THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 1, Number 1, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2010.0002
The Use of Hypothermia Therapy in Cardiac Arrest Survivors Sanjeev U. Nair1 and Justin B. Lundbye1,2
The annual incidence of out-of-hospital cardiac arrests in the United States is *350,000–450,000 per year. The prognosis for cardiac arrest survivors remains extremely poor. Therapeutic hypothermia (TH) is the only therapy proven to improve survival and neurological outcome in these patients. This article discusses the pathophysiology of neurological injury in cardiac arrest survivors and states the presumed mechanisms by which TH mitigates brain injury in these patients. It reviews the contraindications to the use of this therapy, methods of cooling, and phases of TH and elaborates on the intensive care unit management of TH. The use of TH in ventricular fibrillation survivors has become the standard of care and continues to evolve in its application as an essential therapy in cardiac arrest patients.
During cardiac arrest, global ischemia to the brain causes rapid depletion of ATP and a switch to anaerobic glycolysis (White et al., 2000). The transcellular ion pumps fail and transmembrane electrochemical gradients get distorted. As a result, there is an increase in extracellular Kþ and intracellular Ca 2þ concentration with resultant depolarization and release of excitotoxic neurotransmitters, such as glutamate, and of tissue-destroying enzymes, such as proteases and lipases (White et al., 2000). In animal models, the duration of the ischemic insult has a variable affect on different subpopulations of neurons (Petito et al., 1998). Neurons that have a high metabolic rate such as the hippocampal pyramidal neurons, cerebellar Purkinje cells, thalamic reticular neurons, and the medium-sized neurons of the corpus striatum are more sensitive to damage during the initial stage of ischemia when compared with others (Blomqvist and Wieloch, 1985; Hossmann et al., 2001; Taraszewska et al., 2002). This partially explains the wide spectrum of hypoxic brain injury with relation to duration of cerebral ischemia. After reestablishment of blood flow to the brain, there is development of hyperemia with concomitant cerebral edema and raised intracranial pressure (ICP). In addition, there is impaired cerebrovascular autoregulation and microcirculatory dysfunction with microthrombi, endothelial cell swelling, red blood cell sludging, and the presence of inflammatory cells leading to the ‘‘no-reflow’’ phenomenon (Ames et al., 1968). Thus, there is ongoing ischemic damage to the neuronal tissue even after return of spontaneous circulation (ROSC). The second process of injury takes place after normalization of circulation. This reperfusion injury is mainly driven by
he annual incidence of out-of-hospital cardiac arrests in the United States is *350,000–450,000 per year (Schulman et al., 2006). Despite improvements in prehospital and hospital care, the prognosis for cardiac arrest survivors remains extremely poor. The median survival to discharge is 8.4% (Nichol et al., 2008) and many of the survivors have central nervous system sequelae (Wachelder et al., 2009) ranging from mild memory impairment to permanent vegetative state (van Alem et al., 2004). Postischemic brain injury is the leading cause of death among survivors of cardiac arrest (Laver et al., 2004). Presently, mild hypothermia is the only form of therapy that improves both survival and neurological outcome in cardiac arrest survivors (Bernard et al., 2002; Hypothermia After Cardiac Arrest Study Group, 2002). Pathophysiology of Postcardiac Arrest Neurological Injury Although the molecular mechanisms underlying the cellspecific pattern of ischemia-induced neuronal death are not well understood, it can be viewed as two integrated processes (White et al., 1996). The first, characterized by necrosis, occurs during cardiac arrest from hypoxia. The second process, characterized by apoptosis, is the result of reperfusion injury, which activates specific intracellular signaling cascades, after the establishment of circulation. These processes start immediately after resuscitation and progress over 2–3 days. Thus, there is a window of opportunity in the postcardiac arrest period to therapeutically influence these harmful processes.
Cardiovascular Hospitalist Program, Hartford Hospital, Hartford, Connecticut. Cardiovascular Fellowship Program (Hartford Hospital), University of Connecticut School of Medicine, Farmington, Connecticut.
