Ehab Farag, MD, FRCA
Professor, Cleveland Clinic Lerner College of Medicine
Staff Anesthesiologist, Director of Clinical Research
Editorial Advisory Board Member Anesthesiology News
An evidence-based review of therapeutic hypothermia as a neuroprotective agent reveals conflicting conclusions and emphasizes that larger, controlled trials are needed.
Hypothermia therapy is mentioned 5,000 years ago in ancient Egyptian writings, and Hippocrates advised the use of snow and packed ice to reduce hemorrhage in the wounded. Russians have applied hypothermia therapeutically since 1803 by covering the individuals with snow in an attempt to resuscitate them. Baron Dominique Jean Larrey, Napoleon’s chief surgeon during the 1812 campaign, packed limbs in ice prior to amputations to induce analgesia. In 1940, Temple Fay, MD, described the successful recovery of a patient with metastatic disease who underwent hypothermia (32.2°C) for 18 hours by surface cooling under anesthesia.1-3 Therapeutic hypothermia can be defined as mild (33°C-36°C), modest (32°C-34°C), and moderate (28°C-32°C) hypothermia.
Therapeutic hypothermia is different from accidental hypothermia. Therapeutic hypothermia preserves adenosine triphosphate stores and induction of poikilothermia. By contrast, accidental hypothermia induces a stress response, shivering, and depletion of energy stores.4
The aim of this review is to present the most recent evidence-based advances in the use of therapeutic hypothermia as a neuroprotective agent.
Mechanisms of Neuroprotection by Hypothermia
Improvements in Metabolism
Hypothermia reduces the cerebral metabolic rate of oxygen (CMRO2) by approximately 5% per degree Celsius. Thus, in severe traumatic brain injury (TBI) patients, a 1°C reduction in temperature leads to a 5.9% reduction in energy.5 Hypothermia also preserves high-energy phosphate compounds like adenosine triphosphate (ATP) and maintains tissue pH. Therefore, hypothermia preserves the brain’s metabolic stores and prevents development of metabolic acidosis and accumulation of lactic acid. During ischemia, blood flow is reduced; however, during the reperfusion period, there is an overflow of blood (hyperemia), which is followed by a gradual decline over a period of time. Hypothermia blunts the immediate hyperemia and prevents the gradual reduction in cerebral blood flow that follows.6
Hypothermia and Cell Survival
The effect of hypothermia on the production of heat shock protein (HSP70) during ischemia is controversial. Hypothermia may increase HSP70 and therefore would contribute to its neuroprotection. However, other studies have shown no effect, and some have shown a reduction in HSP70 levels during ischemic periods.7-10
MicroRNAs (miRNAs), a subset of noncoding RNAs, were first described in 1993. They play a very important role in silencing messenger RNAs (mRNAs), and so are considered one of the main regulators of the mRNA coding process. The use of hypothermia (33°C) in the model of TBI was found to affect the levels of miRNAs, which increased after injury. Importantly, hypothermia reduced the levels of miRNA-874 when compared with normothermia. The upregulation of miRNA-874 is responsible for decreased production of several key proteins involved in normal cellular function and enhances vulnerability to TBI. Therefore, hypothermia might exert a neuroprotective effect by reducing the level of this miRNA.11
Hypothermia affects the intrinsic and external pathways of apoptotic cell death. The intrinsic pathway is originated mainly at the mitochondria, while the extrinsic one is triggered at the level of cell surface receptors. Ischemia activates the intrinsic pathway by translocating cytosolic pro-apoptotic Bcl-2 family members, such as Bcl-2 associated X (BAX) protein, to the mitochondria, where it oligomerizes with Bcl-2 to create nonspecific protein pores in the outer mitochondrial membrane, thereby leaking the pro-apoptotic proteins and cytochrome c into the cytosol. The loss of cytochrome c reduces the mitochondrial coupling of oxidative phosphorylation.
Moreover, the increased permeability of the mitochondrial membrane causes the release of apoptogenic factors, including second mitochondria–derived activator of caspase (Smac). The direct inhibition of apoptosis-binding protein with low Pi (Diablo) and apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space could induce irreversible cell death.12-14
Upstream triggers such as inflammation and trophic withdrawal activate cell surface death receptors initiating the “extrinsic” pathway to programmed cell death. Conversely, calcium overload and oxygen-free radicals appear to exert their effect predominantly at the mitochondrial level via the “intrinsic” pathway. In addition, crossover activation between the “extrinsic” and “intrinsic” pathway may take place through pro-apoptotic intermediates such as the BID protein.
