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CARDIOLOGY CASEBOOK |
A 57-year-old male immigrant was being driven to the emergency department (ED) of a nearby hospital because of substernal pressure and pain, 1 hour in duration. While getting out of the car he suddenly collapsed; an ED nurse was immediately summoned and determined that the patient was in cardiac arrest. Cardiopulmonary resuscitation was immediately initiated and he was promptly electrically defibrillated. Total time from onset of cardiac arrest to return to cardiac function was estimated to be no greater than 3
minutes. The electrocardiogram after defibrillation revealed an acute anterior myocardial infarction with 6-mm "J" point elevation in leads V1 to V4 and 4-mm elevation in leads V5 and V6. Elevation of "J" point was also noted in leads I and aVL with reciprocal depression in leads II, III, and aVF. The ED was equipped to perform therapeutic hypothermia and elected to apply whole body hypothermia to this patient.
QUESTIONS
ANSWERS
1. a. hyperthermia
b. neurological emergencies
In any clinical state of hyperthermia, the primary goal of therapy is rapid cooling. Active cooling is usually accomplished by one of the following procedures; gastric or colonic lavage with iced isotonic sodium chloride solution, emergence in ice baths, and infusion of room-temperature isotonic sodium chloride solution, among other therapeutic measures.
Clinical investigations into the effects of hypothermia (<35°C) on cardiopulmonary physiology were first described in 1917.1 Throughout the 1940s and 1950s, the induction of deep-to-moderate hypothermia (28–32°C) was used to stabilize neurological emergencies. In the 1950s, induction of moderate hypothermia before controlled cardiac arrest was critical in the evolution of cardiovascular surgery; concurrently, trials were carried out on the use of hypothermia after cardiac arrest. The use of hypothermia continues to gather momentum.
2. a. serious associated complications
d. time constraints
Early applications of hypothermia were accomplished by surface cooling methods (cooling blankets, ice packs, towel wraps with fanning). Achieving a hypothermic state took several hours and the amount of anesthetic and sedating agents required to counteract shivering and subsequent heat production often led to respiratory depression and infection.2 Routine clinical use of therapeutic deep hypothermia in humans outside the surgical arena was largely abandoned in the 1980s due to serious complications, such as, immuno-suppression and infection, ventricular arrhythmia, and coagulopathies.
3. a. can be defined as a 2–3°C drop in core body temperature
b. produces no serious adverse effects
d. can reduce infarct size in AMI
The general use of mild hypothermia was introduced in the 1990s when it was noted that lesser degrees of hypothermia were as effective as deep hypothermia in the treatment of traumatic brain and neurological emergencies. Busto et al3 discovered that only a mild hypothermic state was necessary for reducing neuronal death during ischemia. This mild hypothermia produced none of the serious adverse effects associated with the more profound hypothermia seen in the groups studied 40 years prior. Several studies soon followed that supported the efficacy of mild hypothermia.4–6
Application of mild hypothermia in an AMI has had profound multifactorial benefits on enhancing myocardial microcirculation and protecting ischemic myocardial tissue, thereby reducing infarct size. It is well known that cold cardioplegia and cardiopulmonary bypass can preserve cardiac function during surgery, when the myocardium may be anoxic several hours; however, cold cardioplegia is not practical in AMI.
4. e. all of the above
Instillation of cold cardioplegia has been used for many years by thoracic surgeons to preserve the non-working heart during open heart surgery. The application of whole body and global cardiac hypothermia is also used in other cardiac surgical procedures and is well-established. During surgery, hypothermia combined with cardioplegia lessens the volume of anoxic myocardial damage because it slows cellular metabolism and lowers myocardial oxygen demand.7
The concept of mild hypothermia–induced cardio-protection of the working heart subjected to regional ischemia is currently under study. In the ischemic myocardium, the cardioprotective effects of mild hypothermia are associated with (1) a reduction in the inflammatory response of reperfusion and the preservation of myocardial adenosine triphosphate and cell membrane integrity7,8 and (2) a reduction in cerebrovascular and cardiovascular tissue demand, reduction in destructive inflammatory and enzymatic reactions, suppression of free radical reactions, improvement in postischemic hypoperfusion, stabilization of plasma membranes, and reduction of calcium entry into cells. Hypothermia may also alter the complement cascade and certain immune functions.7,9
5. b. infarct size
The prime focus in the treatment of an AMI in the 1980s and 1990s was on the reestablishment of flow in the acutely occluded coronary artery. Mechanical and pharmacological approaches are currently employed; however, a timely mechanical approach, using angioplasty and coronary artery stenting within 90 minutes, has been shown to be superior to the intravenous administration of lytic agents in reestablishing coronary blood flow. Unfortunately, a significant number of patients in whom epicardial blood flow has been reestablished after percutaneous coronary intervention (PCI) remain ischemic at the microcirculatory level and thus have poor myocyte preservation. Restoration of the micro-circulation is best assessed by the resolution of elevated ST segments, seen in the acute phase of myocardial injury, within 90 minutes of reestablishing epicardial coronary flow. The ST segment resolution is considered by some a more sensitive marker of myocardial reperfusion than TIMI (Thrombolysis in Myocardial Infarction) grade 3 or 4 flow.9
