950s, and 1960s (2–15). Atthat time, it was presumed that hypother-mia exerted its effects exclusivelythrough temperature-dependent reduc-tions in metabolism, leading to decreaseddemand for oxygen and glucose in thebrain. Patients were routinely treatedwith deep hypothermia (�30°C), basedon the (erroneous) assumption that thiswas the sole mechanism of action, andthat large reductions in temperaturewere required to achieve efficacy. In ad-dition, core temperatures that were actu-ally achieved varied considerably both be-tween patients and within the same

patient, because the available cooling andrewarming methods were not very reli-able. The most frequently used coolingmethods were placement of slabs of ice,ice pads, and refrigerated water on thepatient’s skin, and sometimes the open-ing of windows of the hospital wards dur-ing the winter months (to the disconcert-ment of some members of the medicaland nursing staff) (11). Because intensivecare facilities did not become widelyavailable until the early 1960s, the treat-ment initially had to be applied in generalwards (2–11). Duration of cooling variedconsiderably, ranging from 2 to 3 days toup to 10 days.

Despite this lack of well-controllablecooling methods and the use of temper-atures �30°C (with a much greater riskfor severe side effects compared withtemperatures �30°C), many of thesestudies reported benefits compared with“expected outcome” or historical controls(2–11). However, these benefits were

From the Clinical Research, Investigation, and Sys-tems Modeling of Acute Illness (CRISMA) Laboratory,Department of Critical Care Medicine, University ofPittsburgh School of Medicine, Pittsburgh, UnitedStates.

The author has not disclosed any potential con-flicts of interest.

For information regarding this article, E-mail:[email protected] or [email protected]

Copyright © 2009 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3181aa5241

Background: Mild to moderate hypothermia (32–35°C) is thefirst treatment with proven efficacy for postischemic neurologicalinjury. In recent years important insights have been gained intothe mechanisms underlying hypothermia’s protective effects; inaddition, physiological and pathophysiological changes associ-ated with cooling have become better understood.

Objective: To discuss hypothermia’s mechanisms of action, toreview (patho)physiological changes associated with cooling, andto discuss potential side effects.

Design: Review article.Interventions: None.Main Results: A myriad of destructive processes unfold in

injured tissue following ischemia–reperfusion. These include ex-citotoxicty, neuroinflammation, apoptosis, free radical production,seizure activity, blood–brain barrier disruption, blood vessel leak-age, cerebral thermopooling, and numerous others. The severityof this destructive cascade determines whether injured cells willsurvive or die. Hypothermia can inhibit or mitigate all of thesemechanisms, while stimulating protective systems such as earlygene activation. Hypothermia is also effective in mitigating intra-cranial hypertension and reducing brain edema. Side effectsinclude immunosuppression with increased infection risk, colddiuresis and hypovolemia, electrolyte disorders, insulin resis-

tance, impaired drug clearance, and mild coagulopathy. Targetedinterventions are required to effectively manage these side ef-fects. Hypothermia does not decrease myocardial contractility orinduce hypotension if hypovolemia is corrected, and preliminaryevidence suggests that it can be safely used in patients withcardiac shock. Cardiac output will decrease due to hypothermia-induced bradycardia, but given that metabolic rate also decreasesthe balance between supply and demand, is usually maintained orimproved. In contrast to deep hypothermia (<30°C), moderatehypothermia does not induce arrhythmias; indeed, the evidencesuggests that arrhythmias can be prevented and/or more easilytreated under hypothermic conditions.

Conclusions: Therapeutic hypothermia is a highly promisingtreatment, but the potential side effects need to be properlymanaged particularly if prolonged treatment periods are required.Understanding the underlying mechanisms, awareness of physi-ological changes associated with cooling, and prevention of po-tential side effects are all key factors for its effective clinicalusage. (Crit Care Med 2009; 37[Suppl.]:S186–S202)

KEY WORDS: hypothermia; normothermia; fever; mechanisms;neuroprotection; side effects; neurological injury; cardiac arrest;traumatic brain injury

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variable and uncertain, and as is to beexpected there were significant problemsin patient management. In the late 1960s,interest among clinicians in therapeuticusage of hypothermia seems to have sim-ply fizzled out; there is a 38-yr gap be-tween the publication of the first two caseseries describing use of hypothermia incardiac arrest patients and the next study(8, 9, 16). These experiences illustrate thedifficulties that can be encountered dur-ing use of controlled hypothermia.

Interest in cooling was rekindled inthe early 1980s by the positive resultsfrom numerous animal experiments,some of which are discussed below. Manyimportant insights regarding effectiveuse of hypothermia and the mechanismsunderlying its protective effects weregained at that time. An important break-through was the realization that neuro-logical outcome could be improved byusing mild to moderate hypothermia(31°C–35°C) rather than deep hypother-mia (�30°C), with far fewer and less se-vere side effects. The basis for this newinsight was the observation that the pro-tective effects of hypothermia were not(at least not exclusively or mainly) due todecreased oxygen and glucose consump-tion in the brain. Indeed, the mecha-nisms involved are far more complex.

A cascade of destructive events andprocesses begins at the cellular level inthe minutes to hours following an initialinjury. The injury can be ischemic ortraumatic. Ischemia may be induced byobstruction of a blood vessel, by pressure/edema, or by other mechanisms. This de-structive cascade is similar regardless ofthe cause, although there are differencesin regard to how long the cascade is sus-tained. These processes—which havebeen collectively described in terms suchas postresuscitation disease, reperfusioninjury, and secondary brain injury—maycontinue for hours to many days after theinitial injury and can be retriggered bynew episodes of ischemia (17).

A key point is that all of these pro-cesses are temperature dependent; theyare all stimulated by fever, and can all bemitigated or blocked by mild to moderatehypothermia. The wide-ranging effects ofhypothermia may explain why it hasproved to be clinically effective, whereasstudies with agents that affect just one ofthe destructive processes have been farless successful (18–22).

The second important developmentwas the advent of intensive care units(ICUs) to care for critically ill patients.

The side effects of hypothermia can be farmore easily managed in this setting, andthe methods for inducing and maintain-ing hypothermia have improved signifi-cantly since the 1950s. These new in-sights and improvements in facilitieshave set the stage for a successful come-back of hypothermia as a clinical treat-ment.

Studies on mechanisms underlyinghypothermia’s protective effects point tofour key factors determining success orfailure of cooling treatment. These are:

● Speed of induction of hypothermia;outcomes in animal experiments arefar better when cooling is initiated rap-idly after injury.

● Duration of cooling (depending on theseverity of the initial injury and thetime interval until target temperatureis reached).

● Speed of rewarming (this should beslow lest the destructive processes bereinitiated; this happens frequently ifrewarming speeds are high).

● Proper management and prevention ofside effects.

The equation is complicated by thefact that the relative contributions of dif-ferent mechanisms to the ongoing injurymay differ. There may be differences be-tween various types of injury (e.g., trau-matic vs. purely postischemic), betweendifferent patients (depending on geneticfactors, comorbidities, gender, etc.), andeven within the same patient over time.Thus, the available windows of opportu-nity for therapeutic interventions such ashypothermia may vary, and the same mayapply to the required duration for thecooling treatment to be (fully) effective.For all these reasons, a better under-standing of underlying mechanisms mayhelp us to better target our treatments,and help improve outcome.

Many of the available data come fromanimal experiments; translating these re-sults into clinical practice poses somelimitations. Firstly, the relative impor-tance of injury mechanisms may differbetween humans and animals, and alsobetween different animal species. Thus, ifa specific treatment decreases the degreeof histological brain damage in a specificarea in rats, this treatment may have sim-ilar histological effects in humans butmay not make a clinically significant dif-ference in outcome (23, 24). Secondly,some treatments may target specific de-structive mechanisms playing a central

role in injury development in a particularanimal model, whereas this particularmechanism is far less important in hu-mans (25–27). Such a treatment wouldbe highly effective in that animal model,but would prove far less effective in aclinical trial.