AIF, apoptosis inducing factor; Apaf-1, apoptotic protease-activating factor-1; ATP, adenosine triphosphate; BAK, Bcl2-antagonist/killer 1;BAX, Bcl2-associated X protein;Bcl2, B-cell lymphoma 2 protein family; Bcl-XL, B-cell lymphoma-extra-large; BID, BH3 interacting-domain death agonist;Diablo, direct inhibitor of apoptosis binding protein with low Pi;P53, p53 tumor suppressor protein; Smac, Second mitochondria-derived activator of caspase;tBID, truncated BH3 interacting-domain death agonist;TNF, tumor necrosis factor receptor;TRAIL, TNF-related
After the release, cytosolic cytochrome c binds to apoptotic protease–activating factor-1 (Apaf-1) and activates caspase-9 to stimulate the final executioner caspase-3, which leads to DNA fragmentation and apoptosis. Hypothermia reduces caspase-3 activation, cytochrome-c release and BAX, whereas it increases the antiapoptotic member Bcl-2. Hypothermia was shown to reduce the mitochondrial membrane permeability in a swine model of cardiac arrest, which might provide neuroprotection against cerebral injury.15 Moreover, hypothermia blocks the translocation of the pro-apoptotic protein kinase C d (PKCd) to the mitochondria and the nucleus, and stimulates the action of antiapoptotic factor protein kinase C e (PKCe).6,14 The extrinsic pathway is mainly activated by the tumor necrosis factor (TNF) superfamily of cytokines, such as TNF-α, Fas ligand (FasL) and the Fas receptor system. The stimulation of this system induces apoptosis by activating caspase-8. Hypothermia reduces the availability of FasL levels and thereby the activation of caspase-8, which occurs downstream of the extrinsic pathway.16 Phosphatase and tensin homologue (PTEN) is a tumor suppressor molecule with pro-apoptotic functions. Hypothermia deactivates PTEN and induces neuroprotection.6
Hypothermia and Survival Pathways
Hypothermia increases the levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin in the brain. Moreover, hypothermia increases extracellular signal–regulated kinase (ERK) phosphorylation, a downstream element of BDNF signaling. However, the pharmacologic inhibition of ERK by U0126, a highly selective inhibitor of the kinase enzyme MEK, failed to prevent the benefit of hypothermia.6,17 Hypothermia promotes the activation of AKT, a serine/threonine protein kinase that inactivates pro-apoptotic proteins such as glycogen synthase 3β (GSK 3β) and the Bcl-2 antagonist of cell death (BAD).
Hypothermia and Inflammation
Brain injury leads to induction of the inflammatory process with increased release of cytokines and interleukins (IL). The increased inflammatory process enhances microglia activation, leukocyte diapedesis into the ischemic brain, and the production of reactive oxygen species (ROS). The increase in cytokine-mediated inducible nitric oxide synthase (iNOS) expression and NO levels, which compete with O2 at its binding site on cytochrome oxidase, result in reduction of ATP levels.
Hypothermia reduces IL-1 β, TNF-α, and IL-6. However, hypothermia reduces anti-inflammatory agents, such as IL-10 and transforming growth factor-β (TGF-β). Therefore, hypothermia does not have a solely anti-inflammatory effect.
Hypothermia also affects the mitogen-activated protein kinase (MAPK) pathway, an important pathway that stimulates inflammation in a cell-mediated manner. Hypothermia inhibits the p38 pathway (one of the MAPK family), which is responsible for apoptosis and endothelial dysfunction.18
Hypothermia suppresses the activation of nuclear factor-κb (NF-κb), the major transcription factor for activating inflammatory-related genes. Hypothermia prevents NF-κb translocation and DNA binding by inhibiting the activity of inhibitor of NF-κb kinase (IKK). IKK is responsible for the phosphorylation and degradation of NF-κb inhibitor (Iκb). Of note, NF-κb also regulates genes involved in cell survival and growth. Therefore, inhibition of NF-κb by hypothermia might have contradictory effects.