Because infarct size is one of the most important predictors of early and late survival, after AMI, there is a continued need to improve myocyte protection during reperfusion. Current coronary interventions (thrombolytics, PCI, coronary artery bypass graft surgery) facilitate myocardial reperfusion; however, many still develop congestive heart failure or die from extensive myocardial damage. Early and sustained reperfusion is the only proven method of salvaging jeopardized myocardium after acute coronary artery closure. Experimental data suggest that lowering myocardial temperature is also critical to limiting progression of tissue necrosis early in AMI.8
In an experimental animal study10 that used moderate hypothermia (27°C) and selective coronary artery occlusion, ischemic myocardium showed less necrosis (evidenced by nitroblue tetrazolium staining) than did normothermic ischemic myocardium without any effect on blood flow. The decrease in necrosis of ischemic myocardium was considered to be a result of a hypothermia-induced cardioprotective decrease in myocardial tissue demand, rather than a temperature related change in myocardial blood flow.10
6. a. exert a protective effect on myocytes and the microcirculation
b. limit development of tissue necrosis
e. reduce myocardial oxygen demands
The effects of hypothermia on myocardial physiology were demonstrated in the late 1950s by Gerola et al,1 who reported that induced hypothermia (27°C and 32°C) in canine hearts led to a decrease in myocardial oxygen consumption without significant change in coronary blood flow. The decrease in myocardial oxygen consumption was evidenced by a gradual decline in atrioventricular oxygen difference, indicating a decrease in myocardial oxygen uptake relative to supply.1 The combined success of mild hypothermia in cerebrovascular emergencies and a better understanding of hypothermic effects on myocardial tissue led to the broadening of hypothermia applications to cardiovascular ischemic emergencies.2,8 A cool milieu (temperature reduction of as little as 2–4°C) lowers myocardial oxygen demand (unrelated to reductions in blood pressure or heart rate) and exerts a protective effect on both the myocyte and the microcirculation.7 A significant relationship exists between myocardial temperature and the extent of tissue necrosis following coronary occlusion.7,11 In one study, the infarct size was reduced by 10% for every degree of temperature lowered (between 35°C and 42°C).11 Numerous animal studies also confirm that the proportion of ischemic zone at risk of becoming necrotic is correlated with the ambient temperature.12 Hypothermia is most beneficial when applied early after the onset of ischemia. Even when initiated after coronary artery occlusion and the onset of ischemia, hypothermia can still significantly reduce cellular metabolism and limit infarct size.8 In the follow-up of a pilot study evaluating 42 AMI patients, those treated with hypothermia during the reperfusion process had a 70% reduction in infarct size following endovascular cooling compared with those who only underwent reperfusion.8
7. c.cardiopulmonary arrest
It is generally accepted that cardiopulmonary arrest causes the most severe form of global ischemia. Hypothermia in pre-arrest surgery prevents cerebral global ischemia that occurs during various procedures.13 Early investigations in the use of hypothermia following cardiac arrest were successful, but later abandoned since at the time, benefits were uncertain and administration was difficult.13 In recent years, growing evidence in animal and human studies has documented benefits of mild hypothermia during or after cerebral injuries that follow cardiac arrest or other acute anoxic situations. Hypothermia improves post-reperfusion neurological outcomes by reducing the cerebral metabolic rate, and suppression of various chemical reactions associated with reperfusion injury (free radical production, excitatory amino acid release, calcium shifts).2 The induction of hypothermia following cardiopulmonary arrest has been reintroduced. In animals, hypothermic applications have been associated with reduced cerebral histologic deficits and improved functional recovery. Promising preliminary human studies have also been completed in separate trials, 2 groups of unconscious survivors of cardiac arrest due to primary ventricular fibrillation (VF) were evaluated after hypothermia intervention. At discharge, both hypothermia-treated groups were noted to have higher survival and better neurological function than their respective control groups. (Council on Cardiopulmonary and Critical Care).14 The hypothermia-treated group did have some commonly occurring adverse events (lower cardiac index, hyperglycemia, pneumonia, and sepsis).13
In light of current evidence, there is greater support for the use of induced mild hypothermia in comatose survivors of out-of-hospital cardiac arrest caused by VF. Cooling has been initiated as soon as spontaneous circulation returns, even when there is a 4- to 6-hour delay before return of circulation. Continued research in this field should help determine the optimal time of hypothermia application, the duration and optimal temperature target, and the rate of cooling and rewarming. Due to the optimistic outcomes of these preliminary trials, the induction of mild hypothermia has recently been recommended by the Advanced Life Support (ALS) Task Force of the International Committee on Resuscitation (ILCOR) to be added to the cardiopulmonary resuscitation guidelines to prevent cerebral anoxia in the post-VF cardiac arrest patient following spontaneous return of circulation.15 The initial recommended criteria and guidelines for the use of hypothermia in cardiac arrest are the unconscious patient with spontaneous circulation following out-of-hospital and in-hospital cardiac arrest due to VF (cooling to 32–34°C for 12 to 24 hours) and also can be helpful in cardiac arrests due to other rhythms.