Such differences may result in overes-timation of the potential positive effectsof hypothermia; the brains of some ani-mals, especially small animals such asrodents, appear to be more responsive toneuroprotection than the human brain(28, 29). On the other hand, protectiveeffects may also be underestimated whenlooking at only one mechanism and/oronly one animal model. For example,many animal studies have focused on theso-called neuroexcitotoxic cascade,which is central to the development ofpostischemic injury in many primitivemammalian animal models (mice, guineapigs, rats, etc.). This mechanism playsout within relatively short time frames,[�2 hrs or less] (25–30). However, clini-cal studies in cardiac arrest patients havereported significant improvements inoutcome even when induction of hypo-thermia was delayed for up to 8 hrs (17);this indicates that other, more protractedmechanisms must play a role in deter-mining outcome in human brain injury.Thus, focusing exclusively on neuroexcito-toxicity would significantly underestimatethe available time window for application ofhypothermia.

Nevertheless, in spite of such limita-tions there is much that we can learnfrom animal experiments, in particular ifa treatment has shown value in morethan one animal model and/or in pri-mates (orangutans, chimpanzees, etc.).What we have learned regarding ischemia–reperfusion and posttraumatic injuries,and the protective effects of hypothermia,is summarized in Figure 1 and are nowdiscussed in more detail.

Underlying Mechanisms,Physiological Sequelae, andConsequences for PatientManagement

Decrease in Cerebral Metabolism.When hypothermia was first used in aclinical setting it was presumed that itsprotective effects were due purely to aslowing of cerebral metabolism, leadingto reduced glucose and oxygen consump-tion. Indeed this assumption is not com-pletely incorrect: Cerebral metabolismdecreases by 6% to 10% for each 1oC

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reduction in body temperature duringcooling (27, 29, 31–35). Early studies at-tempted to reduce metabolism as far aspossible by using deep hypothermia(�30°C). Our current understanding isthat a reduction in metabolic rate is onlyone of many mechanisms underlying hy-pothermia’s protective effects.

Physiological Consequences and Pa-tient Management. When core tempera-ture drops to 32°C, the metabolic ratedecreases to 50% to 65% of normal; ox-ygen consumption and CO2 productionwill decrease by the same percentage. Ifventilator settings are left unchanged thiswill lead to hyperventilation, with poten-tially adverse consequences such as cere-bral vasoconstriction (36, 37). The de-crease in oxygen consumption willincrease oxygen levels in the blood, pos-ing a (theoretical) risk during reperfusionbecause high oxygen levels may increasereperfusion injury (38). Therefore, venti-lator settings should be adjusted as tem-perature decreases, and frequent checksof blood gasses are necessary especially inthe induction phase. During mainte-nance the feeding rate should also beadjusted to reflect lower metabolic de-mands.

Other metabolic changes include in-creased fat metabolism, leading to an in-crease in the levels of glycerol, free fattyacids, ketonic acids, and lactate. This inturn can cause mild metabolic acidosis.

This phenomenon does not require treat-ment; pH rarely decreases below 7.25,and the drop in extracellular pH is notreflected in intracellular pH, which in-creases slightly under hypothermic con-ditions (33).

Another consequence of hypothermiais decreased insulin secretion and, inmany patients, a moderate (and some-times severe) insulin resistance. This canlead to hyperglycemia and/or a significantincrease in doses of insulin required tomaintain glucose levels within an accept-able range. This temperature-dependenceof insulin requirements is particularlyimportant in the rewarming phase, wheninsulin sensitivity may increase rapidly,leading to hypoglycemia if insulin dosesare not decreased. Thus, glucose levelsshould be checked frequently particularlyduring rewarming and, to a lesser extent,the induction phase of hypothermia (1).For this and other reasons, rewarmingrates following hypothermia treatmentshould be slow and controlled. In ourunit the target rewarming rate is0.25°C/hr for postcardiac arrest patientsand 0.1°C/hr for patients following severeTBI.

Apoptosis, Calpain-Mediated Proteol-ysis and Mitochondrial Dysfunction. Fol-lowing a period of ischemia and reperfu-sion, cells can become necrotic, fully orpartially recover, or enter a path leadingto so-called apoptosis or programmed cell

death. Whether apoptosis will develop isdetermined by cellular processes such asmitochondrial dysfunction, other disor-ders in cellular energy metabolism, andrelease of so-called caspase enzymes. Nu-merous studies have shown that hypo-thermia can interrupt the apoptotic path-way, thereby preventing cellular injuryfrom leading to apoptosis (39–43). Hypo-thermia seems to affect mainly the earlystages of the apoptotic process and apo-ptosis initiation (40). Its effects includeinhibition of caspase enzyme activation(39–41, 43, 44), prevention of mitochon-drial dysfunction (42), decreased overloadof excitatory neurotransmitters, andmodification of intracellular ion concen-trations. (The latter mechanisms are dis-cussed in more detail below.)

Apoptosis begins relatively late in thepostperfusion and/or posttrauma phase,while continuing for a period of 48 to 72hrs or even longer (43–45). Thus, apo-ptosis is one of the mechanisms that canbe mitigated (and perhaps even pre-vented) for some time after injury, pro-viding (at least in theory) a wide windowof opportunity for therapeutic interven-tions such as hypothermia. For this andother reasons, influencing apoptoticpathways could play an important role inproviding neuroprotection and in miti-gating postresuscitation injury in hu-mans.

Ion Pumps and Neuroexcitotoxicity. Alarge body of evidence suggests that hy-pothermia inhibits harmful excitatoryprocesses occurring in brain cells duringischemia–reperfusion. Levels of high-energy metabolites such as adenosinetriphosphate and phosphocreatine de-crease within seconds when oxygen sup-ply to the brain is interrupted (27). Thebreakdown of adenosine triphosphate andthe switch of intracellular metabolism toanaerobic glycolysis lead to an increase inintracellular levels of inorganic phosphate,lactate, and H�, resulting in both intra- andextracellular acidosis and an influx of cal-cium (Ca2�) into the cell. Loss of adenosinetriphosphate and acidosis also inhibits themechanisms that normally deal with exces-sive intracellular Ca2� by sequesteringCa2� from the cell, further aggravating in-tracellular Ca2� overload. These problemsare compounded by failure of adenosinetriphosphate–dependent Na�-K� pumpsand K�, Na�, and Ca2� channels, leadingto an additional influx of Ca2� (46). Theexcess Ca2� induces mitochondrial dys-function (increasing intracellular calciuminflux yet further, in a vicious cycle) and

Figure 1. Schematic depiction of the mechanisms underlying the protective effects of mild tomoderate hypothermia. TxA2, thromboxane A2.


activates numerous intracellular enzymesystems (kinases and proteases). In addi-tion, immediate early genes are activatedand a depolarization of neuronal cell mem-branes occurs, with a release of largeamounts of the excitatory neurotransmitterglutamate into the extracellular space (25).This leads to prolonged and excessive acti-vation of membrane glutamate receptors,further stimulating Ca2� influx throughactivation of Ca2� channels in another vi-cious cycle. Under normal circumstances,neurons are exposed to only very briefpulses of glutamate; prolonged glutamateexposure induces a permanent state of hy-perexcitability in the neurons (the excito-toxic cascade), which can lead to additionalinjury and cell death. Furthermore, highlevels of glutamate can be neurotoxic, es-pecially in energy-deprived cells. Glutamatereceptor activation can persist for sometime after reperfusion, even when gluta-mate levels have returned to normal; thismay be another important mediator ofbrain cell death.

In summary, ischemia and reperfusionlead to an interruption of a delicate bal-ance between calcium influx and seques-tration at the cellular level. Numerousanimal experiments have clearly demon-strated that key destructive processes ofthe neuroexcitatory cascade (such as cal-cium influx, accumulation of glutamate,and the release of its coagonist glycine)can be prevented, interrupted, or miti-gated by hypothermia (23, 25, 45–53).Even a relatively small decrease in tem-perature can significantly improve ionhomeostasis, whereas the occurrence offever can trigger and stimulate these de-structive processes.

