Critical Care Update
David J. Dries, MSE, MD
Targeted Temperature Management: Part 1 Early use of therapeutic hypothermia as part of a targeted temperature management (TTM) strategy is now being considered for application by critical care transport programs. Resources needed to initiate hypothermia outside the hospital are relatively few. These articles are summarized to review relevant clinical concerns in this rapidly evolving area.
The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369:2197-2206. Several studies have shown that moderate systemic hypothermia (30°C) or mild hypothermia (34°C) reduces brain damage after cardiac arrest in study animals. The exact mechanism for this cerebral protection is unclear. A reduction in cerebral oxygen consumption and other multifactorial chemical and physical mechanisms during and after ischemia have been proposed. These include retardation of destructive enzyme reactions, suppression of free radical formation with secondary tissue damage, protection of the fluidity of lipoprotein membranes, reduction of the oxygen demand in low-flow regions, reduction of intracellular acidosis and inhibition of biosynthesis, and release and uptake of excitatory neurotransmitters. The first article from the Hypothermia After Cardiac Arrest Study Group screened over 3,300 patients to obtain a sample size of approximately 270 individuals. Fifty-five percent of these patients had good neurologic outcome, far better than patients who did not receive temperature reduction. This first article targeted temperatures of 32°C to 34°C, maintained hypothermia for 24 hours, and limited study entry to individuals with ventricular fibrillation. The second study from the same issue of the New England Journal of Medicine showed a good outcome in 49% of patients treated with hypothermia as opposed to 26% of individuals who were normothermic after arrest. The presenting rhythm is not emphasized. The interval of hypothermia was 12 hours in this study. Authors of the second New England Journal of Medicine article also point out the potential for hypothermia to blunt inappropriate shifts of calcium from the extracellular to the intracellar space, reduction in the glutamate level, and decreased 128
intracranial pressure as other potential mechanisms for benefit after hypothermia following resuscitated cardiac arrest in the unconscious patient. We lack clinical data to support these proposed mechanisms for cerebral injury after cardiac arrest. Thus, an unfocused approach using hypothermia is the current modality of choice. A more recent study, also from the New England Journal of Medicine, examined targeted temperature management at 33°C versus 36°C after cardiac arrest. These investigators used a 36-hour period of temperature control. Both study groups were carefully managed to avoid the development of fever. In this third trial, published 11 years after the 2 studies discussed earlier, 46% and 48% of patients in the 33°C group and the 36°C group, respectively, survived or had good neurologic function. Authors of the third New England Journal of Medicine article highlight the contemporary debate surrounding targeted temperature management. The first issue is applicability of therapeutic hypothermia to patients with brain injury caused by circulatory arrest of a variety of etiologies. Whole body hypothermia influences all organ systems, and the potential benefits must be balanced against the potential side effects. The population of patients with cardiac arrest is heterogeneous, and the potential risks and benefits of temperature intervention may not be the same across subgroups. The second issue is the beneficial target temperature for therapeutic hypothermia. The recommended temperature of 32°C to 34°C in other studies has been extrapolated from experiments in animals. Similar results have now been reported with milder cooling. Perhaps most important, although unstudied, is the careful avoidance of natural temperature evolution in either the 36°C or the 33°C groups. These investigators actively controlled the temperature of the patients during the intervention period and aimed to prevent fever during the first 3 days after cardiac arrest. Thus, the importance of hypothermia versus fever management warrants additional investigation. The initial rhythm may also affect outcome because a shockable rhythm offers the possibility of more rapid return to spontaneous circulation. These investigators enrolled as many as 20% of patients with nonshockable rhythms.