10 accelerated production of free oxygen radicals and nitric oxide and continuing release of glutamate. Glutamate, an excitotoxic neurotransmitter that activates the NMDA receptors, causes disruption of Ca2þ homeostasis with resultant intracellular Ca2þ overload (Lipton, 1999; Bano and Nicotera, 2007). This triggers Ca2þ-dependent enzyme cascades that lead to lipid peroxidation and intracellular acidosis. In addition, there is a triggering of downstream signaling pathways resulting in apoptosis. A number of such pathways involve downstream signaling molecules such as phosphatidylserine, tumor necrosis factor family of death receptors, mitochondrial cytochrome c, caspases such as caspase-3, and DNA fragments (Scoltock and Cidlowski, 2004; Lopez-Hernandez et al., 2006). The destructive processes of excitotoxicity, free radical production, cytokine release, and the heterogeneity in cerebral blood flow during the pericardiac arrest period generates heat and results in rising brain temperature (Hayashi et al., 1994). This in turn leads to further activation of the cascades of destruction described above. The end point of injuries sustained in the ischemic and reperfusion stages is cellular death by necrosis and apoptosis. The degree of severity of these processes sustained during this period determines the neurological outcome and perhaps survival of patients with cardiac arrest. How Is Therapeutic Hypothermia Neuroprotective? Therapeutic hypothermia (TH) can be defined as the reduction of the core body temperature of a patient to 328C–348C in order to prevent or reduce neurologic injury. Although TH affords robust neuroprotection against global ischemiainduced neuronal death, the underlying neuroprotective mechanisms have not yet been fully understood. It has been shown that brain oxygen utilization reduces by *5%–7% for every 18C reduction in core body temperature (Oku et al., 1993). The reduction in energy demand slows the rate of high-energy phosphate depletion and lactate accumulation. This helps preserve membrane integrity and transcellular ion homeostasis. Current knowledge postulates that this may be one of the many beneficial effects of hypothermia on the brain (Sterz et al., 1996; Xiao, 2002). Hypothermia also retards the temperaturesensitive processes of injury described earlier. There is slowing down of the injury cascade seen in the ischemic phase and reduced cellular swelling and brain edema after establishment of cerebral perfusion (Dempsey et al., 1987). In addition, hypothermia reduces excitotoxic neurotransmitter release and mitigates oxidative stress as well as lipid peroxidation (Busto et al., 1989; Globus et al., 1995). If initiated early on, hypothermia also reduces the release of proinflammatory cytokines, nitric oxide, and glutamate from microglia and neurons (Kumar and Evans, 1997; Berger et al., 2002). Thus, hypothermia can potentially improve neuronal survival and diminish the various neurologic sequelae in the postcardiac arrest period.
NAIR AND LUNDBYE (Hypothermia After Cardiac Arrest Study Group, 2002; Bernard et al., 2002). The number needed to treat in these trials ranged from 4 to 7, which is remarkably low compared with much higher number needed to treat for most interventions in cardiology and neurology (Cohen et al., 1997; Andersen et al., 2003; Bussiere and Wiebe, 2005; Lemos Junior and Atallah, 2009). Since then a multitude of trials looking at the feasibility, safety, and neurologic outcomes using a variety of cooling techniques have been conducted (Fig. 1) (Yanagawa et al., 1998; Nagao et al., 2000; Zeiner et al., 2000; Felberg et al., 2001; Al-Senani et al., 2004; Kim et al., 2005; Busch et al., 2006; Holzer et al., 2006; Rundgren et al., 2006; Sakurai et al., 2006; Scott et al., 2006; Belliard et al., 2007; Haugk et al., 2007; Hovdenes et al., 2007; Kliegel et al., 2007; Laish-Farkash et al., 2007; Pichon et al., 2007; Sunde et al., 2007; Janata et al., 2008; Storm et al., 2008; Fries et al., 2009; Gaieski et al., 2009; Gal et al., 2009; Hammer et al., 2009; Kagawa et al., 2009; Nielsen et al., 2009; Schefold et al., 2009). Based on supportive data of clinical trials, the International Liaison Committee on Resuscitation (ILCOR) and American Heart Association have recommended that ‘‘Unconscious adults with spontaneous circulation after out-of-hospital cardiac arrest be cooled to 32– 348C for 12–24 hours when the initial rhythm is ventricular fibrillation’’ (Nolan et al., 2003). The committee also suggests that cooling may be useful for survivors of cardiac arrest due to other rhythms or for in-hospital cardiac arrests. Contraindications to the Use of TH Most contraindications for TH in cardiac arrest patients are based on the exclusion criteria used in published trials (Bernard et al., 2002; Hypothermia After Cardiac Arrest Study Group, 2002) (Table 1). These contraindications are frequently relative and may change as more studies on this therapy emerge. Patients electing not to be resuscitated will obviously not have this therapy. TH is relatively contraindicated in the