THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 3, Number 2, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2013.0009

Prolonged Hypothermia for Neurological Protection David H. Kung, MD, and Oren A. Friedman, MD

Treatment with mild hypothermia induced after cardiopulmonary resuscitation has become a standard of care, but optimal timing and duration of hypothermia remains unclear. We present a 66-year-old man admitted after an out-of-hospital cardiac arrest. Because of his severe hypoxemia, cardiopulmonary instability, and respiratory acidosis after resuscitation, he was continued on therapeutic hypothermia until his hypoxia resolved. As a result, the patient was kept at the goal hypothermic temperature of 33C for a total of 48 hours, compared with the usual 24-hour standard, with excellent sustained neurological recovery. This case documents the usefulness of extending hypothermia when applied to severely unstable patients and suggests that a sliding-target approach may be applied on a patient-by-patient basis.

medical services. Emergency medical services found the patient in ventricular fibrillation. Initial defibrillation yielded ventricular tachycardia. After two subsequent shocks and administration of an intravenous amiodarone bolus, there was return of spontaneous circulation with a sinus rhythm in the 80s. He was intubated during the resuscitation, and chest compressions were delivered throughout per Advanced Cardiovascular Life Support protocol. An electrocardiogram on arrival to our emergency department showed normal sinus rhythm and a left bundle-branch block of unknown duration. His initial Glasgow Coma Scale score was 3. Therapeutic hypothermia was initiated immediately with crushed ice packs and cold saline infusion. The ST-elevation myocardial infarction pager was activated, and the patient was taken for urgent cardiac catheterization. In the cardiac catheterization laboratory, Arctic Sun Temperature Management System pads (Medivance, Inc.) were applied to the patient for continuance of therapeutic hypothermia. Coronary angiography showed diffuse three-vessel disease with 99% occlusion of the mid-right coronary artery, 99% occlusion of the left circumflex artery, and 50% occlusion of the proximal left anterior descending artery with thrombus present. He had thrombectomy, angioplasty, and deployment of a bare metal stent to his left anterior descending artery, followed by angioplasty and stenting to the proximal right coronary artery. The patient began to decline rapidly during cardiac catheterization manifested by worsening hemodynamic instability and oxygenation. An intra-aortic balloon pump was placed. Profound hypoxemia and lactic acidosis resulted in a large respiratory drive that led to ventilator dyssynchrony and air trapping. Neuromuscular blockade was initiated and multiple ventilator adjustments were made. He was transferred to

Introduction

T

reatment with mild hypothermia (33C) induced after cardiopulmonary resuscitation is recommended to improve recovery after cardiac arrest, based on several randomized controlled trials (Hachimi-Idriss et al., 2001; Bernard et al., 2002; The Hypothermia After Cardiac Arrest Study Group, 2002), a multitude of observational studies, and international consensus guidelines (Noland et al., 2003). However, the optimal timing and duration of hypothermia remains uncertain. Laboratory studies in animal models and clinical reports in neonates suggest that outcomes may be improved with prolonged hypothermia, beyond the recommended 24-hour standard of care. Here, we report the case of a patient who underwent prolonged therapeutic hypothermia for 48 hours to provide neurological protection in the face of severe hypoxia from cardiopulmonary instability postcardiac arrest. Case Report A 66-year-old white male suffered an out-of-hospital cardiac arrest while exercising in a gym. The patient had an extensive smoking history, estimated at 100 pack years, but no other medical history. Over the past decade he had retired from his desk work, stopped smoking, started exercising extensively, and improved his diet. His family history was negative for cardiac disease. He did not drink or take illicit drugs. He had no medications prescribed and had no known allergies. The patient was weight-lifting at his gym on the day of admission when bystanders witnessed him collapse. Bystander cardiopulmonary resuscitation was initiated and was in progress 6 minutes later upon the arrival of emergency

Division of Pulmonary and Critical Care Medicine, New York Presbyterian Hospital–Weill Cornell Medical College, New York, New York.