Rittenberger JC, Polderman KH, Smith WS, Weingart SD. Emergency neurological life support: resuscitation following cardiac arrest. Neurocrit Care. 2012;17(suppl):S21-S28. This summary statement is a great “nuts and bolts” review. I will attempt to summarize the key points. So what does a TTM protocol look like? There are few absolute contraindications to TTM. Patients demonstrating Air Medical Journal 34:3
rapid and complete neurologic recovery should not be cooled. Similarly, patients with “do not resuscitate” orders or contraindications to critical care unit admission or illnesses that preclude meaningful recovery should not be cooled. Relative contraindications are more common. In patients with active bleeding or those at high risk for bleeding, cooling to a temperature of 35°C such that coagulation is not affected is probably advisable. Patients who are greater than 12 hours after cardiac arrest are less likely to benefit from TTM but may benefit from fever prevention. Preclinical data suggest that there is no benefit to TTM begun more than 12 hours after cardiac arrest. Minor contraindications include known cold agglutinins given the risk of aggregation of these proteins below 31°C and that temperature in distal extremities may reach this level with surface cooling. Warming extremities during core hypothermia could be considered. Comatose patients are at risk for aspiration pneumonia, and many patients with out-of-hospital cardiac arrest have aspirated during the event. Induction of TTM frequently requires significant doses of sedation with side effects that include respiratory depression and loss of airway control. Thus, patients receiving TTM should be intubated and mechanically ventilated. Endovascular, esophageal, bladder, or rectal temperature monitoring is essential. Adequate sedation is extremely important. Failure of sedation allowing breakthrough shivering is the most common cause of failure to achieve or maintain hypothermia. The possibility of inadequate sedation should be a primary consideration if hypothermia has not been achieved or maintained. Judicious use of sedation will permit adequate shivering suppression and not result in deep sedation confounding neurologic prognostication. In the hemodynamically stable patient (systolic blood pressure ⬎ 100 mmHg), propofol is the initial choice for sedation because of rapid metabolism allowing meaningful neurologic examination soon after the agent is stopped. In patients with hypotension (systolic blood pressure ⬍ 90 mmHg), a midazolam infusion may be used. The half-life of midazolam is prolonged during hypothermia and may reduce the accuracy of neurologic examination. Therefore, during the maintenance phase of hypothermia, low continuous doses of midazolam supplemented with bolus doses are preferred. Analgesia in addition to sedation is commonly employed using fentanyl or remifentanil infusions. These drugs with opioid properties also suppress shivering. Intravenous magnesium sulfate (4 g over 15 minutes) may also be used to suppress the shivering response. Neuromuscular blockade may also be used to abolish the shivering response. However, this strategy includes a number of drawbacks including the inability to detect convulsive activity that may be an important component of the neurologic evaluation. The incidence of nonconvulsive status epilepticus in the comatose postarrest patient is found to range from 12% to 24%, and an even higher incidence has been reported in pediatric cardiac arrest (47%). Seizures after cardiac arrest have been linked to increased mortality. May-June 2015
Therefore, continuous electroencephalographic monitoring should be used in comatose patients after cardiac arrest, particularly if neuromuscular blockade is used. Rapid induction of hypothermia is best accomplished by a combination of methods. Pressure bag infusion of cold saline or Ringer lactate decreases core body temperature by approximately 1°C for each liter of fluid administered. Fluid should be administered as rapidly as possible except in the patient with left ventricular failure. Automated devices may be used to induce and maintain hypothermia as well as to rewarm the patient in a controlled manner. Surface devices can be set to the maximal rate of cooling and then programmed for the initial desired temperature. Although these devices use patient temperature as feedback, undershoot in temperature can occur. Some surface cooling and intravascular devices only permit a choice of goal temperature and the speed of cooling. Rapid induction of hypothermia is current practice, but there are no studies that have investigated the potential benefit of earlier achievement of goal temperature. Most of these techniques could be used in the transport setting if desired. During the maintenance phase, patients should be followed up for coronary occlusion, the most common cause of cardiac arrest. Angioplasty and stenting may be performed at this time. Computed tomographic imaging of the brain is also essential because up to 5% of postarrest patients show intracranial hemorrhage, which may change the therapeutic approach. Cerebral edema may also be identified during imaging, which has been associated with poor outcomes after cardiac arrest. For patients with cerebral edema, longer cooling periods should be considered. Electroencephalographic monitoring is also appropriate as noted earlier. For the most