Neurocritical Care

13. Hypothermia After Cardiopulmonary Resuscitation

A 61-year-old woman slumped down with rattling breathing and rapidly developing cyanosis. A bystander performed cardiopulmonary resuscitation, but the EMS arrived quickly and documented ventricular fibrillation. Several shocks were needed to restore circulation. The patient remained comatose and was intubated. External ice packs and iced saline was used during transportation, and after arrival to the intensive care unit, the patient was cooled to 33ûC using an external cooling device. An EEG showed suppressed activity but changed to epileptiform discharges during rewarming. Somatosensory-evoked potentials showed absent N20 response on the right side. Serum neuron specific enolase is 55 ng/mL. The patient still requires substantial amount of vasopressors and inotropes for a failing heart. Neurologic examination two days after rewarming reveals no eye opening to pain, no motor response to pain, intact pupil responses to light, normal corneal reflexes, intact grimacing, and cough response to suctioning. The family wants to know what to expect, as does the cardiologist.

What do you do now?

Neurologists seem to be the arbiters of gloomy events in coronary care units, but that may change in the era of therapeutic hypothermia. The truth is that even when comatose patients are cooled immediately after cardiopulmonary resuscitation (CPR), the chance of survival is still about 50/50, and many patients die within a week from withdrawal of support. Hypothermia is now considered standard of care for patients with out-of-hospital arrest from ventricular fibrillation, and a protocol is shown in Table 13.1. Hypothermia protocols—as expected—vary considerably across centers, and this also applies to utilization. Selection of patients also varies with an increasing number of centers, including patients with asystole and in-hospital arrest. Yet, there is no evidence that therapeutic hypothermia is effective under these circumstances. More and more hospitals are set up to provide therapeutic hypothermia, but neurologists currently may see just about equal numbers of patients with or without hypothermia treatment.

Poor predictors of outcome at the time of resuscitation have been identified and the cardiac rhythm causing circulatory arrest is a major determinant of outcome. Outcome of patients with a “nonshockable” rhythm (asystole, pulseless electrical activity) is poor, but rapid defibrillation in other rhythms (ventricular fibrillation, ventricular tachycardia) may be successful, resulting in rapid awakening of the patient and even the probability of intact neurologic function.

TABLE 13.1. Hypothermia Protocol in Comatose Survivors after Cardiopulmonary Resuscitation

1.5 liter of refrigerated (4–6ûC) saline in 30–60 minutes

Operate cooling device to 33ûC

Monitor bladder temperature

Sedate patient before paralysis

Sedate with Midazolam 0.3 mg/kg/hr IV and Fentanyl 0.1 mcg/kg/hr IV

Paralyze (to prevent shivering) with Atracurium 0.2 mg/kg

Normalize serum magnesium and potassium values

Normalize serum glucose values

Monitor electrolytes, WBC, and platelets

Monitor EEG/video during rewarming and for 24 hours (if available)

The clinical picture of postcardiac resuscitation syndrome is concerning. Patients may have a major myocardial dysfunction (which may be reversible), a systemic ischemic-reperfusion syndrome with intravascular volume depletion, for a full-blown acute coronary syndrome requiring reperfusion strategies. More invasive treatments such as extracorporeal membrane oxygenation may be necessary in some cases. A profound kidney and liver injury may be present. The response to treatment of these complications plays an important role in planning the level of care.

The neurological examination is focused on motor response, presence of spontaneous eye movements, appearance of myoclonus or seizures and whether there has been brainstem injury resulting in changes in key brainstem reflexes. The immediate presence of localizing motor responses is the best evidence that the duration of ischemia to the brain has been brief. Long duration of circulatory arrest results in a more profound insult and may be apparent by the documentation of abnormal extensor or flexor response or no response to a noxious stimulus in the arms and legs. Motor response after CPR, however, has never been a very reliable predictor of outcome even before the wide application of induced hypothermia. Patients with withdrawal responses to pain may not wake up or may regain only minimal consciousness. Of even greater concern is myoclonic status epilepticus. Myoclonus involves the face, limbs, and axial muscles. These brief jerks are spontaneous and in the first hours after CPR may be unrelenting and forceful. It may make the patient move in the bed and cause considerable upset to family members.

Brainstem reflexes are typically normal because the brainstem is often spared from anoxic-ischemic injury. Absent brainstem reflexes may occur after prolonged periods of resuscitation or in resuscitation of trauma patients with substantial blood loss. Fixed and dilated pupils are more frequently associated with asystole than with ventricular fibrillation and that may simply be a reflection of more prolonged anoxic- ischemic brain injury. Fixed and dilated pupils throughout the resuscitation procedure usually indicate a poor chance of success. Successful cardiac resuscitation with good neurologic recovery more often occurs in patients with persistently contracted and reactive pupils from the onset.