It is unclear how long the window ofopportunity to interrupt this cascade is.Disruptions in Ca2� homeostasis begin inthe minutes after injury but may con-tinue for many hours (sometimes evendays). Furthermore, the mechanism canbe reinitiated by new episodes of isch-emia. Thus, in theory this mechanismmay be susceptible to therapeutic inter-ventions provided these are initiated inthe hours following injury. However,some animal experiments suggest thatneuroexcitotoxicity can be blocked or re-versed only if the treatment is initiated inthe very early stages of the neuroexcita-tory cascade (26–27, 30, 54). Other stud-ies have reported somewhat wider timeframes, ranging from 30 mins to up to 6hrs (55– 67). Thus, the period duringwhich the neuroexcitatory cascade can bemodified in vivo remains unclear; indeed,

this may vary between different speciesand different types of injury. Some au-thors have suggested that the therapeuticwindow could be extended by combininghypothermia with other, more specifictreatments such as caspase inhibitors orother experimental compounds (41, 68).

Immune Response and Inflammation.In most types of brain injury, a significantand protracted inflammatory response be-gins about 1 hr following a period of isch-emia–reperfusion. Proinflammatory medi-ators such as tumor necrosis factor-� andinterleukin-1 are released in large quanti-ties by astrocytes, microglia, and endothe-lial cells; this rise begins �1 hr after injuryand they remain elevated for up to 5 days(27, 69). This stimulates the chemotaxis ofactivated leukocytes across the blood–brainbarrier, leading to an accumulation of in-flammatory cells in the injured brain, aswell as the appearance of adhesion mole-cules on leukocytes and endothelial cells.Simultaneously, there is an activation ofthe complement system which begins inthe very early stages after brain injury andfurther stimulates the passage of neutro-phils and (in later stages) monocytes-macrophages (69). These inflammatory andimmunologic responses occur especiallyduring reperfusion and are accompanied byfree radical production. This can cause sig-nificant (additional) injury through thephagocytic actions of macrophages, synthe-sis of toxic products, and further stimula-tion of immune reactions in a vicious cycle.

However, it should be realized thatthis inflammatory response is to someextent physiological, and may have a dualrole in the sense that some inflammatorymediators have neuroprotective proper-ties, whereas others are neurotoxic (69–72). Nevertheless, there is strong evi-dence suggesting that certainly adisproportionate and persistent produc-tion of cytokines and leukocyte infiltra-tion can significantly increase the riskand extent of brain cell injury and infarc-tion (68–74). Especially the interleukin-1family appears to be important in thisregard (74). Of note, this effect is to someextent time dependent, with the destruc-tive aspects of inflammation outweighingthe potential benefits especially in thelater stages of injury (69 –72). Thus,again, there may be a potential time win-dow for therapeutic interventions to in-terrupt or mitigate this process before itbecomes destructive.

Numerous animal experiments andsome clinical studies have shown thathypothermia suppresses ischemia-in-

duced inflammatory reactions and releaseof proinflammatory cytokines (75–78).Hypothermia also prevents or mitigatesreperfusion-related DNA injury, lipid per-oxidation, and leukotriene production(47–49), and it decreases the productionof nitric oxide, which is a key agent in thedevelopment of postischemic brain injury(25). In addition, hypothermia can impairneutrophil and macrophage function,and (at temperatures �32°C–33°C) de-crease white blood cell count.

In animal experiments, the extent ofbrain injury and infarct size can be sig-nificantly attenuated if any of these pro-cesses is mitigated or interrupted (25);given that hypothermia can affect all ofthese steps there is (at least in theory) ahuge potential for improving outcome.Furthermore, given that the inflamma-tory response begins relatively late (�1hr following ischemia–reperfusion), andgiven that the destructive processes takesome time to develop fully and continuefor prolonged periods of time, there ap-pears to be a clear therapeutic window foruse of hypothermia to favorably affectthis specific mechanism.

Free Radical Production. A destruc-tive process that is closely linked to butdistinct from the mechanisms discussedabove is the release of free oxygen radi-cals following ischemia–reperfusion. Me-diators such as superoxide (O2

�), per-oxynitrite (NO2

�), hydrogen peroxide (H2

O2), and hydroxyl radicals (OH�) play animportant role in determining whetherinjured cells will recover or die (47, 50,79, 80). Free radicals can oxidize anddamage numerous cellular components.Although brain cells have various enzy-matic and nonenzymatic antioxidantmechanisms that prevent this type of in-jury under normal circumstances, freeradical production following ischemia–reperfusion is so great that these defen-sive mechanisms are likely to be over-whelmed, leading to peroxidation oflipids, proteins, and nucleic acids.

Under hypothermic conditions thequantity of free radicals that is generatedis significantly reduced, although freeradical production is not completely pre-vented (47, 50, 79, 80). This allows theendogenous antioxidative (protective)mechanisms to better cope with free rad-icals that are being released, thereby pre-venting or significantly mitigating oxida-tive damage. This allows the cell to repairitself and recover, rather than sufferingpermanent damage and/or dying. The de-gree of inhibition of free radical produc-


tion appears to be more or less linearlylinked to the temperature; i.e., the lowerthe temperature, the lower the amount offree radicals (79).

Vascular Permeability, Blood–BrainBarrier Disruption, and Edema Forma-tion. Ischemia–reperfusion and/or trau-matic injury can lead to significant dis-ruptions in the blood– brain barrier,which can facilitate the subsequent devel-opment of brain edema (81–83). Thera-peutic interventions such as mannitol ad-ministration in TBI or stroke can add toblood–brain barrier disruption (82). Mildhypothermia significantly reduces blood–brain barrier disruptions (81–83), andalso decreases vascular permeability fol-lowing ischemia–reperfusion, further de-creasing edema formation (84). The con-cept of a membrane- and blood–brainbarrier–stabilizing effect of hypothermiais supported by the observation that hy-pothermia decreases extravasation of he-moglobin following TBI (85). Ischemia–reperfusion affects blood–brain barrierintegrity in other ways, including de-creased fluidity and integrity of cell mem-branes and increased vascular permeabil-ity of microvascular endothelial cells inthe brain, mediated by vascular endothe-lial growth factor via release of nitricoxide (86, 87).

These processes of membrane disinte-gration and hypoxia-induced leakage canbe mitigated or reversed by hypothermia(87). Hypothermia also decreases cyto-toxic edema via the mechanisms de-

scribed above (dampening inflammatoryresponses and free radical production,improving ion homeostasis, etc.), andthrough other mechanisms, which aresummarized in Figure 2. Brain edemacan be monitored by measuring intracra-nial pressure (ICP), which can be re-garded as a final common pathway for thedestructive processes leading to brainedema (88) [Fig. 2].

The key role of brain edema and intra-cranial hypertension as a cause of (addi-tional) neurological injury in severe TBIand ischemic stroke is well recognized(89, 90). Brain edema can also increasebrain injury in acute encephalitis andmeningitis (91), and some evidence sug-gests that edema-related injury can play arole in some patients with posthypoxicinjury following cardiac arrest (92).

As intracranial hypertension appearsto be both a marker for ongoing neuro-logical injury and a cause of additionalinjury (88), it seems plausible that treat-ments that reduce ICP will also help im-prove neurological outcome. ICP is fre-quently used as a parameter to guidetreatments and assess short-term thera-peutic efficacy in patients with TBI (89,93). Hypothermia has been used to treatbrain edema and reduce ICP in a widerange of neurological injuries, includingTBI, ischemic stroke, hepatic encepha-lopathy, meningitis, encephalitis, andsubarachnoid hemorrhage (17, 28).

In theory, this mechanism of actionwould offer a relatively wide therapeutic

window to mitigate neurological injuries.Brain edema may develop rapidly, butmore typically arises several hours afterinjury, often peaking after 24 to 72 hrs(94). It should be noted that althoughhypothermia has been shown to decreaseICP in many clinical studies, the resultsin improving survival and neurologicaloutcomes have been mixed (17, 88), withone large trial failing to show any benefitsduring hypothermia treatment in spite ofhypothermia-induced decreases in ICP(95). These varying results may be(partly) linked to the management of hy-pothermia’s side effects (17, 88); theseissues are discussed more extensively be-low. As explained above, the speed of in-duction, duration and depth of hypother-mia, and rewarming speeds all playimportant roles in determining whetheror not lasting protective effects areachieved (1, 17, 88, 96, 97).