Hypothermia and Excitotoxicity
Excitotoxicity is an important contributor to cell damage during ischemia. Excitatory amino acids (EAA), such as glutamate and aspartate, are significantly elevated in different types of brain injuries and are associated with secondary brain injuries.
The accumulation of glutamate enhances the calcium influx through α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and glutamate receptor-2 (GluR2), a subunit of the AMPA receptor that limits calcium influx. The increased intracellular calcium concentration activates calcium-dependent protease calpain, which further enhances the apoptotic process. Hypothermia limits calcium influx through AMPA and preserves GluR2 mRNA expression.19 Mild hypothermia inhibits the activity of calpain II and thereby reduces its degenerative effect on the cytoskeleton.5
Moreover, mild hypothermia can reduce the level of glutamate by enhancing its uptake.20 Mild hypothermia increases the level of inhibitory amino acid gamma-aminobutyric acid (GABA), thereby counteracting the injurious effects by EAA.21 In addition, hypothermia enhances the restoration of Ca2+/calmodulin–dependent protein kinase II–mediated cell signaling.21
Hypothermia and Nitric Oxide
Nitric oxide plays a role in the development of post-ischemic cerebral edema. Mild hypothermia reduces the activity of neuronal nitric oxide synthase (nNOS) and the NO level, thereby reducing cerebral edema and secondary brain injury.22 During cerebral ischemia, elevated levels of glutamate increases NO and its metabolites (nitrite and nitrate). Mild hypothermia not only inhibits this process but also inhibits iNOS as well. The inhibition of iNOS by hypothermia probably results in part from its inhibitory effect on NF-κb.5
Hypothermia and Blood–Brain Barrier Integrity
The blood–brain barrier (BBB) is the target of damaging effects of several agents such as ROS, cytokines, and proteases, especially matrix metalloproteinases (MMPs), during ischemia. Hypothermia reduces MMP activity and increases the expression of endogenous MMP inhibitors, such as tissue inhibitor of metalloproteinase 2 (TIMP2). Mild hypothermia reduces brain edema formation by suppressing aquaporin-4 expressions in models of intracerebral hemorrhage and cardiac arrest. Of note, aquaporin-4 is the main water channel protein in the central nervous system microvasculature, and its expression is increased in cerebral ischemic lesions.23,24
Hypothermia and Its Effects on Gliogenesis And Angiogenesis
Mild hypothermia promotes progenitor cell differentiation toward neurogenesis over gliogenesis and protects against progenitor cell death. However, hypothermia of less than 30°C suppresses cell proliferation. Therefore, mild hypothermia has a protective effect on progenitor cell differentiation and prevents their apoptosis, while deep hypothermia has deleterious effects on them.
The effect of mild hypothermia on angiogenesis and neurologic outcomes is very controversial. Mild hypothermia has been shown to enhance angiogenesis. However, some studies have shown enhanced angiogenesis has a harmful effect on brain repair. This fact might explain unfavorable outcomes in recent trials following the use of mild hypothermia for TBI.
Physiological Effects of Hypothermia
Hypothermia is associated with an average reduced heart rate of 40 to 45 beats/min at 32°C. Reduced heart rate with hypothermia enhances left ventricular filling, and thereby compensates for hypothermia-associated reduction of cardiac contractility and cardiac output. Cardiac output decreases by ~7% for every 1°C drop in core temperature.25 Therefore, augmentation of heart rate during hypothermia is not recommended, as it will increase the cardiac oxygen consumption and arrhythmia as well as impair contractility. Adults may experience atrial fibrillation at temperatures <32°C and ventricular fibrillation at temperatures <30°C. However, such arrhythmias have not been described in neonates who have been transiently overcooled to <30°C.