88

PROLONGED HYPOTHERMIA FOR NEUROLOGICAL PROTECTION the cardiac intensive care unit, where a chest x-ray showed diffuse bilateral infiltrates. His arterial blood gas showed a profound metabolic acidosis with impaired ventilation giving a pH of 6.91 with a pCO2 of 64 mmHg. A pulmonary artery catheter was inserted and yielded a pulmonary artery pressure of 32/7 mmHg, with a pulmonary wedge pressure of 10 mmHg. These values were felt to be more consistent with acute respiratory distress syndrome (ARDS), secondary to the cardiac arrest, as opposed to an ongoing hydrostatic leak from cardiogenic pulmonary edema. [See initial chest x-ray (Fig. 1) and postcatheterization chest x-ray (Fig. 2).] His indices were consistent with cardiogenic shock. Lung protective ventilation was employed with low tidal volume ventilation delivered in the assist control mode on a Puritan Bennett 840 ventilator. Despite a fractional inspired oxygen concentration of 100%, positive endexpiratory pressure of 12 cmH2O, and initiation of inhaled nitric oxide titrated to 20 parts per million, the patient’s arterial oxygen saturation remained between 80% to 85%, with a corresponding arterial PO2 that remained under 50 mmHg for the first 48 hours. Postcatheterization echocardiography showed severe global left ventricular hypokinesis and akinesis, with an ejection fraction estimated at 19% and reduced right ventricular function. Interarterial balloon pump was continued at 1:1, and dobutamine and dopamine were used for inotropic support in addition to high-dose norepinephrine and vasopressin for vasoconstriction. Because of his refractory hypoxemia and profound shock, we decided to continue therapeutic hypothermia with neuromuscular blockade until the patient could sustain an oxygen saturation above 90%. As a result, we kept the patient at the goal hypothermic temperature of 33C for a total of 48 hours, compared with the usual 24-hour standard. The patient was then slowly rewarmed at 0.25C/hour, and kept euthermic thereafter. He was maintained on continuous video electroencephalogram monitoring without evidence of seizure activity. After 48 hours, hemodynamics and oxygenation began to steadily improve. By day 5 the intra-aortic balloon pump was

89

FIG. 2.

Post-catheterization chest x-ray.

removed and vasopressors were weaned off. His oxygenation gradually improved and he was successfully extubated on hospital day 11. Spontaneous movement on hospital day 6 evidenced neurological recovery, the fourth day post rewarming. He began to localize to pain on hospital day 7, and responded to his name on day 9. He was transferred to the floor and recovered enough to be discharged home without services on hospital day 19. His Glasgow Outcome Scale score was 1 ( Jennett and Bond, 1975). His postarrest, day 13, brain magnetic resonance imaging showed acute infarctions within the left frontal and right parietal lobes without a vascular distribution and mild chronic microvascular ischemic white matter disease. Five months later, the patient had resumed normal living, which included going daily to his gym, where he was capable of walking 20 minutes on a treadmill and lifting light weights. His follow-up echocardiogram 4 months postarrest continued to show severe left ventricular dysfunction with only mild improvement in systolic function compared with his echocardiogram immediately postarrest. One year postarrest, the patient was still alive with preserved neurological function. Discussion

FIG. 1.

Initial chest x-ray.

We have described a case of out-of-hospital cardiac arrest from acute coronary syndrome, complicated by cardiogenic shock and profound hypoxemic respiratory failure. We extended the interval of therapeutic hypothermia beyond the usual 24-hour standard, in an effort to stem ongoing ischemia and reperfusion injury in the setting of extreme hypoxemia and low-flow cardiogenic shock. We hypothesize that our patient’s robust neurological recovery was bolstered by the modification of the cooling interval. There are several possible mechanisms by which mild hypothermia improves neurological outcome after cardiac arrest. The act of cooling reduces cerebral metabolism, as cerebral blood flow is slowed by approximately 6.7% by each decrement of 1C between 35C and 25C (Rosomoff and Holaday, 1954). The putative reduction in the cerebral metabolic rate may be partially caused by reduced electrical