Intra- and Extracellular Acidosis andCellular Metabolism. The diminished in-tegrity of cell membranes, the failure ofvarious ion pumps, development of mito-chondrial dysfunction, inappropriate ac-tivation of numerous enzyme systemswith cellular hyperactivity, and the dis-ruption of various other intracellular pro-cesses all contribute to the developmentof intracellular acidosis, a factor thatpowerfully stimulates many of the above-mentioned destructive processes (98, 99).Ischemia–reperfusion also leads to sub-stantial rises in cerebral lactate levels(100–102). All of these factors can besignificantly attenuated by hypothermia(98–103).

In addition, brain glucose utilizationis affected by ischemia–reperfusion, andthere is evidence suggesting that hypo-thermia can improve brain glucose me-tabolism; i.e., the ability of the brain toutilize glucose (104, 105). Similar obser-vations have been made in severe TBI, forwhich animal experiments and some clin-ical studies suggest that an initial in-crease in cerebral glucose metabolism inthe hours following trauma is followed bya deep and persistent decrease in meta-bolic rate, with a depression of mitochon-drial oxidative phosphorylation and glu-cose utilization that can last for severalweeks (106–108). Induced hypothermiaapplied during or after reperfusion in-creases the speed of metabolic recovery,with a better preservation of high-energyphosphates and reduced accumulation oftoxic metabolites (106–108).

Brain Temperature and CerebralThermopooling. Even in healthy individ-

Figure 2. Schematic depiction of the potential role of intracranial pressure as both a marker ofongoing brain injury and a potential cause of additional injury, and of the factors that may contributeto a rise in intracranial pressure. CSF, cerebrospinal fluid.


uals, the temperature of the brain isslightly higher than the measured coretemperature (109–111). This differencecan increase significantly in patients fol-lowing neurological injury, with gradi-ents ranging from 0.1°C to more than2°C (112–118), although this phenome-non does not occur in all brain-injuredpatients (118). These differences may in-crease even further when a patient devel-ops fever, a very frequent phenomenon inpatients with neurological injuries (119–123). In addition, there may be smalltemperature differences between differ-ent areas of the brain even in healthyindividuals, with active areas having aslightly higher temperature (124–127).These differences increase significantlywhen brain injury occurs, with injuredareas becoming more hyperthermic thannoninjured areas (128). The reason forthis is that some of the destructive mech-anisms discussed above lead to excessivegeneration of heat. These include excito-toxicity (which, as described above, in-duces “cellular hyperactivity” with ex-treme activation of enzyme systems, withconcomitant generation of heat), theneuroinflammatory response, free radicalproduction, and a process known as “ce-rebro thermopooling” (128, 129), mean-ing that excess heat generated in injuredareas of the brain becomes more difficultto remove via the normal heat dissipationmechanisms (lymph and venous drain-age) due to development of local brainedema. The heat thus becomes trapped ininjured areas, further adding to hyper-thermia-related injury.

Thus, a vicious cycle can arise: Braininjury leads to general overheating of thebrain; more overheating occurs especiallyin injured areas; this leads to local andsometimes general brain edema, whichthen makes it more difficult to removethe excess heat. Due to this chain ofevents, brain temperatures in injuredbrain areas may exceed measured coretemperatures by as much as 2°C to 4°C.

This is relevant because there isstrong evidence from animal studies that(external) induction of hyperthermia sig-nificantly increases the risk and extent ofneurological injury (17, 130–136). Hy-perthermia increases the likelihood thatischemic areas become apoptotic or ne-crotic, even when fever develops (or isexternally induced) some time after theinitial injury. Baena et al (131) reported a2.6-fold increase in neuronal injury inthe rat hippocampus if mild warming

(1°C–2°C above normal for 3 hrs) wasinduced 24 hrs after a brief episode offorebrain ischemia. This suggests that fe-ver can be detrimental even when it is ofshort duration and occurs on the dayafter injury. Others have reported similarobservations in different animal models(132–136). The effects of fever appear tobe more pronounced when they coincidewith an episode of cerebral ischemia, sug-gesting that ischemic brain cells becomeeven more susceptible to the harmful ef-fects of hyperthermia (135–136).

Numerous clinical studies have con-firmed that fever is indeed an indepen-dent predictor of adverse outcome instroke, TBI, and postanoxic injury follow-ing cardiac arrest (121–123, 137–142).Schwarz et al (121) found that even verymild hyperthermia (�37.5°C!) within thefirst 72 hrs was independently associatedwith poor outcome in patients with intra-cerebral hemorrhage, and that there wasa linear relationship between the severityand duration of fever and the risk foradverse outcome. In patients with isch-emic stroke, fever is associated with a3.4-fold increase in risk for adverse out-come (140), a higher brain infarct volume(141), and increased mortality (142). Al-though it has not been conclusively proventhat these relationships are causal (i.e., thatfever increases injury rather than just beinga marker), this is strongly suggested by thetemporal relationship and the results fromanimal studies (130–136).

Coagulation Activation and Forma-tion of Microthrombi. Cardiopulmonaryarrest and resuscitation are accompaniedby a marked activation of coagulation,which can lead to intravascular fibrin for-mation with blockage of the microcircu-lation in the brain and heart (143–146).Administration of anticoagulants such asheparin and recombinant tissue-typeplasminogen activator improves micro-circulatory reperfusion and survival inanimal experiments (146, 147); in addi-tion, thrombolysis can improve cerebraltolerance to ischemia (148). Initial clini-cal reports suggesting that administra-tion of thrombolytic agents could im-prove neurological outcome and survivalin cardiac arrest (149) have not been con-firmed in larger studies (150). Neverthe-less, activation of coagulation seems toplay an important role in developing isch-emia–reperfusion injury, and althoughreversing this mechanism by itself maynot improve outcome, this may be differ-ent if additional mechanisms are targetedsimultaneously.

Hypothermia has some anticoagula-tory effects. Mild platelet dysfunction oc-curs at temperatures �35°C, and someinhibition of the coagulation cascade de-velops at temperatures �33°C; plateletcount can also decrease during cooling(1, 151–154). In theory, this anticoagula-tion effect may constitute yet anotherneuroprotective mechanism. This re-mains speculative given that no studiesdirectly addressing this issue have beenperformed.

Vasoactive Mediators. Several studieshave shown that hypothermia affects thelocal secretion of vasoactive substancessuch as endothelin, thromboxane A2

(TxA2), and prostaglandin I2 in the brainand at other sites. Endothelin and TxA2

are powerful vasoconstrictive agents,whereas prostaglandin I2 is a vasodilator.TxA2 also stimulates platelet aggregation(155–157). TxA2 and prostaglandin I2 playan important role in regulating local ce-rebral blood flow, and a balance betweenthe two is required to maintain ho-meostasis (155). This local homeostasiscan be disrupted following an ischemic ortraumatic event, with a relative increasein production of TxA2 (158–161). Thisdisruption in equilibrium can lead to va-soconstriction, hypoperfusion, andthrombogenesis in injured areas of thebrain.

Animal experiments and small clinicalstudies suggest that this relative predom-inance of local vasoconstrictors can becorrected or modified by hypothermia(49, 162, 163). Aibiki et al (162) reportedthat moderate hypothermia (32°C–33°C)led to a reduction in prostanoid produc-tion and attenuation of the imbalancebetween TxA2 and prostaglandin I2 in pa-tients with severe TBI. Chen et al (163)found decreased production of the vaso-constrictor endothelin-1 during induc-tion of hypothermia.

This and other preliminary evidencesuggests that hypothermia may favorablyaffect vasoactive mediator secretion inbrain-injured patients. However, regula-tion of cerebral perfusion is a highly com-plex issue, especially in the injured brain;local circulation can be influenced by thepresence or absence of cerebral autoreg-ulation, ventilator settings and blood gasmanagement, systemic blood pressure,fluid management including osmotictherapy, etc. Thus, the impact of hypo-thermia on this equation needs to bestudied in greater detail.

Improved Tolerance for Ischemia. Hy-pothermia improves the tolerance for


ischemia in various animal models (164–166). For this reason, it is widely used inthe perioperative setting, especially inmajor vascular surgery, cardiothoracicsurgery, and neurosurgical interventions(17). An ability to better withstand peri-ods of ischemia would be an importantprotective mechanism, because manytypes of neurological injury can be com-plicated by ischemic events in the daysfollowing the initial insult.