part, maintenance hypothermia is in the range of 32°C to 34°C. Rewarming should be gradual, typically over 12 to 24 hours. The maximal rate of rewarming is 0.5°C per hour. Rewarming may be complicated by hyperkalemia and hypoglycemia. Rebound hyperthermia is common, and cooling should be resumed if core temperature increases beyond 37.5°C. Recooling may be rapidly accomplished with a bolus of cold intravenous fluids because fever after cardiac arrest has been associated with worse neurologic prognosis. Physiologic consequences of hypothermia include bradycardia with heart rate in the range of 30 to 40 beats per minute. Atropine is not an effective management for this problem. Catecholamines including dopamine, dobutamine, or isoproterenol may be used. In general, bradycardia is not dangerous unless associated with hypotension (see below). Arrhythmias may develop if the core temperature decreases below 28°C. Should a significant arrhythmia develop with a core temperature less than 30°C, the patient should be rewarmed to a core temperature greater than 30°C followed by gradual warming to a higher goal temperature. Arrhythmias should not be viewed as a reason to discontinue treatment. QT prolongation is common during hypothermia. QT-prolonging drugs are used with caution. 129
Because of failure of cerebral vasoregulation, a mean arterial pressure greater than 80 mmHg is needed to provide adequate perfusion. Response to PCO2 remains intact, and a goal PCO2 is 32 to 40 mmHg. Renal performance reflects cold-induced diuresis with a transient increase in glomerular filtration. This diuresis may produce hypokalemia, hypomagnesemia, and hypophosphatemia. Hypothermia shifts potassium from the extracellular to the intracellular space. Given these changes, frequent assessment of electrolytes with electrolyte replacement is indicated. Goal potassium levels are greater than 4 mmol/L with magnesium greater than 2 mg/dL and phosphorus greater than 3 mg/dL. Other organ systems affected include the gastrointestinal tract where motility is diminished with hypothermia. Relative coagulopathy is noted at temperatures less than 35°C. Mild bleeding may be seen in up to 20% of patients managed with hypothermia. Insulin resistance has also been described. Hyperglycemic patients may require high doses of insulin.
Staer-Jensen H, Sunde K, Olasveengen TM, et al. Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Crit Care Med. 2014;42:2401-2408. Terman SW, Hume B, Meurer WJ, Silbergleit R. Impact of presenting rhythm on short- and longterm neurologic outcome in comatose survivors of cardiac arrest treated with therapeutic hypothermia. Crit Care Med. 2014;42:2225-2234. Kilgannon JH, Roberts BW, Jones AE, et al. Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest. Crit Care Med. 2014;42:2083-2091. Polderman KH, Varon J. When better is the enemy of good: the optimal heart rate during therapeutic cooling. Crit Care Med. 2014;42:2452-2454. This group of articles presents some “dos and don’ts” in early management of the cardiac arrest patient. Terman et al at the University of Michigan examine the impact of the presenting rhythm on prognosis in patients with out-of-hospital cardiac arrest. This work is valuable in that long-term outcomes are examined, and contemporary experience includes an increasing number of patients with nonshockable rhythms. This retrospective study suggests that the identification of a shockable rhythm is associated with improved neurologic outcome and overall survivability from out-of-hospital arrest. Thus, the first “to do” is rigorous evaluation of the patient to identify the possibility of a shockable rhythm. It is important to note that the Michigan patients had demographics including a significant incidence of diabetes, dialysis dependence, and a higher fraction of unwitnessed arrest. 130
Respiratory dysfunction was more common in patients with nonshockable rhythms. Clearly, these demographics could affect the outcomes reported. The possibility of bradycardia with therapeutic hypothermia after cardiac arrest has been described earlier. StaerJensen et al associate improved neurologic outcome with bradycardia presenting during therapeutic hypothermia. Polderman and Varon provide an excellent summary of relevant physiology. Hypothermia has direct and indirect effects on cardiac rhythm and myocardial function. A drop in temperature to levels just below normal initially leads to an increase in catecholamines and activation of the sympathetic nervous system. Constriction of peripheral vessels and a shift of blood from peripheral vascular beds to deeper veins in the core occur, leading to an increase in venous return to the heart. This hypothermia-induced rise in venous return initially produces mild sinus tachycardia and contributes to the diuresis observed with early stages of hypothermia. Other changes are a decrease in antidiuretic hormone, renal tubular dysfunction, and activation of atrial natriuretic peptide. The initial increase in heart rate is reversed as core temperature decreases below 35.5°C. Heart rate begins to drop progressively as core temperature falls and soon sinus bradycardia ensues. At 32°C, the normal heart will beat 35 to 45 beats per minute. This is caused by a hypothermiainduced decrease in the rate of spontaneous depolarization of cardiac pacemaker cells including those of the sinus node combined with decreased speed of