TABLE 13.2 Poor Outcome Anticipated

0–24 hours

Myoclonus status epilepticus

24–72 hours

SSEP: absent cortical (N20) responses

24–72 hours

Serum NSE > 33 ug/L*

> 72 hours

Absent pupil or corneal reflexesExtensor motor responsesAbsent motor responses*

* These findings are not as reliable after therapeutic hypothermia

Prognostic factors for poor neurologic outcome have been identified in a recent evidence-based guideline from the American Academy of Neurology (Table 13.2). Several of these factors may be difficult to reliably assess due to use of sedative and analgesic agents needed with therapeutic hypothermia, and particularly the reliability of the motor response is currently questioned. Moreover the prognostic value of a single sample of serum neuron specific enolase (NSE) is very uncertain (serial measurements showing an increase may have more value, but this remains to be proven). Failure to awaken several days after cardiopulmonary resuscitation may prompt MR imaging, but studies on its prognostic importance are yet not definitive. However, finding diffuse laminar cortical necrosis in an unchanged comatose patient likely predicts a poor outcome (nursing home and major functional disability).

So how do we approach this patient? First, there is a renewed concern that patients in therapeutic hypothermia—who are also paralyzed—may be actively seizing, and failure to treat seizures may result in worse outcome. No evidence has yet been presented that aggressive management of seizures (and in particular subclinical status epilepticus) may impact outcome. Generalized epileptiform discharges or overt epileptic seizures (without clinical accompaniment of myoclonus status epilepticus) may occur and can be treated with additional increasing doses of midazolam. However, patients with EEG patterns of status epilepticus, burst suppression, or generalized suppression with no reactivity remain comatose despite aggressive antiepileptic drug administration. It is far more likely these EEG patterns reflect severe anoxic-ischemic injury rather than a treatable condition. The value of aggressive treatment of these “malignant” EEG patterns is thus very doubtful and there has not been published evidence to the contrary.

Second, we usually proceed with summarizing clinical signs and laboratory data that are inarguably linked to poor prognosis in a comatose patient. In our patient we did not find myoclonus status epilepticus or loss or pupil and cornea reflexes, SSEP showed a preserved cortical (N20) response on one side, and only the NSE was elevated (an uncertain finding in patients treated with hypothermia). Thus, in our patient’s example, we were unable to prognosticate with certainty, and continued support was warranted. The patient gradually awakened but remained in a severely disabled state requiring nursing home placement. This case illustrates the current limitations of early prognostication in comatose patients treated with therapeutic hypothermia after cardiac resuscitation. The whole notion of being able to tell early on who is going to do well and who is not remains a challenge for the neurologist with only a few clinical cues to go by. We may know who is going to do poorly but we have difficulty predicting who is going to regain independence and recover full use of intellectual capabilities.

KEY POINTS TO REMEMBER REGARDING HYPOTHERMIA AFTER CARDIOPULMONARY RESUSCITATION

· Certain clinical and laboratory findings are helpful in prognostication. Poor prognosis can be expected in patients with absence of pupillary light responses, corneal reflexes, and an extensor or absent motor response, or myoclonus status epilepticus.

· Documented seizures on EEG may need treatment, but the value of aggressive antiepileptic treatment is uncertain.

· The confounding effects of sedative drugs during hypothermia needs careful judgment.

Further Reading

Chamorro C, Borrallo JM, Romera MA, et al. Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: a systemic review. Anesth Analg 2010;110:1328–1335.

Dumas F, Grimaldi D, Zuber B, et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation. 2011;123:877–886.

Fugate JE, Wijdicks EFM, Mandrekar J, Claassen DO, Manno EM, White RD, Bell MR, Rabinstein AA. Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol 2010; 68:907–914.

Fugate JE, Wijdicks EFM, White R,Rabinstein AA. Does therapeutic hypothermia affect time to awakening in survivors of cardiopulmonary arrest? Neurology 2011, in press

Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. Int Emerg Nurs 2010;18:8–28.

Walters JH, Morley PT, Nolan JP. The role of hypothermia in post-cardiac arrest patients with return of spontaneous circulation: a systematic review, Resuscitation 2011; 82: 508–516.

Wijdicks EFM, Hijdra A, Young GB, Bassetti CL, Wiebe S; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 67:203–210.