For example, in patients with TBI acombination of biological factors (cyto-toxic and vasogenic edema) and mechan-ical factors (blockage of spinal fluiddrainage) can lead to cerebral edema andintracranial hypertension in the hoursand days following initial injury (Fig. 2);cerebral edema can then cause additionalischemic injury. In patients with sub-arachnoid hemorrhage the developmentof vasospasms in the days and weeks fol-lowing a bleeding episode can lead tosignificant ischemic injury. The risk forischemic injury occurring in the postad-mission period may also apply to postcar-diac arrest patients, in whom cerebralischemia may persist for several hoursfollowing successful resuscitation evenwhen arterial oxygen levels are normal(167). Thus, a hypothermia-induced in-crease in tolerance for ischemia could beanother powerful protective mechanism.

Suppression of Epileptic Activity.Nonconvulsive status epilepticus (i.e., ep-ileptic activity without obvious clinicalsigns and symptoms) occurs frequently in

patients with postanoxic encephalopathy,stroke, TBI, and subarachnoid hemor-rhage (168–172). It remains uncertainwhether nonconvulsive status is a directcause of additional injury; however,mounting evidence suggests that braininjury can be significantly increasedwhen nonconvulsive status occurs in theacute phase of brain injury; i.e., while thedestructive processes outlined above areongoing (168, 169). In other words, al-though the role of nonconvulsive statusby itself has not been fully clarified, whenit occurs in combination with ongoingbrain injury the two are synergisticallydetrimental (168, 169).

Evidence from various sources showsthat hypothermia can suppress epilepticactivity. Small case series report success-ful use of cooling to treat grand mal sei-zures (173–175). Animal studies haveshown that external warming increasesthe extent of epilepsy-induced brain in-jury, that prevention or prompt treat-ment of fever reduces these injuries, andthat induction of hypothermia further de-creases seizure-induced brain injury(176–179). This antiepileptic effect offersyet another pathway through which hy-pothermia could provide neuroprotec-tion, and by which fever may increaseneurological injury.

Spreading Depressionlike Depolariza-tions. Some animal studies have sug-gested that neuronal damage in varioustypes of neurological injury can be signif-icantly increased by so-called spreading

depressionlike depolarizations (23, 179).This has been studied mainly in modelsfor TBI and stroke; its potential role inthe relatively brief global ischemic braininjury that characterizes cardiac arrest isunclear. Hypothermia can suppressspreading depressions in different typesof neurological injury (23, 180–182), pro-viding yet another mechanism by whichhypothermia could improve outcome.

Influence on Genetic Expression. Hy-pothermia increases the expression of so-called immediate early genes, which area part of the protective cellular stressresponse to injury, and stimulates theinduction of cold shock proteins, whichcan protect the cell from ischemic andtraumatic injury (97). This provides yetanother mechanism through which hy-pothermia can provide neuroprotection.

Thus, hypothermia favorably affects awhole range of destructive mechanismsunfolding in the injured brain after isch-emia or trauma. This wide range of ef-fects probably explains its efficacy, incontrast to interventions that target justone or two of these mechanisms and havemostly proved unsuccessful in clinicaltrials. Different mechanisms may play agreater or smaller role in different typesof brain injury, and/or during differentphases of ongoing brain injury. A moredetailed understanding of these processeswill help us apply therapeutic hypother-mia and controlled normothermia moreeffectively.

The other key element for successfuluse of therapeutic cooling is awarenessand proper management of the physio-logical consequences and side effects.These issues are dealt with in the nextsection.

Physiological Aspects ofCooling

Phases of Cooling Treatment. A hypo-thermia treatment cycle can be dividedinto three distinct phases (Fig. 3):

● The induction phase, when the aim isto get the temperature below 34°C andthen down to the target temperature asquickly as possible;

● The maintenance phase, when the aimis to tightly control core temperature,with minor or no fluctuations (maxi-mum, 0.2°C–0.5°C);

● The rewarming phase, with slow andcontrolled warming (target rate,0.2°C–0.5°C/hr for cardiac arrest pa-tients and 0.1°C– 0.2°C/hr for other

Figure 3. Graphic depiction of the three phases of hypothermia treatment. The induction phaseshould last between 30 and 120 mins; rapid cooling may lead to a small overshoot, which should beaccepted provided it is no greater than 1°C. The maintenance phase usually lasts 24 hrs in cardiacarrest patients (may be longer for other indications) and should be characterized by no or minimalfluctuations in temperature. The rewarming phase should be slow and controlled, with rewarmingrates of 0.2°C to 0.5°C in cardiac arrest patients and lower rewarming rates for other indications. Fevershould be prevented after rewarming.


categories such as patients with severeTBI) (183).

Each of these phases has specific man-agement problems. The risk for immedi-ate side effects such as hypovolemia, elec-trolyte disorders, and hyperglycemia isgreatest in the induction phase (17, 184,185). This phase presents the greatestpatient management problems, requiringfrequent adjustments in ventilator set-tings; dosing of sedation, insulin, and va-soactive drugs; and fluid and electrolyteadministration (185). The risks can bereduced by rapid induction of hypother-mia; i.e., minimizing the duration of theinduction phase and reaching the morestable maintenance phase as quickly aspossible. Rapid cooling can be achievedby combining different cooling methods,for example, surface cooling with infu-sion of 1500–3000 mL of cold (4°C) fluidsusing a pressure bag (186). Furthermore,some of the new intravascular devicesmay have more rapid cooling rates thanpreviously used methods (1).

The maintenance phase is characterizedby increased stability of the patient, with adecreased shivering response and less riskfor hypovolemia and electrolyte loss. In thisphase, attention should shift toward pre-vention of longer-term side effects such asnosocomial infections and bedsores.

In the rewarming phase, the patient’stemperature should be increased veryslowly, for a number of reasons. Firstly,rapid rewarming can cause electrolyte dis-orders (in particular, hyperkalemia) causedby shifts from the intracellular to the ex-tracellular compartment. This can belargely prevented by slow and controlledrewarming. Secondly, insulin sensitivitycan increase during rewarming, and slowrewarming decreases the risk for hypogly-cemia if the patient is being treated withinsulin. Thirdly, some animal experimentsand clinical observations suggest that rapidrewarming could lead to loss of some oreven all of the protective effects of hypo-thermia (187–191). Significant decreases injugular venous oxygen saturation havebeen reported during rapid rewarming ofpatients following cardiac surgery underhypothermic conditions, indicating hyp-oxia of the brain (190); more slow rewarm-ing led to a decrease in the incidence andseverity of jugular bulb desaturations (190).In another study, Bissonnette et al (191)reported that patients who were rapidly re-warmed following cardiopulmonary bypasssurgery often developed severe brain hyper-thermia, even when core temperature mea-

sured at other sites remained normal. Al-though none of these experiments directlyaddressed optimal rewarming rates for car-diac arrest patients treated with hypother-mia, these and other findings indicate thatrapid rewarming can increase ischemia andaggravate destructive processes in the in-jured brain (1).

Another important concept is themaintenance of strict normothermia fol-lowing the rewarming phase. As dis-cussed above, fever is independentlylinked to adverse outcome in all types ofneurological injury, including postanoxicinjury following cardiac arrest (17). Inaddition, cerebrovascular reactivity maybe impaired following hypothermia treat-ment (192), increasing the potentialharmful effects of fever.

Physiological Changes and SideEffects of Cooling

The induction of mild hypothermia in-duces numerous changes throughout thebody. The most important physiologicalchanges and side effects, and their conse-quences for patient management, are dis-cussed below.

Shivering and Cutaneous Vasoconstric-tion. A separate article in this supplementis devoted to shivering (193); therefore,this topic is discussed only briefly here.

In awake patients, shivering inducesunfavorable effects such as increased ox-ygen consumption and metabolic rate,excess work of breathing, and increasedheart rate with increased myocardial ox-ygen consumption (1, 184, 194–197). Inthe perioperative setting, hypothermiahas been linked to an increased risk formorbid cardiac events, particularly inolder patients with heart disease (194–196). However, these adverse conse-quences are linked to the hemodynamicand respiratory responses rather than toshivering per se; these responses can belargely suppressed through administra-tion of sedatives, anesthetics, opiates, orother drugs during therapeutic cooling(1). For example, in contrast to the tachy-cardia associated with perioperative (ac-cidental) hypothermia, heart rates aremarkedly reduced during therapeuticcooling (1). Nevertheless, it is importantto prevent or aggressively treat shiveringbecause it significantly complicates hypo-thermia induction, and leads to an unde-sirable increase in metabolic rate and ox-ygen consumption (1). Appropriatesedation and analgesia will also cause va-

sodilation, which can facilitate heat lossthrough surface cooling.

