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Koyirov Akmal,
Republican Research Center of the Emergency Medicine, Tashkent, Uzbekistan, PhD in Cardiology, Intensive cardiac care department E-mail: [email protected] Khaitov Sukhrob,
Republican Research Center of the Emergency Medicine, Tashkent, Uzbekistan, Ph D., student, Intensive cardiac care department Ganiev Ulubek,
Republican Research Center of the Emergency Medicine, Tashkent, Uzbekistan, PhD student, Intensive cardiac care department Egamova Nargiza,
Republican Research Center of the Emergency Medicine, Tashkent, Uzbekistan, PhD student, Intensive cardiac care department Mirmaksudov Mirakhmadjon, Tashkent Medical Academy, Tashkent, Uzbekistan, Master's student, Cardiology department E-mail: [email protected]
HYPOTHERMIA IN COMPLICATIONS OF CARDIOVASCULAR DISEASES
Abstract. This report focuses on cardioprotection and describes the advantages and disadvantages of various methods of inducing therapeutic hypothermia (TH) with regard to neuroprotection and cardioprotection for patients with cardiac arrest and ST-segment elevation myocardial infarction (STEMI). TH is recommended in cardiac arrest guidelines. For patients resuscitated after out-of-hospital cardiac arrest, improvements in survival and neurologic outcomes were observed with relatively slow induction of TH. More rapid induction of TH in patients with cardiac arrest might have a mild to modest incremental impact on neurologic outcomes. TH drastically reduces infarct size in animal models, but achievement of target temperature before reperfusion is essential. Rapid initiation of TH in patients with STEMI is challenging but attainable and marked infarct size reductions are possible. To induce TH, a variety of devices have recently been developed that require additional study. Of particular interest is transcoronary induction of TH using a catheter or wire lumen, which enables hypothermic reperfusion in the absence of total-body hypothermia. At present, the main methods of inducing and maintaining TH are surface cooling, endovascular heat exchange catheters, and intravenous infusion of cold fluids. Surface cooling or endovascular catheters may be sufficient for induction of TH in patients resuscitated after out-of hospital cardiac arrest. For patients with STEMI, intravenous infusion of cold fluids achieves target temperature very rapidly but might worsen left ventricular function. More widespread use of TH would improve survival and quality of life for patients with out-ofhospital cardiac arrest; larger studies with more rapid induction of TH are needed in the STEMI population.
Keywords: Hypothermia; Circulatory cardiac arrest, Myocardial infarction; Myocardial protection; Ischemia-reperfusion injury.
The effectiveness of achieving low-grade hypothermia stroke, spinal cord injury, hepatic encephalopathy, traumatic (HT), which is defined as a decrease in body temperature brain injury and hypoxic ischemic encephalopathy of new-to 32-35 °C, was evaluated in many experimental models borns. In turn, the results of randomized control trial (RCT) of brain damage, in particular, in ischemic and hemorrhagic including patients, who have circulatory cardiac arrest (CCA)
[5; 42], as well as newborns with ischemic hypoxic encephalopathy [3; 60], may indicate the possibility of using HT in clinical practice. Given the data on the possible protective effect of HT on the myocardium, it is believed that the role of HT may not be limited to the protective effect on the nervous system in the development of coma after CCA in patients hospitalized for acute myocardial infarction (MI).
Experimental and clinical data confirmed the protective effect of HT on the nervous system. The mechanisms responsible for the positive effects of HT are multifactorial and include a decrease in glucose metabolism in the brain and oxygen consumption [14; 24], as well as a decrease in the severity of factors such as accumulation of excitotoxic neurotransmitters, development of intracellular acidosis, calcium intake into cells and the formation of free oxygen radicals [36; 54], a change in the expression of "cold shock proteins" [5; 54]. In addition, HT leads to a decrease in the severity of cerebral edema [10; 32], minimizing the risk of thrombosis, as well as reducing the risk of epileptic activity due to increased electrical stability [54].