myocardial impulse conduction and increased duration of action potentials. Changes in the electrocardiogram may include prolonged PR intervals, increased QT intervals, and widened QRS complexes. Osborne waves may develop. Mild to moderate hypothermia decreases the risk of arrhythmias and makes the myocardium less resistant to defibrillation. This has been shown in a variety of swine models. Hypothermia also increases myocardial contractility in most patients, and blood pressure remains stable or increases unless the patient is hypovolemic. If hypothermia-induced bradycardia is treated by the administration of agents to increase the heart rate, myocardial contractility may decrease, and an inappropriate increase in myocardial oxygen demand may occur. Whether bradycardia actually improves outcome cannot be answered by these data. However, the clinician should not attempt to fix low heart rates, which are appropriate during hypothermia. Patients should be monitored for shivering, hypovolemia, and hypotension. Kilgannon et al found that the time-weighted average mean arterial pressure was associated with improved neurologic outcome at a mean arterial pressure threshold greater than 70 mmHg. A physiologic rationale can be created for the maintenance of higher mean arterial pressure in the post–cardiac arrest patient. These individuals experience systemic inflammation with myocardial stunning and adrenal axis suppression. This combination of factors results in hemodynamic instability, which may compromise outcomes of the injured Air Medical Journal 34:3
brain where dysfunctional autoregulation of cerebral blood flow is likely. Disruption of normal cerebral vascular autoregulation links cerebral blood flow to cerebral perfusion pressure, which is dependent on mean arterial pressure. The 2010 American Heart Association guidelines for post–cardiac care recommend goal-directed hemodynamic optimization after return of spontaneous circulation. These guidelines acknowledge a lack of high-quality evidence to support a specific mean arterial pressure target with return of spontaneous circulation. In a subanalysis of the data obtained by Kilgannon et al, patients who are able to maintain a mean arterial pressure greater than 70 mmHg without vasopressor administration had a higher proportion of good neurologic outcomes compared with patients who achieved a mean arterial pressure greater than 70 mmHg with vasopressor administration (48% vs. 24%, P ⫽ .01). It is possible that patients able to respond by maintaining adequate cerebral perfusion pressure without vasoactive drug administration are more likely to have good neurologic outcome and that supporting mean arterial pressure with vasoactive drugs may not confer benefit. Animal data, however, do suggest benefit to pharmacologic support of blood pressure. It is important to note that the work of Kilgannon and associates did not test a therapeutic vasopressor approach. Thus, the ideal target blood pressure and the means to this goal after cardiac arrest remain unclear. Available evidence supports a strong recommendation that clinicians at the bedside carefully monitor blood pressure avoiding hypotensive insults after resuscitation from cardiac arrest.
• Some data suggest that a mean arterial pressure of 70 mmHg is associated with improved outcomes in these patients. Clinical data to support vasoactive drug use in these patients is not available. Watch these individuals for hypothermia contributing to hypotension due to early fluid shifts and diuresis. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in St Paul, MN, and can be reached at [email protected]. Acknowledgment The author acknowledges the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal. 1067-991X/$36.00 Copyright 2015 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2015.02.003
Summary Points • Examination of the literature reviewed suggests that air medical programs can initiate hypothermia protocols and should consider this therapeutic strategy. • Aggressively seek to identify shockable rhythms in evaluation of patients with cardiac arrest. These individuals are likely to have better ultimate outcome with hypothermia protocols. • It may be that avoiding fever is as important or more important than the degree of hypothermia employed after cardiac arrest. • Bradycardia is an appropriate physiologic response to cardiac arrest. Bradycardia should be anticipated in patients with retained ventricular function. • Patients with return of spontaneous circulation after cardiac arrest will require airway management where TTM is used. • Best care for these patients uses sedation to suppress the shivering response. Clinical exam is better maintained with sedation than neuromuscular blockade. • Arrhythmias are not a contraindication to hypothermia. In fact, mild to moderate hypothermia should decrease the risk of arrhythmia in the resuscitated cardiac arrest patient and make the myocardium less resistant to defibrillation. May-June 2015
131
David J. Dries, MSE, MD
Targeted Temperature Management: Part 1 Early use of therapeutic hypothermia as part of a targeted temperature management (TTM) strategy is now being considered for application by critical care transport programs. Resources needed to initiate hypothermia outside the hospital are relatively few. These articles are summarized to review relevant clinical concerns in this rapidly evolving area.