presence of severe sepsis and severe active bleeding, as there is an increased risk of both infection and bleeding at low body temperatures. TH is unproductive in the presence of advanced malignancy and severe chronic disease with poor life expectancy. In addition, TH is presently not recommended in patients with unwitnessed cardiac arrest or with a Glasgow Coma Scale of 8 (Hypothermia After Cardiac Arrest Study Group, 2002). It is also not recommended if >30 minutes elapse before ROSC or if >6 hours have elapsed after ROSC. TH is presently contraindicated in the presence of hemodynamic instability despite aggressive vasopressor treatment, in pregnant patients, and in those 18 years or younger. There is also no role of TH in patients who are already hypothermic (T 30 minutes or >6 hours after ROSC Hemodynamic instability despite appropriate vasopressor therapy Pregnancy Age l8 years Core body T on admission 0.28C–0.58C). This requires very frequent or continuous measurement of core body temperature. The new catheter-based cooling systems are able to constantly monitor core body temperature and appropriately adjust the temperature of cooling liquid by feedback mechanisms, making it easier and more accurate to maintain target temperature. During the maintenance phase, the patient’s condition usually stabilizes and standard intensive care measures can be continued. Rewarming
There are four phases of TH. The induction phase is followed by the phase of maintenance of hypothermia, then the rewarming phase, and finally the phase of maintenance of normothermia. The latter three phases requires ICU level care with close monitoring, because there are profound shifts in the hemodynamic, electrolyte, and metabolic parameters, which require appropriate clinical and pharmacologic intervention. Induction of hypothermia TH is induced by either external cooling alone or a combination of external and internal cooling methods. The aim is to quickly reduce the core body temperature and achieve a target temperature range between 328C and 348C. The natural thermoregulatory response of the body to produce heat during this phase must be overridden using sedatives and paralytics. External cooling using cooling blankets/mattresses and application of ice packs and infusion of large volume of icecold isotonic crystalloid can rapidly reduce core body temperature (Bernard et al., 2003). These cooling techniques can be initiated by emergency medical technicians in the field and en route to the hospital. Combining external and intravascular cooling methods is an attractive strategy to safely and rapidly achieve target temperatures. However, only external cooling methods are practical in the community health setting because of their user-friendly and inexpensive nature. During the induction of TH, the challenge is to monitor and treat side effects such as shivering (see below), hypovolemia, electrolyte disorders, and hyperglycemia. Frequent adjustments to the dosing of sedatives, paralytics, vasoactive agents, and ventilator settings are required during this phase. Maintenance of hypothermia During this phase, the goal is to maintain target hypothermic temperatures (328C–348C) for at least 12 hours with-
The rewarming phase brings the patient’s core body temperature back to normothermia. It is important to have a slow and controlled rewarming, to prevent complications (Hildebrand et al., 2005; Maxwell et al., 2005; Alam et al., 2006). Blood–metabolism mismatch may contribute to ‘‘rebound’’ hyperthermia, cerebral edema, and raised ICP commonly seen with rapid rewarming (Diao and Zhu, 2006). Thus, patients should be slowly rewarmed at a rate of 0.28C–0.58C per hour, which generally achieves normothermia in 5–8 hours. Rewarming can be done either actively or passively. Active rewarming with continuous temperature monitoring and feedback can be done using the same devices used for cooling (e.g., circulating fluid in intravascular catheters or hydrogel pads). Active rewarming may be safer than passive rewarming as it leads to a reduced incidence of the aforementioned neurologic complications, prevents sudden shifts in body electrolytes, and reduces the risk of hypoglycemia occurring from increased insulin sensitivity as the body temperature increases. Maintenance of normothermia This final phase is important in preventing the rebound rise in core body temperature after normothermia has been achieved. Rebound hyperthermia, as mentioned earlier, is common and can exacerbate brain injury (Lavinio et al., 2007; Polderman, 2008). Thus, frequent monitoring of patients for temperature elevations is necessary, especially when only external cooling has been used. With newer cooling devices with temperature auto-feedback, target temperatures of 36.58C–378C can be easily set on the device to maintain normothermia once rewarming is done. For this purpose, intravascular cooling devices are left in situ even after normothermia is achieved. Aggressive prevention of shivering is needed during this phase as well, to reduce the risk of hyperthermia (see next page).