Mean arterial pressure (MAP) is increased during hypothermia due to increased peripheral vascular resistance from hypothermia-induced peripheral vasoconstriction. The increase in venous return from peripheral vasoconstriction leads to atrial natriuretic peptide (ANP) activation and reduces the secretion of antidiuretic hormone and, therefore, cold diuresis. With prolonged hypothermia, a decrease in intravascular volume may occur from cold diuresis and the fluid shifts resulting from the shedding effect of ANP on endothelial glycocalyx. This may result in hypotension and hemoconcentration.3,26
Pulmonary Effects and Infectious Complications
The incidence of adult respiratory distress syndrome (ARDS) is nearly 50% in intubated patients with neurologic injuries treated with hypothermia compared with normothermic patients.27 The reduced incidence of ARDS in hypothermic patients most probably results from the reduction in metabolic rate, oxygen consumption, and carbon dioxide (CO2) during hypothermia. Moreover, the reduction in PaCO2 is still present following rewarming, as is an increase in the PaO2-FiO2 (fraction of inspired oxygen) ratio.28
Hypothermia may increase pulmonary vascular resistance, and therefore may worsen oxygenation in newborn infants with perinatal asphyxia who are at high risk for persistent pulmonary hypertension.
Hypothermia does not increase the incidence of pneumonia. However, it may increase the risk for wound infections.3
Coagulation System Effects
Hypothermia can induce mild coagulopathy. At 33°C, platelet function and number as well as synthesis and kinetics of clotting enzymes are reduced. In addition, there is significant prolongation of activated thromboplastin time (aPTT) at lower temperatures. Hypothermia is associated with a reduction in fibrinolytic system activity, which could increase the risk for thrombus formation.
Renal, Endocrine, and Gastrointestinal Effects And Drug Metabolism
Hypothermia induces hypomagnesemia and hypokalemia. The magnesium depletion in particular can worsen neurologic injury. Hypothermia induces hyperglycemia via increasing insulin resistance, gluconeogenesis, and glycogenolysis. Of note, hyperglycemia has been associated with worse neurologic outcomes, increased infection rates and a higher incidence of renal failure. Therefore, it is very important to monitor and correct hyperglycemia while avoiding hypoglycemia, which also has serious adverse effects on the injured brain.
Hypothermia may induce ileus and delayed gastric emptying. Moreover, hypothermia reduces drug clearance of commonly used medications such as opiates, sedatives, volatile anesthetics, vasopressors, and neuromuscular agents. Care should therefore be taken in dosing these medications in patients treated with hypothermia.3,29,30
Upon traumatic brain injury, stroke, and other brain insults, patients may receive pharmacotherapy as well as hypothermic treatment, which may influence the kinetic as well as dynamic parameters of pharmacotherapy. Patients should be carefully monitored to avoid drug toxicity and treatment failure. (Based on Han et al.Current Neuropharmacology. 2012;10:80-87.)
ADME, absorption, distribution, metabolism and elimination
Hypothermia as a Neuroprotective Agent In Clinical Practice
Hypothermia was shown to be a very effective neuroprotective agent in animal studies of ischemic stroke, with a 44% reduction in infarct size and a robust improvement in functional outcome.31 The problem in translating those animal studies to clinical practice was that the hypothermia was induced very early, either prior to the stroke or within less than 3 hours after the stroke, which may not be feasible in clinical practice.
The first COOL AID (Cooling for Acute Ischemic Brain Damage) study was a controlled study of 19 patients with middle cerebral artery occlusion; 10 were cooled to target moderate hypothermia (32°C) with a surface-cooling blanket in combination with intravenous or intra-arterial thrombolysis. All patients were intubated and mechanically ventilated, and shivering was controlled with neuromuscular blockade.32 No significant differences in mortality or complications were observed between hypothermic and nonhypothermic patients. However, neurologic outcomes were only slightly better in the hypothermic group. The extended time to induce hypothermia from stroke onset (6.2 hours) and to reach the target temperature (3.5 hours) could explain the lack of therapeutic effect from hypothermia in this trial.32
The COOL AID II study randomized 40 acute stroke patients to either standard therapy or hypothermia to a target temperature of 33°C, and used an endovascular heat exchange catheter through the inferior vena cava for 24 hours.33 This study achieved target temperatures more quickly (an average of 77 minutes) than the previous one. Moreover, no mechanical intubation or neuromuscular blockade was used in this trial. Complications from the endovascular cooling device included deep venous thrombosis and a case of retroperitoneal hematoma. Clinical outcomes measured by the National Institutes of Health Stroke Scale (NIHSS) score showed no differences between groups. Nevertheless, the infarct volume measured by diffusion-weighted imaging (DWI) was lower in the hypothermic group (73%) versus the nonhypothermic group (124%).33