Relatively effective and rapidly actingantishivering agents include fentanyl, al-fentanyl, meperidine, dexmedetomidine,propofol, clonidine, and magnesium (1).Specific advantages and disadvantages ofthese and other agents are reviewed inmore detail elsewhere (1). Brief-actingparalyzing agents can be useful in theinduction phase, especially when hypo-thermia is initiated outside the ICU set-ting, but prolonged paralysis is usuallyunnecessary (1). The effectiveness of theshivering response decreases with age;therefore, the doses of drugs required tosuppress shivering are usually lower inolder patients. Warm-air skin counter-warming can be used as an accessorymethod to lower the shivering threshold,and to decrease drug doses required toprevent shivering (198, 199).

In our unit, the standard approach isto administer a loading dose of magne-sium (30 mmol) and fentanyl (50–100�g) when cooling is initiated, togetherwith continuous infusion of either mida-zolam or propofol (the latter only in he-modynamically stable patients). If shiver-ing occurs, another bolus of fentanyl(50–150 �g) is given, and more magne-sium if serum Mg2� is �2.0 mmol/L. Insome patients, the dose of sedatives willbe temporarily increased during induc-tion and/or a bolus dose of midazolam(5–10 mg) will be given. If shivering per-sists, one of the following drugs is given,depending on the clinical circumstances:clonidine, meperidine, ketanserin, or (inrare cases) a brief-acting paralyzingagent. All patients should be carefullymonitored for shivering during all phasesof hypothermia treatment. Use of a re-cently developed shivering assessmentscale (200) may be considered for thispurpose.

The importance of adequate sedationand suppression of hypothermia-inducedstress responses is underscored by obser-vations from animal experiments sug-gesting that some or all of hypothermia’sneuroprotective effects can be lost if cool-ing is used in nonsedated animals. Oneresearch group observed no protective ef-fects when cooling was used after globalanoxia in unsedated newborn piglets(201); when the experiment was repeatedin the same model under adequate seda-tion, significant improvements in out-come were noted in hypothermia-treatedanimals (202). The authors concluded


that stress effects of cooling in unsedatedanimals could negate protective effects.Although this phenomenon has not beenwell studied in humans, it seems reason-able to avoid a cooling-related stress re-sponse.

Metabolism, Blood Gases, Glucoseand Electrolytes. Hypothermia decreasesthe metabolic rate by �8% per 1oC dropin core temperature, with a parallel de-crease in oxygen consumption and pro-duction of carbon dioxide. This meansthat ventilator settings need to be ad-justed frequently especially in the induc-tion phase of hypothermia, to avoid acci-dental hyperventilation that can causecerebral vasoconstriction. Blood gas val-ues are temperature dependent, and ifblood samples are warmed to 37°C beforeanalysis (as is common in most laborato-ries), PO2 and PCO2 will be overestimatedand pH underestimated in hypothermicpatients (1). This topic has been reviewedelsewhere (203).

Blood gas management when CO2 val-ues measured at 37°C are kept constant(for example, at 40 mm Hg) regardless ofthe patient’s actual core temperature iscalled alpha-stat management. The alter-native is pH-stat management, in whichPCO2 is corrected for temperature and ismaintained at a prespecified value. Thisimplies that the temperature-correctedpH will remain constant during pH-statmanagement and will increase during al-pha-stat management (1). Which of thesetwo methods is superior remains to bedetermined, and may depend in part onwhether or not cerebral autoregulation ispreserved (1). Strictly applied alpha-statmanagement could lead to hyperventila-tion and cerebral vasoconstriction; strictpH-stat management could lead to hyper-capnia, cerebral vasodilation, and in-creased ICP. Which option is preferablemay depend on the precise nature of theneurological injury and the presence orabsence of brain edema. Excessive hypo-capnia can increase ischemia in injuredareas of the brain, while excessive hy-percapnia can increase brain edema;thus both can cause additional braininjury. These issues are more exten-sively addressed in a recently publishedreview (1).

For accurate temperature correction,blood samples should be analyzed at thepatient’s real temperature; this can bemost easily accomplished by performingon-site analysis in the ICU. If this is notpossible, the blood gas values can be es-timated in the following way.

In a sample assayed at 37°C:

● Subtract 5 mm Hg PO2 per 1°C that thepatient’s temperature is �37°C;

● Subtract 2 mm Hg PCO2 per 1°C thatthe patient’s temperature is �37°C;

● Add 0.012 pH units per 1°C that thepatient’s temperature is �37°C.

Thus, a sample from a patient with acore temperature of 33°C analyzed in thelab at 37°C with the results pH 7.45, PCO2

35 mm Hg, and PO2 80 mm Hg wouldhave the following temperature-correctedvalues: pH 7.50, PCO2 27 mm Hg, and PO2

60 mm Hg.In our unit, we use temperature-

corrected blood gas values but avoid se-vere hypercapnia. Target PCO2 values at32°C (our usual target temperature incardiac arrest patients) are 32 to 36 mmHg, which would be 42 to 46 mm Hg inan uncorrected sample.

Hypothermia can also decrease insulinsensitivity and the amounts of insulinsecreted by the pancreas. This can lead tohyperglycemia and/or an increase in thedoses of insulin required to maintain glu-cose levels within target range. Sustainedhyperglycemia has been linked to adverseoutcome in critically ill patients, and maypose additional risks in patients with neu-rological injuries (39), although the opti-mal targets for glucose control remaincontroversial (39). Prevention and/orprompt correction of severe hyperglyce-mia should be part of the therapeuticstrategy during hypothermia treatment.Furthermore, it should be realized thatdoses of insulin required to maintain nor-moglycemia are likely to decrease whenthe patient is rewarmed; this means thathypoglycemia can easily develop in therewarming phase as insulin sensitivity isrestored, particularly if the patient is re-warmed (too) quickly.

Cooling can also affect electrolyte lev-els. A combination of hypothermia-induced intracellular shift and tubulardysfunction leading to an increase in re-nal excretion of electrolytes can lead todepletion of magnesium, potassium, andphosphate during cooling (185). Theseelectrolyte disorders can increase the riskfor arrhythmias and other potentiallyharmful complications (204, 205). Thereis evidence suggesting that magnesiumcould play a role in mitigating varioustypes of brain injury (204, 205); hy-pophosphatemia has been linked to respi-ratory problems and increased infectionrisk (206). Thus, electrolyte levels should

be kept in the high-normal range duringand after hypothermia treatment.

Extra care should be taken during re-warming because hyperkalemia may de-velop during this phase, due to release ofpotassium sequestered to the intracellularcompartment during hypothermia induc-tion (1). Hyperkalemia can be prevented byslow and controlled rewarming, allowingthe kidneys to excrete the excess potas-sium. Thus, the risk for rebound hyperka-lemia in the rewarming phase should notbe regarded as a reason to accept hypoka-lemia in the induction and maintenancephase. However, in patients with anuria orsevere oliguria, renal replacement therapyshould be started before the patient is re-warmed.

Cardiovascular and HemodynamicEffects. Hypothermia has complex andopposing effects on the myocardium andmyocardial contractility, depending onthe patient’s volume status and whetheror not the patient is adequately sedated.Under normal circumstances, mild hypo-thermia will decrease heart rate and in-crease myocardial contractility in sedatedand euvolemic patients (1, 207–211). Sys-tolic function will improve but a milddegree of diastolic dysfunction may occurin some patients (1, 207–211). Bloodpressure remains stable or increasesslightly in most patients during mildhypothermia (1, 186, 211–213). Cardiacoutput decreases along with the heartrate; however, the hypothermia-in-duced decrease in metabolic rate usu-ally equals or exceeds the decrease incardiac output, so that the balance be-tween supply and demand remains con-stant or improves (1).