90 activity (Steen et al., 1983). More importantly, hypothermia may suppress many chemical reactions associated with reperfusion injury, such as free radical production, excitatory amino acid release, and calcium shifts that lead to cell damage and apoptosis (Ginsberg et al., 1992). The mild range of hypothermia used after cardiac arrest likely has more important effects on stemming reperfusion injury than it does on cerebral metabolic rate. The optimal duration of therapeutic hypothermia is still unclear. In the two landmark trials in 2002, the times were between 12 and 24 hours. A duration of 24 hours, used by the Hypothermia After Cardiac Arrest group, has since become standard. A Japanese group at Nihon University in Tokyo previously published a case series in 2000, in which they applied venoarterial extracorporeal membrane oxygenation to patients with refractory cardiac arrest in combination with at least 2 days of mild therapeutic hypothermia at 34C in 23 patients, with 52% showing good recovery (Nago et al., 2000). There are no human trials we are aware of that directly compare two different cooling duration times. A study in rats demonstrated that 48 hours of cooling postarrest did not lead to a mortality benefit, but it did result in histological evidence of better neuron protection compared with 24 hours of hypothermia (Che et al., 2001). Reperfusion injury after cardiac arrest has a wide and extended time frame, starting immediately after resuscitation and possibly extending for many days (Adrie et al., 2002). This raises the question whether patients might, on the whole, benefit from longer intervals of hypothermia than the standard 24 hours. This may suggest that the reperfusion interval varies from patient to patient, depending on their ischemic insult and their body’s capacity to respond to cellular damage. There are some patients who will continue to have ischemic insults after cardiac arrest from a range of problems: from low flow states or, in the case of our patient, a low flow state and severe hypoxemic respiratory failure. There is rationale for applying hypothermia as a sliding target, tailored to each individual patient. In many cases the injury may be happening at a subclinical cellular level, and perhaps markers of cellular injury such as neuron-specific enolase could dictate duration of therapy (Celtik et al., 2004). In other cases, such as ours, the injury is glaringly obvious, and hypothermia should be continued until the clinical situation stabilizes. Certainly, there will be a point at which the known side effects of hypothermia, such as immune suppression, coagulopathy, and requirement of deep sedation with or without neuromuscular blockade will outweigh potential benefits of extended duration. Clinical judgment is necessary to dictate discontinuing or maintaining therapy as the patient’s condition evolves. Our case raises two other interesting clinical facets. First, there is increasing evidence that hypothermia can be applied in severely unstable patients, with good outcome. A recent trial of therapeutic hypothermia in hemodynamically unstable patients in cardiogenic shock after successful resuscitation from out-of-hospital cardiac arrest showed improvements in hemodynamics, including increased cardiac index and increased systemic vascular resistance resulting in decreased inotrope and vasopressor use (Zobel et al., 2012). Second, our case furthers the question whether there is a future role of hypothermia in acute lung injury. Our patient was pro-