The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369:2197-2206. Several studies have shown that moderate systemic hypothermia (30°C) or mild hypothermia (34°C) reduces brain damage after cardiac arrest in study animals. The exact mechanism for this cerebral protection is unclear. A reduction in cerebral oxygen consumption and other multifactorial chemical and physical mechanisms during and after ischemia have been proposed. These include retardation of destructive enzyme reactions, suppression of free radical formation with secondary tissue damage, protection of the fluidity of lipoprotein membranes, reduction of the oxygen demand in low-flow regions, reduction of intracellular acidosis and inhibition of biosynthesis, and release and uptake of excitatory neurotransmitters. The first article from the Hypothermia After Cardiac Arrest Study Group screened over 3,300 patients to obtain a sample size of approximately 270 individuals. Fifty-five percent of these patients had good neurologic outcome, far better than patients who did not receive temperature reduction. This first article targeted temperatures of 32°C to 34°C, maintained hypothermia for 24 hours, and limited study entry to individuals with ventricular fibrillation. The second study from the same issue of the New England Journal of Medicine showed a good outcome in 49% of patients treated with hypothermia as opposed to 26% of individuals who were normothermic after arrest. The presenting rhythm is not emphasized. The interval of hypothermia was 12 hours in this study. Authors of the second New England Journal of Medicine article also point out the potential for hypothermia to blunt inappropriate shifts of calcium from the extracellular to the intracellar space, reduction in the glutamate level, and decreased 128
intracranial pressure as other potential mechanisms for benefit after hypothermia following resuscitated cardiac arrest in the unconscious patient. We lack clinical data to support these proposed mechanisms for cerebral injury after cardiac arrest. Thus, an unfocused approach using hypothermia is the current modality of choice. A more recent study, also from the New England Journal of Medicine, examined targeted temperature management at 33°C versus 36°C after cardiac arrest. These investigators used a 36-hour period of temperature control. Both study groups were carefully managed to avoid the development of fever. In this third trial, published 11 years after the 2 studies discussed earlier, 46% and 48% of patients in the 33°C group and the 36°C group, respectively, survived or had good neurologic function. Authors of the third New England Journal of Medicine article highlight the contemporary debate surrounding targeted temperature management. The first issue is applicability of therapeutic hypothermia to patients with brain injury caused by circulatory arrest of a variety of etiologies. Whole body hypothermia influences all organ systems, and the potential benefits must be balanced against the potential side effects. The population of patients with cardiac arrest is heterogeneous, and the potential risks and benefits of temperature intervention may not be the same across subgroups. The second issue is the beneficial target temperature for therapeutic hypothermia. The recommended temperature of 32°C to 34°C in other studies has been extrapolated from experiments in animals. Similar results have now been reported with milder cooling. Perhaps most important, although unstudied, is the careful avoidance of natural temperature evolution in either the 36°C or the 33°C groups. These investigators actively controlled the temperature of the patients during the intervention period and aimed to prevent fever during the first 3 days after cardiac arrest. Thus, the importance of hypothermia versus fever management warrants additional investigation. The initial rhythm may also affect outcome because a shockable rhythm offers the possibility of more rapid return to spontaneous circulation. These investigators enrolled as many as 20% of patients with nonshockable rhythms.