ICTuS-L (Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke) was a randomized feasibility study of endovascular cooling and intravenous tissue plasminogen activator in awake patients treated within 6 hours of ischemic stroke. Eighteen patients were treated at a target temperature of 33°C for either 12 or 24 hours with an endovascular heat exchange catheter. The anti-shivering regimen used in this trial was either a conservative regimen involving surface warming and low-dose meperidine or a proactive regimen that added prophylactic buspirone and meperidine. NIHSS clinical outcomes were similar in both groups at 30 days and 3 months. Of note, more effective cooling was achieved using the proactive anti-shivering regimen.34
Selective antegrade cerebral perfusion (ACP) is employed via the right axillary artery, which allows for hypothermic cooling of the brain while avoiding such hypothermic side effects as shivering. Moderate hypothermia induced by ACP during aortic arch surgery was associated with lower mortality and fewer neurologic complications than deep hypothermia.35
The combination of caffeine and ethanol infusion (caffeinol) has been shown to be neuroprotective. Caffeinol combined with hypothermia was therefore tried in stroke patients.35 Those trials highlighted important clinical insights into the use of hypothermia in ischemic stroke. Patients can tolerate temperatures up to 33°C without neuromuscular blockade and mechanical ventilation. Endovascular cooling techniques work faster than surface cooling to reach targeted temperatures, but present more technical challenges. Hypothermia is usually tolerated for 12 to 24 hours, but longer periods of hypothermia are associated with more adverse events.23,36
Neonatal Hypoxic–Ischemic Brain Injury and Hypoxic–Ischemic Encephalopathy
Perinatal hypoxic–ischemic brain injury (HIBI) stems from a variety of etiologies that include acute perinatal asphyxia, brain hemorrhage, stroke, birth trauma and congenital brain abnormalities. HIBI produces hypoxic–ischemic encephalopathy (HIE) in neonates and preterm infants. HIE is a major cause of global child mortality and morbidity (eg, cerebral palsy, mental retardation, epilepsy) occurring in an estimated 2.5 of every 1,000 term births in developed countries, with a 10-fold higher incidence of 26 per 1,000 term births in the developing world.37,38 Brain injury following hypoxic ischemia (HI) has provided the opportunity to use hypothermia to reduce or even arrest secondary brain injury.
The Cool-Cap trial used selective head cooling with mild systemic hypothermia for treatment of perinatal asphyxia. The trial enrolled 234 infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography: 116 patients were cooled to a rectal temperature of 34°C to 35°C for 72 hours within 5.5 hours of birth versus 118 infants treated with conventional care.39 The neurologic outcomes were not different between the groups at 18-month follow-up. Nonetheless, the post hoc analysis after controlling for baseline clinical severity showed improvement in outcomes.
In a multicenter trial of 208 infants with perinatal asphyxia, which used cooling blankets to reach a target temperature, 102 infants were assigned to be cooled to esophageal temperature of 33.5°C within 6 hours of birth for 72 hours, with slow rewarming, and 106 infants were assigned to a control group.40 Follow–up assessment occurred between 18 and 22 months of age, and revealed adverse outcomes (ie, death or disability) that were significantly reduced in the hypothermic group of patients (44% vs 62%; risk ratio, 0.72; 95% CI, 0.54-0.95;P=0.01).
Moreover, those patients were reevaluated at 6 to 7 years of age. Of the 208 trial participants, primary outcomes were available for 190. Of the 97 children in the hypothermic group and 93 children in the control group, death or IQ score less than 70 occurred in 46 (47%) and 58 (62%) of the children, respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03).41 Thus, the rate of the combined end point of death or IQ score less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than those receiving conventional care, but the difference was not significant.
The TOBY (Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy) trial enrolled 325 infants with moderate to severe asphyxia. The target temperature was 33°C to 34°C for 72 hours using gel packs in 163 patients versus 162 in the control group. The infants in the cooled group had increased rates of survival without neurologic sequelae at 18-month follow-up (relative risk [RR], 1.57; 95% CI, 1.16-2.12;P=0.03).42 In addition, the incidence of cerebral palsy was lower among survivors in the hypothermic group.