In the course of several preclinical studies, such positive effects of HT as a reduction in the MI zone were noted; and the most pronounced advantages of HT were revealed with cooling of the heart to the development of reperfusion, which suggests a connection between the degree ofviable myocardial preservation and the temperature of the myocardium at the time of reperfusion [60]. Despite the fact that the mechanisms by which HT enhances myocardial protection have not been studied to the same extent as the mechanisms of its protective effect on the brain, suggest a number of explanations for this effect of HT on the myocardium. These include reducing the metabolic needs of the myocardium, which is at risk of damage [46], increasing the integrity of cell membranes by maintaining adenosine triphosphate [8; 46], increasing the stability of mitochondrial membranes [11; 45] and improving blood flow in the vessels of the microcirculatory bed [20; 26; 52].
After receiving the results of observational studies that suggested that the use of HT had a positive effect on the survival of patients who underwent CCA [53], during the implementation of 2 RCTs, data on the efficacy of using HT in such a clinical situation were confirmed [5; 42]. The results of the first study [42] indicated a link between the use of HT and the improvement of neurological outcomes and survival within 6 months after the CCA due to ventricular fibrillation (VF) or ventricular tachycardia in the absence of a pulse. During the second RCT [5], the use of HT initiated in an ambulance was also accompanied by an improvement in neurological outcomes compared with the absence of such intervention. The results of a meta-analysis performed later to assess the effectiveness of HT use indicated that the number of patients needed to treat for discharge from hospital with
improvement of neurologic symptoms was 6 at 95% confidence interval from 4 to 13 (ie, to improve the neurological symptoms 1 patient who underwent CCA, HT should be used in 6 patients) [28]. Experts from the International Committee for the Links of Reanimation Specialists recommend, on the basis of the results of such studies, the use of HT (with the maintenance of body temperature in the range of 32 to 34 °C for 12-24 hours) in patients unconscious in restoring spontaneous circulation after of the hospital CCA, if FV was initially recorded (class of recommendations II a). Cooling was also recommended to be used in patients who survived after CCA, not due to VF [48; 49]. This tactic of using HT is also included in more modern versions of the reanimation recommendations [27; 47].
The possibility of using HT and its positive effect on neurological outcomes have been confirmed in the course of carrying out numerous observational studies [1; 62]. Presented by M. Holzer et al. [29] The results of a retrospective study that included all comatose patients who survived the CCA developed against any heart rhythm indicated that HT was associated with improved survival and improved neurologic outcomes within 1 month of follow-up. Data from the ERC HACA (European Resuscitation Counc il Hypothermia After Cardiac Arrest), which collected information on 650 patients who were comatose after an CCA developed against any heart rhythm, also confirmed the view that the use of HT leads to increasing survival at the time of hospital discharge and improving neurological outcomes [2]. Similar results confirming the clinical effectiveness of HT use were obtained in the analysis of the Hypothermia Network Registry registry database, which included data on all 986 patients who underwent CCA at any heart rhythm [44].
The results of experimental animal studies suggested a positive effect of HT in cardiogenic shock due to influence on the processes of inflammation, apoptosis and remodeling [21; 41]. Despite the fact that in a person the shock that develops after CCA belongs to quite frequent complications, such patients were not included in RCTs, and the interpretation of the results of observational studies is difficult due to the great variability of the applied shock criteria, as well as the lack of reports on these studies of data on the impact of HT on the incidence of adverse clinical outcomes in these patients. In the course of 2 retrospective studies involving patients hospitalized with shock, which developed after resuscitation, the use of HT did not adversely affect the clinical outcomes studied [30; 61].
The results of several on observational studies indicated the possibility of combined use of HT and immediate coronary angiography both in combination with percutaneous coronary artery intervention and in its absence, and that such combined use of these interventions can improve clini-
cal outcomes in patients successfully resuscitated after CCA, developed against a background of acute myocardial infarction with ST segment elevation (AMI-ST) [33; 56; 63; 64]. In the course of one of the earliest studies evaluating the effectiveness of the combined use of such interventions [63] improvement in neurological outcomes and survival at the time of discharge following the introduction into clinical practice of a standardized protocol for the treatment of patients who underwent resuscitation, which included HT.