Table 2. Cooling Techniques Noninvasive methods Ice packs Forced cold air tents/blankets Cooling blankets and mattress (air/water circulating) Cooling hydrogel pads Cold water immersion Helmets or caps (air/water circulating) Cooling neck collara
Uncommon and experimental cooling techniques.
Invasive methods Intravenous ice-cold saline infusion Intravascular (caval) catheter cooling Body cavity cooling (nasogastric/intraperitoneal/bladder/rectal)a Selective brain cooling (femoral-carotid bypass cooling)a Intra-aortic flush coolinga Retrograde jugular vein flush coolinga Nasopharyngeal balloon catheter coolinga Intrapulmonary cooling (cooling gas or perfluorocarbons)a Extracorporeal cooling via heat exchange circuita
14 Core Body Temperature Monitoring Postcardiac arrest, the initial goal is to reduce core body temperature as quickly as possible to the target temperature range of 328C–348C (mild hypothermia) and to maintain this temperature with minimal fluctuations for up to 24 hours, before rewarming the patient back to normothermia. Further, it is necessary to prevent overcooling with its antecedent complications as well as prevent ‘‘rebound’’ hyperthermia, which can mitigate the beneficial effects of hypothermia. Thus, frequent and accurate monitoring of the core body temperature during this therapy is vital to its application. Core body temperature of patients while in transit and in the emergency room is most frequently measured using the rectal and aural canal routes. However, during the induction phase when there is need for rapid cooling, these routes may not truly represent the core body/blood temperatures (Imamura et al., 1998; Greenes and Fleisher, 2004). Thus, more invasive temperature monitoring is done via temperature probes in the distal esophagus or the bladder (Eshel and Safar, 1999; Moran et al., 2007). In the ICU, central venous temperature can also be measured using central pulmonary artery catheters. This method of monitoring with feedback to the cooling device reduces fluctuations in target hypothermic temperatures and prevents rebound hyperthermia by actively varying the temperature of the circulating fluid in the cooling balloons of the catheter. ICU Management of TH Ventilator management Patients undergoing TH are comatose and require mechanical ventilation. ILCOR recommends using the lowest FiO2 that can maintain SaO2 between 94% and 96%, to minimize oxidative stress during reperfusion injury (Nolan et al., 2003). Forehead oximetry is recommended as this is more reliable than peripheral oximetry in the presence of coldinduced digital vasoconstriction (Branson and Mannheimer, 2004; Schallom et al., 2007). Presently, hyperventilation is not used to reduce intracranial hypertension in these patients, because this may lead to worsening of cerebral ischemic injury by hypocapnic vasoconstriction. Conversely, hypercapnia should be avoided as it can exacerbate cerebral edema. During the different phases of cooling, it is vital to frequently monitor blood gas values. Unless appropriate corrections for hypothermia are applied, reference values routinely used for blood gas analysis can lead to overestimation of PO2 and PCO2 and underestimation of pH in hypothermic patients (Bacher, 2005). This results in erroneous adjustment of ventilator settings for minute ventilation. The resultant alkalosis leads to electrolyte disturbances and cerebral vasoconstriction. Patients undergoing TH are also at increased risk for ventilator-associated pneumonia because hypothermia is immunosuppressive. To prevent this, the use of standard protocols for ventilator-associated pneumonia prophylaxis in the ICU as well as use of prophylactic antibiotics is recommended (Sirvent et al., 1997; Liberati et al., 2009). Hemodynamic monitoring As mild hypothermia sets in, there is a gradual reduction in the heart rate as well as cardiac index. There is also a slight increase in blood pressure and central venous pressure due to
NAIR AND LUNDBYE peripheral vasoconstriction and increased venous return (Bergman et al., 2010). However, over a period of time, there is a ‘‘cold diuresis’’ caused by hypothermia-induced renal tubular dysfunction as well as decreased antidiuretic hormone levels (Allen and Gellai, 1993; Broman et al., 1998). This leads to hypovolemia, which requires administration of isotonic intravenous fluids to prevent concomitant drop in cardiac output and blood pressure. Often during the induction and maintenance stages of TH, it also becomes necessary to use vasopressors to maintain an adequate mean arterial pressure (70–100 mm Hg). Arterial catheters for accurate monitoring of mean arterial pressure are preferable and should be placed during the induction phase before cold-induced vasoconstriction sets in. In the presence of significant myocardial dysfunction