Shah et al have shown in their meta-analysis a significant reduction in the risk for death or moderate to severe neurodevelopmental disability in a hypothermic (n=249) infant group compared with a control (n=284) group (RR, 0.76; 95% CI, 0.65-0.88).43 Cardiac arrhythmias and thrombocytopenia were common with hypothermia; however, they were clinically benign.
Hypothermia and Traumatic Brain Injury
Hypothermia has been used very successfully in the preclinical setting for TBI models in both animals and humans in isolated trials.44-46 However, the outcome from using hypothermia for TBI over multicenter trials has been either negative or even harmful. Hutchison et al studied the effect of hypothermia in pediatric patients after TBI.47 The study randomized 108 patients to the hypothermia (33°C) group and 117 to the normothermia group. The use of hypothermia proved to be harmful, as the mortality rate was 21% in the hypothermic group and 12% in the normothermia group (P=0.06). However, the study was criticized for its short cooling period of only 24 hours and fairly rapid rewarming.48
In the Cool Kids trial, the patients (younger than 18 years old) were randomized to either hypothermia (rapidly cooled to 32°C-33°C for 48-72 hours, then rewarmed by 0.5°C-1.0°C every 12-24 hours) or normothermia (maintained at 36.5°C-37.5°C). The Cool Kids trial was stopped early for futility as there was no difference between the 2 groups in mortality at 3 months, secondary global function outcomes using the Glasgow Outcome Scale (GOS), the pediatrics version of the GOS-extended revision, or the occurrence of serious adverse events.47 A recent meta-analysis of the efficacy of using therapeutic hypothermia in children with TBI showed no benefit. However, the authors concluded that further large-scale, well-designed, randomized controlled trials on this topic are needed.
There have been 3 noteworthy multicenter studies of therapeutic hypothermia in adults with TBI: NABIS:H–I (National Acute Brain Injury Study: Hypothermia I), NABIS:H-II, and the Japanese Brain Hypothermia (B-HYPO) trial.49-51 These studies found either no difference or worse mortality rates in the hypothermia group compared with the normothermia group.49-51
The European Study of Therapeutic Hypothermia, an international, multicenter, randomized controlled trial, examined the effect of titrated therapeutic hypothermia (32°C-35°C) on intracranial pressure (ICP) and neurologic outcome. The study, which enrolled 387 patients at 47 centers in 18 countries, failed to prove any benefit for using hypothermia in TBI patients, and indeed outcomes may be worsened.52 However, patients in the hypothermia group had better control of ICP since they required fewer stage 3 interventions (eg, barbiturates, decompressive craniotomy). There were some limitations to the study. First, the assessment of complications during the trial might have been biased, since the investigators were not blinded. Second, the rate of adherence, defined as more than 80% of core temperature measurements within range in 4 days was lower in both groups (64.8% in the hypothermia group vs 68.8% in the control group). Third, the enrollment included patients with TBI resulting from a variety of causes and there was no subgroup analysis, such as patients with subdural hematomas.
NABIS:H-II has shown the benefit of therapeutic hypothermia in a selected group of patients. For instance, early hypothermia improved outcomes in patients undergoing surgical decompression surgery for focal insults, but early cooling did not improve outcomes in patients with diffuse brain injury.1,4 Moreover, the combined vasoconstrictive effects of barbiturates and hypothermia resulted in reduced cerebral blood flow. The subsequent reduction in cerebral blood flow might have worsened cerebral ischemia. Thus, although these measures could reduce ICP, they did not result in beneficial outcomes.48
Maintenance of normocapnia is important since excessive hypocapnia can increase ischemia in injured brain tissue, and excessive hypercapnia can increase brain edema.53 In addition, a slow rewarming rate should be guided not only by the ICP but also by brain injury biomarkers and brain chemistry.54 Two ongoing studies—the POLAR-RCT (Prophylactic Hypothermia Trial to Lessen Brain Injury) and the LTH-1 (Long-Term Mild Hypothermia For Severe Traumatic Brain Injury-1) trial—may provide valuable data for the use of therapeutic hypothermia in TBI patients.55,56
Until the results of ongoing trials are published, maintaining normothermia and avoiding hyperthermia should be advised in managing patients with TBI. However, therapeutic hypothermia can be reserved as a final option in patients with refractory increased ICP.57
Hypothermia and Cardiac Arrest
In 2002, 2 landmark randomized controlled trials showed that induction of mild hypothermia for 12 or 24 hours increased survival and improved neurologic outcomes for a selected group of patients who had experienced out-of-hospital cardiac arrest (OHCA).57,58 Subsequently, therapeutic hypothermia after cardiac arrest was implemented as standard care for unconscious survivors of OHCA by international guidelines.59 However, the 2 trials were criticized for including patients with only shockable rhythms.