Several questions remain about extending the use of mild hypothermia to other populations not yet studied (survivors of non-VF arrest, patients who sustain in-hospital noncardiac arrest, children). Continued trials are needed to clarify and further delineate selection and exclusion criteria. Hypothermia is not advised in severe cardiogenic shock, primary coagulopathies, or during pregnancy.13
8. e. all of the above
Systemic cooling is employed during surgery that requires cardiopulmonary bypass (cold cardioplegia), during organ transport and transplantation, and in select neurological procedures. In the past, applications of hypothermia involved surface cooling methods requiring more than 24 hours to achieve temperatures that were generally unregulated. More recently efficient methods have evolved, providing more precise temperature control and the capability to achieve a hypothermic state within 30 to 40 minutes of application.9 Careful monitoring of temperature is crucial for preventing adverse events, such as, infection, coagulopathies, arrhythmias, that are associated with temperatures below 32°C.13 A variety of cooling techniques have been described, yet none combines ease of use with efficacy. The therapeutic benefit of hypothermia can be greater when better physical and pharmacological rapid cooling techniques become available. Current hypothermic application models include external devices and the endovascular heat exchange system.
External devices (cooling blankets, wet towels, and fanning) are simple to use but slow in reducing core temperature. Selective head cooling (cooling helmets), although free of many adverse effects associated with systemic surface cooling, does not lower brain temperatures in adults, but is effective in newborns, in whom no major complications have been reported.2 Systemic cooling using intravenous or intraarterial routes can lower temperatures faster than the surface cooling methods. The infusion of iced isotonic sodium chloride solution has the potential to induce hypothermia more rapidly than surface cooling. The short time of administration (30 minutes) and the use of large fluid volumes with this process creates concern for critically ill patients with compromised cardiac function. Invasive cooling methods (extracorporeal cooling, cardiopulmonary bypass, and peritoneal lavage) offer rapid and more controlled cooling but remain too invasive and technically complicated for use in the prehospital or ED environments.
The endovascular heat exchange system is a novel and promising approach (see Figure
).8 Systemic cooling can be achieved without fluid exchange or the need for cumbersome equipment.
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9. e. any of the above
The induction of therapeutic hypothermia is complicated by the need to overcome vasoconstriction and shivering. Vasoconstriction is the primary autonomic defense against cool environments. Subsequent shivering during hypothermia induction generates heat in attempt to raise the core body temperature and leads to warming. Shivering can also lead to harmful tachycardias, hypertension, and increase overall oxygen consumption.16 In order to achieve and maintain effective hypothermia, the shivering response must be attenuated. Although numerous drug combinations can reduce the cold-defense threshold, most are anesthetic or major sedatives and could compromise airway competence when given in sufficient dose to counteract shivering and vasoconstriction. The recent combination of intravenous meperidine and oral buspirone have a synergistic effect, reducing the shivering threshold without respiratory deterioration. Meperidine, unlike other opioids, possesses a special anti-shivering action. Unfortunately, large plasma concentrations are necessary to reduce the shivering threshold and can make spontaneous breathing unreliable.9,16 The addition of oral buspirone, a serotonin partial agonist, and mild sedative, reduces the amount of meperidine needed. Together these agents inhibit thermoregulatory control via different mechanisms and facilitate the induction of therapeutic hypothermia without respiratory toxicity.16
Summary
The clinical use of mild hypothermia to preserve ischemic cardiac and cerebral tissue continues to grow in popularity. This is a result of the known fact that hypothermia reduces myocardial oxygen demands more than any other intervention.
The Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR) made the following recommendations a year ago, in October 2002: "Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm was VF," or in-hospital even when arrest is due to other rhythms. Therapeutic use of hypothermia is in progress.13
ACKNOWLEDGMENT
Supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.
Reprint requests: Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), P.O. Box 016960, Miami, FL 33101.
Behringer W, Safar P, Xianren W, Nozari A, et al. Veno-venous extracorpo-real blood shunt cooling to induce mild hypothermia in dog experiments and review of cooling methods. Resuscitation. 2002;54:89–98.[Medline]
Dae MW, Gao DW, Sessler DI, et al. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol. 2002;282:H1584–H1591.
Dave RH, Hale SL, Kloner RA. Hypothermic, closed circuit pericardioperfusion: a potential cardioprotective technique in acute regional ischemia. J Am Coll Cardiol. 1998;31:1667–1671.
Hale SL, Kloner RA. Ischemic preconditioning and myocardial hypothermia in rabbits with prolonged coronary artery occlusion. Am J Physiol. 1999;276(6Pt2):H2029–34.
Miki T, Liu GS, Cohen MV, et al. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol. 1998;93(5):372–383.[Medline]
Smith TL, Bleck TP. Hypothermia and neurologic outcome in patients following cardiac arrest: should we be hot to cool off our patients? Crit Care. 2002;6:377–380.[Medline]
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