or damage, central venous pressure or pulmonary artery catheter monitoring also becomes necessary. It must be stressed that TH does not preclude the use of percutaneous coronary intervention or intra-aortic balloon counterpulsation support when indicated (Hovdenes et al., 2007). Electrocardiographic abnormalities especially prolongation of the PR and QT intervals along with widening of the QRS complex may be seen with TH. The presence of Osborne waves on electrocardiogram is not commonly seen with the mild hypothermic temperatures used in TH (Rankin and Rae, 1984; Vassallo et al., 1999). Significant cardiac arrhythmias are not common at temperatures of 328C–348C, unless caused by a primary cardiac pathology (Tiainen et al., 2009). Moreover, the presence of mild hypothermia perhaps facilitates the treatment of arrhythmias by reducing the energy threshold for successful defibrillation (Boddicker et al., 2005). Shivering The normal thermoregulatory mechanisms in humans are very sensitive to changes in core body temperature and even a reduction in temperature of 0.28C can trigger shivering and cutaneous vasoconstriction (Lopez et al., 1994) (Table 3). In fact, 20% of thermoregulatory input is derived from the skin and hence it is an important organ that contributes to shivering (Mahmood and Zweifler, 2007). The use of cutaneous counter-warming where warm air is made to flow gently over the skin of the face, neck and extremities during intravascular cooling reduces the thermoregulatory threshold and thus the risk of shivering (Mekjavic and Eiken, 1985; Sharkey et al., 1993; Badjatia et al., 2009). Shivering can raise oxygen consumption, increase energy demands and raise body temperature, thus hindering the initiation and overall efficacy of TH. Shivering may also lead
Table 3. Strategies to Mitigate or Prevent Shivering During Therapeutic Hypothermia Nonpharmacological Cutaneous counterwarming Slow rate of rewarming Pharmacological (can be used in combination) Propofol Opiates Dexmedetomidine Buspirone, nefopam, midazolam Magnesium sulfate Neuromuscular paralyzing agents
THE USE OF HYPOTHERMIA THERAPY to increased cardiac complications in postcardiac arrest patients (Frank et al., 1997). Objective assessment of the patient using scales such as the Bedside Shivering Assessment Scale is recommended for optimal control of shivering (Badjatia et al., 2008). Various medications and methods to prevent shivering have been shown to be successful in this setting. Since the majority of patients undergoing TH are intubated, anesthetics, sedatives and paralytics can be safely used to reduce or prevent shivering. Propofol, the most commonly used anesthetic in the ICU, has been shown to reduce both vasoconstriction and shivering (Matsukawa et al., 1995). Unlike other opioids, meperidine is a potent antishivering drug due to its kappa-opioid receptor agonism (Kurz et al., 1997). Although less effective, opioids such as fentanyl, sulfentanil and alfentanil are also used for this purpose since they impair thermoregulatory mechanisms (Kurz et al., 1995; Alfonsi et al., 1998). Dexmedetomidine, a selective a2-receptor subtype 2a agonist, is an effective sedative and analgesic and is used in combination with meperidine in the induction and maintenance of TH (Talke et al., 1997; Doufas et al., 2003). Buspirone, an anxiolytic, nefopam, a centrally acting analgesic, or intravenous magnesium sulfate can also be used as adjuvants to reduce shivering (Alfonsi et al., 2004; Zweifler et al., 2004; Lenhardt et al., 2009). Paralytics should be considered only if shivering continues in spite of maximal use of sedative and anesthetic drugs. When using paralytics there should be continuous electroencephalographic (EEG) monitoring to detect seizures that would require treatment (Rundgren et al., 2006). The use of prostaglandin E1 (PGE1) to reduce vasoconstriction is not beneficial in TH (Kawaguchi et al., 1999). The use of inodilators like amrinone accelerates cooling in neurosurgical patients, but their effect as an additive in TH therapy of postcardiac arrest patients has not been studied (Inoue et al., 2001).
15 of invasive ICP monitoring and jugular bulb oximetry to monitor cerebral perfusion pressure may become routine (Feldman and Robertson, 1997; Nordmark et al., 2009). Early use of osmotherapy in consultation with the neurologist should be considered if there is persistently high ICP or signs of cerebral herniation (Koenig et al., 2008). Glucose control Hyperglycemia is commonly seen following cardiac arrest and during TH and is associated with poor neurological outcomes (Longstreth et al., 1983; Mullner et al., 1997; Langhelle et al., 2003). Therefore, appropriate prevention and treatment of hyperglycemia in these patients is a priority. ILCOR recommends keeping blood glucose levels