© Springer International Publishing Switzerland 2015
Davide Chiumello (ed.)Practical Issues Updates in Anesthesia and Intensive Care10.1007/978-3-319-18066-3_22. Therapeutic Hypothermia in the Intensive Care Unit
(1)
Department of Anesthesia and Intensive Care Medicine, University Hospital of Modena, L.go del Pozzo, 71, 41100 Modena, Italy
Keywords
Therapeutic hypothermiaReturn of spontaneous circulationCardiocirculatory arrestCoolingComa2.1 Introduction
The idea that low temperatures could be “useful” in the medical field is anything but modern. Since the ancient times, Hippocrates had observed a beneficial effect of low temperatures on the bleeding of the wounds. Galen described in his “Opera Omnia” some treatments based on hypothermia [1]. In relatively more recent era, Napoleon’s general of armies, Larrey, described a higher percentage of survivors among the hypothermic injured in respect to the soldiers who were warmed near the fire [2]. But the first job with scientific approach on this issue is due to a neurosurgeon named Temple Fay and dates back to the mid-twentieth century. Fay applied hypothermia in patients with pain for advanced intracranial neoplasia and patients undergoing craniotomy, using devices of his own invention as a cooling blanket and an irrigation system through invasive metal capsules. These systems can be considered rudimentary prototypes of modern invasive and superficial equipment for patients’ cooling [3]. In 1945, Botterel et al. described hypothermia in patients undergoing surgery for brain aneurysm [4]. In 1950, a cardiac surgeon named Bigelow applied hypothermia in order to ensure a degree of neuroprotection in interventions with circulatory arrest [5]. The first study in critically ill patients was published in 1959 by Benson et al. [6] who successfully used hypothermia in 12 patients after cardiocirculatory arrest (CCA) [6]. Later, Rosomof and Safar (father of modern cardiopulmonary resuscitation) published other experiences on small numbers of patients treated with hypothermia after CCA [7]. Despite the promising results, the technique was abandoned due to the high incidence of side effects and the difficult management of these patients. For about 20 years, works and publications on hypothermia disappeared from the international scene. The Russian philosopher and essayist Petr Kropotkin wrote: “Science is not real progress until a new truth finds an environment ready to accept it.” Indeed the story of “modern” therapeutic hypothermia is strongly linked to technological progresses and to the birth of intensive care and monitoring departments.
2.2 Clinical Indications
According to the World Health Organization, the incidence of out of hospital cardiac arrest is between 56 and 138 cases per 100,000 population per year. From 20 to 50 % of these are successfully resuscitated and anoxic brain damage remains the major cause of morbidity and mortality. To better understand the extent of the problem, only 10–20 % of the patients who were admitted to the hospital after return of spontaneous circle (ROSC) will return to home without neurological sequels [8]. In this field, two observational prospective studies published in the 1990s [9, 10] opened the way for two large randomized controlled clinical trials conducted at the beginning of the new century in Australia and in Europe. Both trials showed that TH provides a significant improvement in the neurological outcome of patients with ROSC after CCA [11, 12]. After the publication of these two studies, the Advanced Life Support Task Force of the International Liaison Committee on Reanimation (ILCOR) published an Advisory Statement on the basis of new evidence by defining first hypothermia’s therapeutic indications. A core temperature between 32 and 34° Celsius must be applied for a period of 24 h in all patients who experienced a return of cardiac activity after ACC and presenting a state of coma. The evidence for this recommendation was high for patients with the ACC and early defibrillating rhythm [13]. Two years later, the European Resuscitation Council (ERC) introduced in its guidelines the same recommendations. Although in recent years the trend of application of the method in the ICU increased sharply, a recent survey indicated that in Italy only 50 % of the patients with ROSC receive an appropriate TH management [14].
A large debate about the application of TH is related to the lack of evidence regarding the definition of target temperature. In 2013, Nielsen et al. have published the results of a large multicenter trial (TTM-Trial) in which more than 900 patients with ROSC post ACC in 36 intensive care units in Europe and Australia have been enrolled. Patients have been assigned to the hypothermia (33 ° C) or to the normothermia groups (36 ° C) and the 6-month mortality and neurological outcome have been assessed. The study showed no difference in the two groups with regard to the main outcome, leaving many doubts about the best choice of treatment in these patients [15].
Large randomized controlled trials showed also the beneficial effects of TH in neonates with hypoxic-ischemic encephalopathy, and the use of this strategy has spread throughout the world [16, 17].
The use of TH has been also evaluated in neurological vascular disease, namely, in ischemic stroke, in order to reduce extension of brain damage. Unfortunately, at this time there is no evidence to justify the inclusion of therapeutic hypothermia in the international guidelines for the treatment of ischemic stroke [18].
2.3 Mechanisms of Action
The exact mechanisms by which hypothermia would be able to provide neuroprotection are still unclear. Historically, the protective effects of hypothermia have been attributed to the reduction of cerebral metabolism with consequent reduction of the oxygen and glucose’s consumption. Indeed, cerebral metabolism is reduced by about 7 % for each degree of body temperature.
In the last few years, the mechanisms related to the death of neuronal cell and to the damage reported by it after reperfusion have been studied in more details. The ischemic cells after CAA may undergo necrosis or may trigger processes of programmed cell death (apoptosis). Apoptosis is achieved by mitochondrial dysfunction with alteration of cellular metabolism and release of lytic enzymes called caspases. Some studies on animals have shown that hypothermia is able to act in the early stages of the same apoptotic mechanism inhibiting its activation [19]. Several recent studies showed also the key role of hypothermia in the homeostasis of calcium. The sudden decrease of intracellular adenosine triphosphate concentration occurring during ischemia triggers the anaerobic pathway that leads to intra- and extracellular acidosis with impairment of all the ATP-dependent ionic pumps present on the cell membrane. The consequence is the loss of the cell gradient for sodium associated to accumulation of intracellular calcium which is the primary cause of mitochondrial dysfunction. Moreover, rapid and uncontrolled cell depolarization is due to the release of glutamate, the excitatory neurotransmitter normally reabsorbed by the presynaptic terminals with energy consumption. In the conditions of low-energy substrates, glutamate accumulates in the extracellular environment and stimulates specific membrane receptors, in turn increasing the influx of intracellular calcium. Many studies on animals have shown that hypothermia is able to reduce the accumulation of excitatory neurotransmitters [20, 21]. Therapeutic hypothermia seems also able to reduce and modulate the production of free radicals and superoxide dismutase [20].
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