The results of experimental animal studies using the MI model suggested that the use of HT may be effective in reducing the size of MI [12; 25]. In several studies in humans, the effects of HT as a method of reducing myocardial damage in patients with AMI-ST have been studied [13; 20]. Based on data on the possibility of using HT, which were obtained by S. R. Dixon et al. [13], studies of COOL-MI (Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients with Acute Myocardial Infarction) [22] and ICE-IT (Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention) [50] were performed. Their results were to answer the question of whether the use of HT leads to a decrease in the size of myocardial infarction estimated with a single-photon emission computed tomography 30 days after the development of AMI-ST. However, these studies failed to identify the benefits of using HT to reduce the size of myocardial infarction. Nevertheless, it should be noted that in a subgroup of patients with AMI-ST who had an internal body temperature of less than 35 °C, there was a favorable tendency to decrease the size of myocardial infarction. Moreover, the results of the analysis in the subgroups of patients included in the ERC HACA study [34] indicated the absence of a statistically significant effect of the use of HT on blood concentration of creatine phosphokinase and its CF fraction, as well as electrocardiographic parameters. It should be noted, however, that in a subgroup of patients with a shorter duration of the period before reaching the target temperature (8 hours or less), a statistically significant decrease in the concentration of creatine phosphokinase and its CF fraction was observed. Perhaps the earlier onset of cooling, rather than its duration, may be a key factor in reducing the size of MI [12; 25]. The results of experimental and clinical studies suggest that in addition to early cooling, the optimal protective effect of HT can be achieved by achieving an internal body temperature of less than 35 °C [12; 19]. Additional confirmation of this hypothesis was obtained by M. Gotberg et al. [20]. The results of their study showed that in patients who perform primary PCI for AMI-ST, achieving internal body temperature of less than 35 °C can be achieved without increasing the period between the development of clinical manifestations of myocardial infarction and the time to inflation of the balloon, but also
is accompanied by a 38% decrease in the size of myocardial infarction according to the evaluation using magnetic resonance imaging (MRI). Despite the relatively small number of patients included in this study, this was the first study, during which data were obtained on the benefits of using HT in this category of patients. The achievement of internal body temperature of less than 35 °C and the use of MRI, which is now considered a "gold standard" for measuring the size of MI [6; 7], can be suggested in As an explanation of the effectiveness of HT in this study. In contrast to single-photon emission computed tomography, which was used in most of the studies mentioned above, the benefits of MRI include information on not only geometric characteristics such as the volume of the ventricles, but also violations of local contractility and left ventricular function, and its remodeling. However, despite such encouraging results, the optimal method and timing for the use of HT in patients with AMI-ST should be studied during RCT with sufficient statistical power.