KUNG AND FRIEDMAN foundly hypoxemic with an arterial PO2 less than 50 mmHg for 48 hours and less than 60 mmHg for the first 72 hours despite an inspired oxygen concentration of 100%. There exist animal data that hypothermia may be protective against the development of acute lung injury and may be protective against worsening inflammation in pre-existing acute lung injury (Lim et al., 2003; Hong et al., 2005). By reducing metabolism and oxygen consumption, hypothermia might reduce ischemia at the tissue level in extreme hypoxic environments such as those encountered in severe ARDS. It is plausible that an injured brain may be even more susceptible to the hypoxic effects of ARDS. For example, the development of acute lung injury is associated with worse neurological outcome and is an independent factor affecting mortality in patients with severe traumatic brain injury (Holland et al., 2003). Human trials are warranted for the role of hypothermia in both isolated ARDS and ARDS complicating neurologic injury, given the enormous morbidity and mortality associated with these disease states. In summary, we report the use of extended therapeutic hypothermia postcardiac arrest in the setting of profound circulatory disturbance and refractory hypoxemia. We hypothesize that our patient’s excellent neurologic recovery was related to the protective effect that hypothermia had on stemming ischemia reperfusion injury postarrest, and in the days postarrest when he was subject to ongoing injury. There is rationale for extending the duration of hypothermia postarrest, and there is a need for randomized controlled trials to elucidate this further. We propose that the future of postarrest care will involve using a sliding-target approach to hypothermia in which the therapy’s duration is adjusted on a patient-by-patient basis. Lastly, we believe that there may be a future role of therapeutic hypothermia as applied to acute lung injury and ARDS. References Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, Fraisse F, Dinh-Xuan AT, Carli P, Spaulding C, Dhainaut JF, Cavaillon JM. Successful cardiopulmonary resuscitation after cardiac arrest as a ‘‘sepsis-like’’ syndrome. Circulation 2002;106:562–568. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of outof-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563. Celtik C, Acunas B, Oner N, Pala O. Neuron-specific enolase as a marker of the severity and outcome of hypoxic ischemic encephalopathy. Brain Dev 2004;26:398–402. Che D, Li L, Kopil C, Liu Z, Guo W, Neumar RW. Impact of therapeutic hypothermia onset and duration on survival, neurological function, and neurodegeneration after cardiac arrest. Crit Care Med 2001;39:1423–1430. Ginsberg MD, Sternau LL, Globus MY, Dietrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 1992;4: 189–225. Hachimi-Idriss S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51:275–281. Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R, Erickson VR, Pittet JF. The development of acute lung injury is associated with worse neurologic outcome in

PROLONGED HYPOTHERMIA FOR NEUROLOGICAL PROTECTION patients with severe traumatic brain injury. J Trauma 2003;55: 106–111. Hong SB, Koh Y, Lee IC, Kim MJ, Kim WS, Kim DS, Kim WD, Lim CM. Induced hypothermia as a new approach to lung rest for the acutely injured lung. Crit Care Med 2005;33:2049–2055. 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. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975;7905:480–484. Lim CM, Kim MS, Ahn JJ, Kim MJ, Kwon Y, Lee I, Koh Y, Kim DS, Kim WD. Hypothermia protects against endotoxininduced acute lung injury in rats. Intensive Care Med 2003;29: 453–459. Nago K, Hayashi N, Kanmatsuse K, Arima K, Ohtsuki J, Kikushima K, Watanabe I. Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patient with cardiac arrest outside the hospital. J Am Coll Cardiol 2000;36: 776–783. Noland JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck WG, Billi J, Bo¨ttiger BW, Morley PT, Nolan JP, Okada K, Reyes C, Shuster M, Steen PA, Weil MH, Wenzel V, Hickey RW, Carli P, Vanden Hoek TL, Atkins D; International Liaison Committee on Resuscitation. Therapeutic hypothermia after

91

cardiac arrest: an advisory statement by the Advance Life Support Task Force of the International Liaison Committte on Resuscitation. Circulation 2003;108:118–121. Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 1954; 179:85–88. Steen PA, Newberg L, Milde JH, Michenfelder JD. Hypothermia and barbiturates: individual and combined effects on canine cerebral oxygen consumption. Anesthesiology 1983;58:527– 532. Zobel C, Adler C, Kranz A, Seck C, Pfister R, Hellmich M, Kochanek M, Reuter H. Mild therapeutic hypothermia in cardiogenic shock syndrome. Crit Care Med 2012;40:1715–1723.

Address correspondence to: David H. Kung, MD Division of Pulmonary and Critical Care Medicine New York Presbyterian Hospital–Weill Cornell Medical College 525 East 68th Street Starr 505, Box 96 New York, NY 10065 E-mail: [email protected]

Prolonged hypothermia for neurological protection.

Treatment with mild hypothermia induced after cardiopulmonary resuscitation has become a standard of care, but optimal timing and duration of hypother...
125KB Sizes 0 Downloads 3 Views