Rittenberger JC, Polderman KH, Smith WS, Weingart SD. Emergency neurological life support: resuscitation following cardiac arrest. Neurocrit Care. 2012;17(suppl):S21-S28. This summary statement is a great “nuts and bolts” review. I will attempt to summarize the key points. So what does a TTM protocol look like? There are few absolute contraindications to TTM. Patients demonstrating Air Medical Journal 34:3
rapid and complete neurologic recovery should not be cooled. Similarly, patients with “do not resuscitate” orders or contraindications to critical care unit admission or illnesses that preclude meaningful recovery should not be cooled. Relative contraindications are more common. In patients with active bleeding or those at high risk for bleeding, cooling to a temperature of 35°C such that coagulation is not affected is probably advisable. Patients who are greater than 12 hours after cardiac arrest are less likely to benefit from TTM but may benefit from fever prevention. Preclinical data suggest that there is no benefit to TTM begun more than 12 hours after cardiac arrest. Minor contraindications include known cold agglutinins given the risk of aggregation of these proteins below 31°C and that temperature in distal extremities may reach this level with surface cooling. Warming extremities during core hypothermia could be considered. Comatose patients are at risk for aspiration pneumonia, and many patients with out-of-hospital cardiac arrest have aspirated during the event. Induction of TTM frequently requires significant doses of sedation with side effects that include respiratory depression and loss of airway control. Thus, patients receiving TTM should be intubated and mechanically ventilated. Endovascular, esophageal, bladder, or rectal temperature monitoring is essential. Adequate sedation is extremely important. Failure of sedation allowing breakthrough shivering is the most common cause of failure to achieve or maintain hypothermia. The possibility of inadequate sedation should be a primary consideration if hypothermia has not been achieved or maintained. Judicious use of sedation will permit adequate shivering suppression and not result in deep sedation confounding neurologic prognostication. In the hemodynamically stable patient (systolic blood pressure ⬎ 100 mmHg), propofol is the initial choice for sedation because of rapid metabolism allowing meaningful neurologic examination soon after the agent is stopped. In patients with hypotension (systolic blood pressure ⬍ 90 mmHg), a midazolam infusion may be used. The half-life of midazolam is prolonged during hypothermia and may reduce the accuracy of neurologic examination. Therefore, during the maintenance phase of hypothermia, low continuous doses of midazolam supplemented with bolus doses are preferred. Analgesia in addition to sedation is commonly employed using fentanyl or remifentanil infusions. These drugs with opioid properties also suppress shivering. Intravenous magnesium sulfate (4 g over 15 minutes) may also be used to suppress the shivering response. Neuromuscular blockade may also be used to abolish the shivering response. However, this strategy includes a number of drawbacks including the inability to detect convulsive activity that may be an important component of the neurologic evaluation. The incidence of nonconvulsive status epilepticus in the comatose postarrest patient is found to range from 12% to 24%, and an even higher incidence has been reported in pediatric cardiac arrest (47%). Seizures after cardiac arrest have been linked to increased mortality. May-June 2015
Therefore, continuous electroencephalographic monitoring should be used in comatose patients after cardiac arrest, particularly if neuromuscular blockade is used. Rapid induction of hypothermia is best accomplished by a combination of methods. Pressure bag infusion of cold saline or Ringer lactate decreases core body temperature by approximately 1°C for each liter of fluid administered. Fluid should be administered as rapidly as possible except in the patient with left ventricular failure. Automated devices may be used to induce and maintain hypothermia as well as to rewarm the patient in a controlled manner. Surface devices can be set to the maximal rate of cooling and then programmed for the initial desired temperature. Although these devices use patient temperature as feedback, undershoot in temperature can occur. Some surface cooling and intravascular devices only permit a choice of goal temperature and the speed of cooling. Rapid induction of hypothermia is current practice, but there are no studies that have investigated the potential benefit of earlier achievement of goal temperature. Most of these techniques could be used in the transport setting if desired. During the maintenance phase, patients should be followed up for coronary occlusion, the most common cause of cardiac arrest. Angioplasty and stenting may be performed at this time. Computed tomographic imaging of the brain is also essential because up to 5% of postarrest patients show intracranial hemorrhage, which may change the therapeutic approach. Cerebral edema may also be identified during imaging, which has been associated with poor outcomes after cardiac arrest. For patients with cerebral