Until the results of such studies are obtained, the utility of HT may be considered conjectural and this intervention cannot be recommended as a standard tactic for treating such patients in conditions of actual clinical practice. Currently available cooling methods have mainly been developed for use in patients who are in a coma after CCA; detailed descriptions of such methods are presented in the relevant publications [9; 57]. There is evidence that infusion of cold solutions can be an effective method of cooling patients, especially during the introductory phase, given the availability of its use in the prehospital stage. Several protocols have been proposed, for example infusion of cold solution 0.9% ice solution (4 °C) sodium chloride with lactate 30 ml per 1 kg body weight for 30 min [57] or 500-2000 ml 0.9% chloride solution sodium, cooled to 4 °C, as soon as possible after the completion of Reanimation [4]. The use of external cooling refers to inexpensive, easy-to-use methods that are achieved by placing ice packs in the groin, trunk, axillary and neck and / or applying moistened in ice water towels and the use of fans. The use of such methods can be taken into account both during the introductory and supporting phases in intensive care units, but their drawbacks include the inability to regulate the rate of warming of the patient, as well as the need for careful monitoring and experience to prevent hypothermia [55]. Currently, several cooling devices are sold, including cooling mattresses filled with circulating air or water, blankets for cooling and special clothes with a device cooling its surface [40]. Methods of intravascular cooling include the installation of a cooling catheter, which is usually inserted transdermally into the lower vena cava and connected to a cooling system that automatically maintains the desired temperature. Such a system absorbs heat directly from the so-called core of the body and
its functioning does not depend on vasoconstrictor reactions of the skin that participate in thermoregulation [39]. This allows the use of such devices to quickly and accurately set the desired body temperature, and also maintains a stable temperature after the intervention starts and allows for effective observation of the temperature regime during the warming phase [16; 17; 59]. These new methods include rinsing the stomach with ice salt solution [18], using a cooling helmet [23], a system for general immersion cooling with cold water [15], as well as cooling devices introduced through the nose [31], the use of which allows you to quickly reduce the internal temperature of the body to 34 °C. The possibility of using more modern methods of cooling is taken into account in the implementation of the study CHILL-MI (Efficacy of Endovascular Catheter Cooling Combined With Cold Saline for the Treatment of Acute Myocardial Infarction), which is funded by Philips Innercool. The use of HT can be divided into 3 phases: introductory, supporting and warming phase. Use of HT is accompanied by a change in a number of physiological parameters and the possibility of complications development [40; 54]. Trembling refers to natural physiological responses to HT and can hamper HT during both the introductory and maintenance phases due to heat generation, as well as increased oxygen consumption of tissues and their metabolic needs [38]. In addition to the narrowing of the peripheral vessels, tremor appears to be the "last resort" that the body uses to counteract a decrease in internal body temperature of less than 35.5 °C. The use of several therapeutic interventions aimed at counteracting such a reaction of the organism is suggested [39]. In patients reanimated after CCA, a combination of benzodiazepines is widely used to achieve a sedative effect, as well as opioid analgesics and drugs that cause systemic blockade of neuromuscular conduction to achieve muscle relaxation [5]. In contrast, the combined use of meperidine (both in combination with buspirone and in its absence) and skin warming to reduce the threshold temperature at which the trembling develops, as well as the prevention of discomfort associated with HT, has become a standard approach in the treatment of conscience patients [13; 37; 50].
The effect of HT on the cardiovascular system is complex [40; 54]. After completion of the introductory phase, HT may be accompanied by the development of bradycardia and an increase in the contractility of the myocardium [35; 40]. Such a decrease in the heart rate may, in turn, lead to a decrease in the minute volume of the heart, which, however, is not sufficiently pronounced to lead to hemodynamic disturbances [40; 54].
Despite the fact that during the RCT, the use of HT was not accompanied by the development of arrhythmias, and the stable arrhythmias developing during the observational studies could be the result of excessive cooling (with a decrease in the internal temperature of the body to 32 °C or less), an electrolyte balance disorder and dysfunction tubules [54]. Although the use of HT may lead to an increase in the incidence of infectious complications due to a disorder of cellular and humoral immunity caused by HT [58], the results of clinical studies do not give an unambiguous answer to the question of whether the hypothetical risk of developing such complications is clinically important. The results of several studies indicated an increase in this risk [29; 64], while in other studies such data were not confirmed [43; 51; 63]. The use of HT may lead to an increased risk of bleeding due to impaired platelet function, thrombocytopenia, and clotting system disorders [40]. It should, however, be noted that an increase in this risk was not observed in clinical practice, both in the isolated use of HT and in the use of HT in combination with PCI.
Thus, based on the available evidence and in accordance with current clinical guidelines, the possibility of using HT as a standard treatment for patients who undergo CCA, regardless of the baseline heart rate, should be considered. At the same time, many questions remain, the answers to which have not yet been received. In particular, the question of the optimal duration of HT, the depth of cooling, as well as the speed of warming, the best method of cooling and the cost-effectiveness of the intervention. At present, there are no convincing data that could serve as a basis for recommendations on the use of HT in clinical practice in the treatment of patients hospitalized for acute myocardial infarction if its development was not accompanied by CCA.
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