A recently published targeted temperature management (TTM) trial questioned whether induced hypothermia or avoidance of hyperthermia actually benefited patients after cardiac arrest.60 The TTM trial found that cooling to 33°C after witnessed cardiac arrest conferred no benefits compared with maintaining a temperature of 36°C. The TTM authors concluded that benefits of temperature management result mainly from fever control and that further lowering of core temperature provides no benefit.60 However, the study had some limitations, such as late-start cooling (up to 4 hours after the return of spontaneous circulation), slow cooling rates (up to 10 hours to target temperature), and rapid rewarming rates.61 A recent meta-analysis confirmed the TTM results that support avoiding hyperthermia rather than inducing hypothermia following OHCA.62 Rittenberger and Clifton, in their editorial, rightly insist that “we should not regress to a pre-2002 style of care that does not manage temperature at all.”63
Hypothermia and Spinal Cord Injury
Spinal cord injury (SCI) is a catastrophic health problem around the world. In the United States, it is estimated that 12,000 to 20,000 new SCIs occur each year, and currently over 200,000 Americans are living with disability due to SCI.64
Therapeutic hypothermia is the only available method for preventing secondary neural damage combined with surgery after SCI. Therapeutic hypothermia applied either locally via epidural catheter or systemically in animal models of SCI reduced neural cell apoptosis as measured by transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL), lipid oxidation measured by malondialdehyde (MDA) and reduced monomeric glutathione-peroxidase (GSH-peroxidase), spinal cord edema, and motor function recovery.65-67
Moreover, therapeutic hypothermia enhances neural stem cell (NSC) differentiation into a glial lineage after SCI by attenuating secondary mechanisms and thereby improving the microenvironment for NSC differentiation and functional recovery.2,68 The clinical experience in humans for use of hypothermia in SCI management dates back to the 1970s and 1980s. Therapeutic hypothermia was mainly applied locally by irrigating the exposed spinal cord or dura with ice-cold (4°C-5°C) saline after laminectomy.
These early studies had small sample numbers, lacked randomization and control groups, and did not reach sufficient statistical power to justify widespread use of hypothermia. Recently, the use of endovascular cooling for inducing modest hypothermia (33°C) after SCI has been shown to be potentially therapeutic. In 2007, modest hypothermia using endovascular cooling to 33.5°C gained public attention after its use in a professional case with cervical SCI. The patient exhibited significant neurologic recovery within 2 hours of endovascular cooling and additional improvement over the weeks following his injury.69
This case was followed by a randomized trial through the Miami Project to Cure Paralysis (University of Miami). The trial employed modest hypothermia (33°C) with endovascular cooling within 8 hours of SCI, which was continued for 48 hours, with a slow rewarming rate of 0.1°C/h. In total, 6 of 14 patients (42.8%) demonstrated some improvement from American Spinal Injury Association (ASIA) grade A (complete motor and complete sensory impairment) to another grade at 12-month follow-up. Three patients improved to grade B (complete motor and incomplete sensory impairment), 2 to grade C (some muscle movement below level of injury), and 1 to grade D (incomplete motor impairment with intact sensation), exceeding the baseline expectations of spontaneous recovery after complete cervical SCI, as reported elsewhere.2,70 The American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS) joint section on disorders of the spine and peripheral nerve, in November 2013, considered systemic modest hypothermia to be a grade C therapy (with level IV evidence) and might be applied safely in SCI victims.4
In conclusion, the use of therapeutic hypothermia is considered to be a promising neuroprotective agent in several clinical settings. However, there is still a need for large, randomized, well-powered trials to prove the usefulness of hypothermia as a neuroprotective agent.
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