edema, longer cooling periods should be considered. Electroencephalographic monitoring is also appropriate as noted earlier. For the most part, maintenance hypothermia is in the range of 32°C to 34°C. Rewarming should be gradual, typically over 12 to 24 hours. The maximal rate of rewarming is 0.5°C per hour. Rewarming may be complicated by hyperkalemia and hypoglycemia. Rebound hyperthermia is common, and cooling should be resumed if core temperature increases beyond 37.5°C. Recooling may be rapidly accomplished with a bolus of cold intravenous fluids because fever after cardiac arrest has been associated with worse neurologic prognosis. Physiologic consequences of hypothermia include bradycardia with heart rate in the range of 30 to 40 beats per minute. Atropine is not an effective management for this problem. Catecholamines including dopamine, dobutamine, or isoproterenol may be used. In general, bradycardia is not dangerous unless associated with hypotension (see below). Arrhythmias may develop if the core temperature decreases below 28°C. Should a significant arrhythmia develop with a core temperature less than 30°C, the patient should be rewarmed to a core temperature greater than 30°C followed by gradual warming to a higher goal temperature. Arrhythmias should not be viewed as a reason to discontinue treatment. QT prolongation is common during hypothermia. QT-prolonging drugs are used with caution. 129
Because of failure of cerebral vasoregulation, a mean arterial pressure greater than 80 mmHg is needed to provide adequate perfusion. Response to PCO2 remains intact, and a goal PCO2 is 32 to 40 mmHg. Renal performance reflects cold-induced diuresis with a transient increase in glomerular filtration. This diuresis may produce hypokalemia, hypomagnesemia, and hypophosphatemia. Hypothermia shifts potassium from the extracellular to the intracellular space. Given these changes, frequent assessment of electrolytes with electrolyte replacement is indicated. Goal potassium levels are greater than 4 mmol/L with magnesium greater than 2 mg/dL and phosphorus greater than 3 mg/dL. Other organ systems affected include the gastrointestinal tract where motility is diminished with hypothermia. Relative coagulopathy is noted at temperatures less than 35°C. Mild bleeding may be seen in up to 20% of patients managed with hypothermia. Insulin resistance has also been described. Hyperglycemic patients may require high doses of insulin.
Staer-Jensen H, Sunde K, Olasveengen TM, et al. Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Crit Care Med. 2014;42:2401-2408. Terman SW, Hume B, Meurer WJ, Silbergleit R. Impact of presenting rhythm on short- and longterm neurologic outcome in comatose survivors of cardiac arrest treated with therapeutic hypothermia. Crit Care Med. 2014;42:2225-2234. Kilgannon JH, Roberts BW, Jones AE, et al. Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest. Crit Care Med. 2014;42:2083-2091. Polderman KH, Varon J. When better is the enemy of good: the optimal heart rate during therapeutic cooling. Crit Care Med. 2014;42:2452-2454. This group of articles presents some “dos and don’ts” in early management of the cardiac arrest patient. Terman et al at the University of Michigan examine the impact of the presenting rhythm on prognosis in patients with out-of-hospital cardiac arrest. This work is valuable in that long-term outcomes are examined, and contemporary experience includes an increasing number of patients with nonshockable rhythms. This retrospective study suggests that the identification of a shockable rhythm is associated with improved neurologic outcome and overall survivability from out-of-hospital arrest. Thus, the first “to do” is rigorous evaluation of the patient to identify the possibility of a shockable rhythm. It is important to note that the Michigan patients had demographics including a significant incidence of diabetes, dialysis dependence, and a higher fraction of unwitnessed arrest. 130
Respiratory dysfunction was more common in patients with nonshockable rhythms. Clearly, these demographics could affect the outcomes reported. The possibility of bradycardia with therapeutic hypothermia after cardiac arrest has been described earlier. StaerJensen et al associate improved neurologic outcome with bradycardia presenting during therapeutic hypothermia. Polderman and Varon provide an excellent summary of relevant physiology. Hypothermia has direct and indirect effects on cardiac rhythm and myocardial function. A drop in temperature to levels just below normal initially leads to an increase in catecholamines and activation of the sympathetic nervous system. Constriction of peripheral vessels and a shift of blood from peripheral vascular beds to deeper veins in the core occur, leading to an increase in venous return to the heart. This hypothermia-induced rise in venous return initially produces mild sinus tachycardia and contributes to the diuresis observed with early stages of hypothermia. Other changes are a decrease in antidiuretic hormone, renal tubular dysfunction, and activation of atrial natriuretic peptide. The initial increase in heart rate is reversed as core temperature decreases below 35.5°C. Heart rate begins to drop progressively as core temperature falls and soon