The heart rate can be artificially in-creased by external pacing, or throughadministration of chronotropic drugssuch as isoprenalin or dopamine. How-ever, this is usually unnecessary; further-more, myocardial contractility may beadversely affected (210, 211, 214). Twoanimal studies (210, 214) and one clinicalstudy in patients undergoing cardiac sur-gery (211) reported that while increasingheart rate under normothermic conditionsincreased myocardial contractility and car-diac output, increasing the heart rate underhypothermic conditions significantly de-creased myocardial contractility. Whenheart rates were not artificially increased,induction of mild hypothermia improvedmyocardial contractility (211).

Thus, in most patients the heart rateshould be allowed to decrease along withthe patient’s core temperature; further-


more, it should be realized that normal val-ues for heart rate change with temperature.

Despite these data, hypothermia is of-ten still viewed as a (potential) cause ofhypotension and (additional) myocardialdysfunction. There are several reasons forthis:

Firstly, in contrast to mild hypother-mia, deep hypothermia (�30°C) does de-crease myocardial contractility (1, 215).Secondly, hypothermia can cause hypo-volemia by inducing “cold diuresis”through a combination of increased ve-nous return, activation of atrial natri-uretic peptide, decreased levels of antidi-uretic hormone and renal antidiuretichormone receptor levels, and tubulardysfunction (185, 216–221). The increasein venous return is caused by constric-tion of peripheral vessels (particularly inthe skin) due to hypothermia-induced in-creases in plasma norepinephrine levelsand activation of the sympathetic nervesystem. This leads to a shift of the bloodfrom peripheral (small) veins to deeperveins and the core compartment of thebody, increasing the venous return. Inthis way, hypothermia can induce hypo-volemia, which if uncorrected can causehypotension as well as electrolyte deple-tion and an increase in blood viscosity.The risk for hypovolemia increases signif-icantly if the patient is simultaneouslytreated with diuretic agents such as man-nitol. However, hypotension can be quiteeasily prevented by avoiding or promptlycorrecting hypovolemia, and by avoidingexcessive stimulation of the heart rate.

Three studies in pediatric patients en-rolling a total of 127 patients and twosmall studies in adult patients enrolling18 patients have reported successful useof mild hypothermia (32°C–33°C) as res-cue therapy to reverse refractory cardiacshock following cardiac surgery (222–226). Two additional studies have re-ported successful use of hypothermia inpatients who remained comatose after amassive cardiac arrest leading to severecardiac shock (227, 228). Rates of favor-able outcome in patients with cardiacshock were 61% (14 of 23) in the firststudy and 39% (11 of 28) in the secondstudy. Oddo et al (229) recently reportedthat the presence of cardiac shock onadmission did not correlate with adverseoutcome in a prospective series of 74patients with witnessed cardiac arresttreated with hypothermia, regardless ofinitial rhythm or hemodynamic status.These observations suggest that cardiac

shock should not be regarded as a coun-terindication for hypothermia treatment.

Hypothermia also causes changes inthe heart rhythm and electrocardiogram.The hypothermia-induced increase in ve-nous return discussed above initiallyleads to mild sinus tachycardia. Tachy-cardia can be much more pronounced ifthe patient is insufficiently sedated, andthe shivering response with increased ox-ygen consumption and heat generationcan lead to more marked tachycardia.

This is soon followed by sinus brady-cardia when core temperature drops be-low 35.5°C. The heart rate decreases pro-gressively as core temperature drops, andat 33°C the normal heart rate will be 45to 55 bpm (although there is wide inter-patient variability). The underlyingmechanism is a decrease in the rate ofspontaneous depolarization of cardiacpacemaker cells (including those of thesinus node), as well as prolongation ofthe duration of action potentials and amild decrease in the speed of myocardialimpulse conduction. The most commonelectrocardiogram changes are prolongedPR intervals, increased QT interval, andwidening of the QRS complex. Some-times so-called Osborne waves can beseen, although this is relatively rare dur-ing mild hypothermia.

These electrocardiogram changes usu-ally do not require treatment. It is oftenassumed that mild hypothermia increasesthe risk for arrhythmias and decreasesthe chance of successful treatment of ar-rhythmias, because the hypothermicmyocardium becomes less responsive toantiarrhythmic drugs and more difficultto defibrillate. However, in general thisapplies only to deep hypothermia(�28°C); experimental evidence suggeststhat mild hypothermia can actually de-crease the risk for arrhythmias, by stabi-lizing cell membranes and increasing thelikelihood of successful defibrillation ifarrhythmias do occur. Two studies haveassessed the likelihood of successful defi-brillation under hypothermic conditionscompared with normothermia in a swinemodel. Both found higher rates of returnof spontaneous circulation, increasedlikelihood of successful defibrillation,fewer shocks required to reach return ofspontaneous circulation, and lower inci-dence of postdefibrillation asystole dur-ing mild hypothermia (230, 231). Similarobservations have been reported in a rab-bit model (232). Various case studies de-scribe successful use of hypothermia totreat arrhythmias (junctional ectopic

tachycardia) in young infants (233–235).All of this indicates that mild hypother-mia decreases rather than increases therisk for arrhythmias, and facilitatesrather than complicates the treatment ofarrhythmias.

However, this changes if core temper-ature drops below 28°C (in rare cases,�30°C in patients with severe electrolytedisorders and/or severe myocardial isch-emia). More profound hypothermia doesincrease the risk for arrhythmias, usuallybeginning with atrial fibrillation, whichcan progress to more severe arrhythmiasincluding ventricular tachycardia andventricular fibrillation if temperature de-creases further. Thus, a de novo develop-ment of atrial fibrillation in a patient witha core temperature �30°C should beviewed as a warning sign, and the patientshould be rewarmed to �30°C immedi-ately. In general, a temperature drop be-low 30°C should be strenuously avoidedduring therapeutic cooling in the ICU,but cooling treatment should not bewithheld because of the presence or riskfor arrhythmias.

In addition, attending physicians andnurses should be aware that the myocar-dium becomes more sensitive to mechan-ical manipulations during deep hypother-mia. For example, if a physician decidesto perform chest compressions because ofsevere bradycardia at a core temperature�28°C, this manipulation can induce ar-rhythmias including ventricular fibrilla-tion (1). An additional problem is that ifarrhythmias do develop during deep hy-pothermia, they become significantlymore difficult to treat, because the hypo-thermic myocardium can become less re-sponsive to antiarrhythmic drugs (1).Furthermore, other treatments for atrialfibrillation, such as electric cardiover-sion, are frequently unsuccessful at lowtemperatures, and may actually trigger aconversion from atrial fibrillation to ven-tricular fibrillation. Cardioversion fornonlife-threatening arrhythmias shouldbe avoided at core temperatures �34°C.

Coronary Perfusion and Ischemia.Hypothermia reduces metabolic rate andinduces bradycardia, thereby providingprotective effects for the ischemic myo-cardium. In addition, it has been shownthat mild hypothermia (35°C) inducescoronary vasodilation and increases myo-cardial perfusion in healthy volunteers(236, 237). In contrast, hypothermia caninduce vasoconstriction in severely ath-erosclerotic coronary arteries (237). Inaddition, hypothermia can cause shiver-


ing, tachycardia, and increased myocar-dial oxygen consumption in insufficientlysedated patients. Indeed, accidental hypo-thermia in the perioperative setting in-creases the risk for morbid cardiac events(194, 195). Thus, preventing adverse ef-fects depends on avoiding a stress re-sponse and effective suppression of shiv-ering.

Some animal experiments and prelim-inary clinical studies have suggested thatinducing mild hypothermia in the earlystages following myocardial infarctioncould mitigate myocardial injury (17).This issue needs to be addressed in largerstudies, but the available evidence cer-tainly does not suggest that hypothermiaincreases myocardial injury.

Coagulation. Mild hypothermia caninduce mild coagulopathy (1). Tempera-tures below 35°C can cause platelet dys-function and a mild decrease in plateletcount; at temperatures �33°C, othersteps in the coagulation cascade, such asthe synthesis and kinetics of clotting en-zymes and plasminogen activator inhibi-tors, may also be affected (1). These ef-fects have been studied mostly in vitro.Clinical observations suggest that therisk for severe bleeding associated withtherapeutic cooling is relatively small;none of the studies in patients with car-diac arrest, severe TBI, or stroke havereported significant bleeding problems,although it should be emphasized thatactively bleeding patients were excludedfrom all of these studies (1, 17). Schefoldand coworkers (238) recently assessed therisk and severity of bleeding during si-multaneous use of mild hypothermia andthrombolysis. They found that bleedingrisks were similar to historical controlstreated with thrombolytics alone, al-though there was a trend toward morered blood cell units being required toreach target hematocrit in hypothermicpatients who developed bleeding compli-cations and needed transfusions. How-ever, neurological outcomes were signif-icantly better in patients treated withboth thrombolytics and hypothermia,even in those who developed bleedingcomplications (238). The authors con-clude that bleeding risks should not beviewed as a reason to withhold hypother-mia treatment.

These factors should be taken into ac-count when deciding whether or not touse hypothermia in patients who are ac-tively bleeding, or who have a high bleed-ing risk. If possible the (potential) sourceof bleeding should be (surgically) con-

trolled before cooling is initiated. If thisis not possible, the risks of bleedingshould be weighed against the benefits ofcooling, and careful consideration shouldbe given to the appropriate depth of hy-pothermia for that patient. Very mild hy-pothermia (35°C) does not affect coagu-lation, and can be safely used even ifbleeding risks are high. Temperatures of33°C to 35°C affect platelet function only;if surgical procedures are performed un-der hypothermic conditions, platelettransfusion may be considered. Coagula-tion factors other than platelet functionare affected only when temperatures de-crease below 33°C.

Drug Clearance. The speed of mostenzyme-mediated reactions is tempera-ture-dependent; therefore, the speed ofthese reactions is significantly slowed byhypothermia. One of the consequences isa decrease in the rates of drug metabo-lism by the liver (17, 239). Hypothermia-induced reductions in clearance havebeen demonstrated for a number of com-monly used ICU medications, includingvasoactive drugs such as epinephrine andnorepinephrine; opiates such as mor-phine, fentanyl, and remifentanil; seda-tives such as propofol, volatile anesthet-ics, barbiturates, and midazolam;neuromuscular blocking agents such asrocuronium, atracurium, and vecuro-nium; and other drugs such as phenytoin,nitrates, and some beta-blockers (1, 239).Other drugs metabolized by the liver arelikely to be affected in similar ways.

The net effects of hypothermia ondrug action may be more complex thansimply increasing the concentration ofactive metabolites. Temperature can alsodirectly affect the body’s response to spe-cific drugs. For example, the effects ofvasoactive drugs, such as epinephrineand norepinephrine, on blood pressurecan be slightly blunted by hypothermia.Hypothermia-induced changes in the vol-ume of distribution and renal functionmay also influence how drugs work underhypothermic conditions.

However, in most cases the effect ofhypothermia will be to increase drug levels,thereby enhancing drug potency and effectduration. From a practical perspective, itseems reasonable to make empirical doseadjustments in drugs with relatively shorthalf-lives that are metabolized by the liver(e.g., midazolam). When an increase indepth of sedation is required, or an episodeof shivering needs to be treated, it is pref-erable to use bolus doses rather than toincrease maintenance dose.

Drugs with long half-lives (e.g., amio-darone) are far less affected by thesemechanisms, because the amounts elim-inated in 24 hrs are low regardless oftemperature; therefore, effects of amioda-rone are less temperature-dependent, andclearance is only slightly decreased underhypothermic conditions.

Risk for Infections. Hypothermia in-hibits the proinflammatory responsethrough inhibition of leukocyte migra-tion and phagocytosis and decreased syn-thesis of proinflammatory cytokines (1).Indeed, suppression of harmful neuroin-flammation is one of the mechanismsthrough which hypothermia may exert itsprotective effects; the downside of thisprotective mechanism is an increasedrisk for infections. Development of (acci-dental) hypothermia in the perioperativesetting has been linked to increased riskfor infections of the respiratory tract and(surgical) wounds (1, 240–242). Some ev-idence suggests that this may even applyto controlled normothermia; i.e., sup-pression of a febrile response. For thera-peutic cooling (i.e., cooling of sedatedand mechanically ventilated patients) therisk for nosocomial infections appears tobe closely linked to treatment duration(higher risk if treatment is continued for�24 hrs) and to the category of patients(lowest risk in cardiac arrest patients,highest risk in patients with severestroke). Most of the studies reporting in-creased risks of infection during thera-peutic cooling also observed that finaloutcomes did not appear to be adverselyaffected, even when infections occurred(17). The suppression of inflammatory re-sponses in the lung has also been usedtherapeutically to improve oxygenationin patients with severe acute respiratorydistress syndrome (17).

Strategies to deal with increased infec-tion risks include considering antibioticprophylaxis. Recent publications suggestthat the use of selective decontaminationof the digestive tract can significantly re-duce the risk for nosocomial infectionsand decrease mortality in ICU patients(243, 244). Clinical studies with thera-peutic cooling in settings in which selec-tive decontamination of the digestivetract was used have reported low infec-tion rates (186, 216), even when hypo-thermia was used for prolonged periods(216).

Patients should be carefully moni-tored for signs of infection during thera-peutic temperature management. Somenormal signs of infection are absent or


suppressed during hypothermia; this ob-viously applies to development of feverbut may also apply to increased C-reac-tive protein level and elevated whiteblood cell count. One telltale sign of de-veloping infection can be a sudden in-crease in the “workload” of the coolingdevice; i.e., a decrease in water tempera-ture and increase in noise levels of thedevice that is being used to cool the pa-tient. Such increases in cooling powermay indicate either shivering or an at-tempt by the body to generate fever, andthus the presence of an infection.

Many treatment protocols (includingin our ICU) include daily blood surveil-lance cultures to screen for bacteremia.The threshold for antibiotic treatmentshould be low. In patients developing in-fections after hypothermia treatment, fe-ver should be treated symptomatically, toprevent new or additional neurologicalinjuries (17).

The risk for wound infections may befurther increased by hypothermia-in-duced cutaneous vasoconstriction. Thesame applies to the development of bed-sores, which once formed will be morelikely to progress and become infectedbecause of the immune-suppressed stateand complete immobilization of the pa-tient. Nurses and physicians should beaware of these additional risks and takeextra precautionary measures. Extra at-tention should also be paid to catheterand central line insertion sites, as localinfections also are more likely to develophere.

Other Effects. Hypothermia is associ-ated with impaired bowel function anddelayed gastric emptying. There is nospecific strategy to deal with this issue;routine measures such as insertion of du-odenal probes and/or administration ofmetoclopramide or low-dose erythromy-cin may be considered, taking care thatthe combination of hypothermia withthese drugs does not cause QT prolonga-tion (1). Hypothermia often causes a mildrise in serum amylase; however, the riskfor clinically significant pancreatitis is ex-tremely low (1).

Many other changes in laboratorymeasurements can develop during hypo-thermia. Apart from those already men-tioned (hyperglycemia; low electrolytelevels; decreased platelet and white bloodcell counts; increased levels of glycerol,free fatty acids, ketonic acids, lactate, andamylase), these may include a rise in liverenzymes (serum glutamic oxaloacetictransaminase and serum glutamic pyru-

vic transaminase) and increased levels ofcortisol, norepinephrine, and epineph-rine (184).

CONCLUSION

Hypothermia is the first treatmentwith a proven ability to reverse postisch-emic injury in the clinical setting. Assuch, it represents a major breakthrough,the importance of which is only just be-ginning to be fully appreciated. However,there are numerous pitfalls in using ther-apeutic cooling to maximum efficacy,particularly if prolonged treatments arerequired to improve outcome, as seemsto be the case for stroke and severe TBI.Understanding the mechanisms that un-derlie hypothermia’s protective effects,awareness of the physiology of cooling,and knowing and understanding the po-tential side effects are all key factors ineffectively using this therapeutic strat-egy. There are still many misconceptionssurrounding therapeutic cooling; somerisks are imagined or overestimated,whereas others are not fully appreciated.

Temperature management strategiesare likely to play an increasingly impor-tant role in the care of (neuro)critically illpatients. In view of the numerous poten-tial applications for induced hypothermiaor controlled normothermia, it is in-creasingly important that physicians andnurses caring for critically ill patients,particularly those with neurological inju-ries, be aware of these issues, to helpthem avoid the pitfalls and risks of thistreatment.

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