sinus bradycardia ensues. At 32°C, the normal heart will beat 35 to 45 beats per minute. This is caused by a hypothermiainduced decrease in the rate of spontaneous depolarization of cardiac pacemaker cells including those of the sinus node combined with decreased speed of myocardial impulse conduction and increased duration of action potentials. Changes in the electrocardiogram may include prolonged PR intervals, increased QT intervals, and widened QRS complexes. Osborne waves may develop. Mild to moderate hypothermia decreases the risk of arrhythmias and makes the myocardium less resistant to defibrillation. This has been shown in a variety of swine models. Hypothermia also increases myocardial contractility in most patients, and blood pressure remains stable or increases unless the patient is hypovolemic. If hypothermia-induced bradycardia is treated by the administration of agents to increase the heart rate, myocardial contractility may decrease, and an inappropriate increase in myocardial oxygen demand may occur. Whether bradycardia actually improves outcome cannot be answered by these data. However, the clinician should not attempt to fix low heart rates, which are appropriate during hypothermia. Patients should be monitored for shivering, hypovolemia, and hypotension. Kilgannon et al found that the time-weighted average mean arterial pressure was associated with improved neurologic outcome at a mean arterial pressure threshold greater than 70 mmHg. A physiologic rationale can be created for the maintenance of higher mean arterial pressure in the post–cardiac arrest patient. These individuals experience systemic inflammation with myocardial stunning and adrenal axis suppression. This combination of factors results in hemodynamic instability, which may compromise outcomes of the injured Air Medical Journal 34:3
brain where dysfunctional autoregulation of cerebral blood flow is likely. Disruption of normal cerebral vascular autoregulation links cerebral blood flow to cerebral perfusion pressure, which is dependent on mean arterial pressure. The 2010 American Heart Association guidelines for post–cardiac care recommend goal-directed hemodynamic optimization after return of spontaneous circulation. These guidelines acknowledge a lack of high-quality evidence to support a specific mean arterial pressure target with return of spontaneous circulation. In a subanalysis of the data obtained by Kilgannon et al, patients who are able to maintain a mean arterial pressure greater than 70 mmHg without vasopressor administration had a higher proportion of good neurologic outcomes compared with patients who achieved a mean arterial pressure greater than 70 mmHg with vasopressor administration (48% vs. 24%, P ⫽ .01). It is possible that patients able to respond by maintaining adequate cerebral perfusion pressure without vasoactive drug administration are more likely to have good neurologic outcome and that supporting mean arterial pressure with vasoactive drugs may not confer benefit. Animal data, however, do suggest benefit to pharmacologic support of blood pressure. It is important to note that the work of Kilgannon and associates did not test a therapeutic vasopressor approach. Thus, the ideal target blood pressure and the means to this goal after cardiac arrest remain unclear. Available evidence supports a strong recommendation that clinicians at the bedside carefully monitor blood pressure avoiding hypotensive insults after resuscitation from cardiac arrest.
• Some data suggest that a mean arterial pressure of 70 mmHg is associated with improved outcomes in these patients. Clinical data to support vasoactive drug use in these patients is not available. Watch these individuals for hypothermia contributing to hypotension due to early fluid shifts and diuresis. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in St Paul, MN, and can be reached at [email protected]. Acknowledgment The author acknowledges the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal. 1067-991X/$36.00 Copyright 2015 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2015.02.003
Summary Points • Examination of the literature reviewed suggests that air medical programs can initiate hypothermia protocols and should consider this therapeutic strategy. • Aggressively seek to identify shockable rhythms in evaluation of patients with cardiac arrest. These individuals are likely to have better ultimate outcome with hypothermia protocols. • It may be that avoiding fever is as important or more important than the degree of hypothermia employed after cardiac arrest. • Bradycardia is an appropriate physiologic response to cardiac arrest. Bradycardia should be anticipated in patients with retained ventricular function. • Patients with return of spontaneous circulation after cardiac arrest will require airway management where TTM is used. • Best care for these patients uses sedation to suppress the shivering response. Clinical exam is better maintained with sedation than neuromuscular blockade. • Arrhythmias are not a contraindication to hypothermia. In fact, mild to moderate hypothermia should decrease the risk of arrhythmia in the resuscitated cardiac arrest patient and make the myocardium less resistant to defibrillation. May-June 2015
131
