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Received 04/09/14 Received 04/09/14

THERAPEUTIC HYPOTHERMIA: POSSIBILITIES AND PROSPECTS

Grigoriev E.V.1, Shukevich D.L.1, Plotnikov G.P.1, Tikhonov N.S.2

1FGBU "Research Institute of Complex Problems of Cardiovascular Diseases" SB RAMS; 2MBUZ "Kemerovo Cardiological Dispensary", 650002 Kemerovo

Hypothermia occupies one of the leading places in relation to the protection of organs, especially the brain. The mechanisms for implementing protective effects (modulation of metabolism, prevention of damage to the blood-brain barrier, modulation of the local inflammatory response, normalization of nitric oxide synthesis, blockade of apoptosis) and hypothermia technologies are described. The greatest progress has been made in terms of effectiveness and safety in the main clinical areas.

Key words: therapeutic hypothermia; mechanisms; clinical implementation.

THERAPEUTIC HYPOTHERMIA: THE POTENTIAL AND PROSPECTS Grigor"ev E.V.1, Shukevich D.L.1, Plotnikov G.P.1, Tikhonov N.S.2

"Research Institute of Complex Problems of Cardiovascular Diseases, Siberian Division of Russian Academy of Medical Sciences; 2Kemerovo Cardiological Dispensary, Kemerovo, Russia

Hypothermia is a most powerful tool for the protection of various organs especially brain. The review is focused on the mechanisms of protective action (modulation of metabolism and local inflammatory reaction, prevention of blood-brain barrier disorders, normalization of nitric oxide synthesis) and technology of therapeutic hypothermia. Main clinical situations in which the most effective and safe application of this technology was achieved are described.

Key words: therapeutic hypothermia; mechanisms; clinical implementation.

Over the past decade, hypothermia, as the most promising method of protecting organs from hypoxia, has crossed the threshold of the laboratory and began to be actively introduced into clinical practice. Historically, this method of protection was one of the first to be proposed by both foreign (A. Labori) and domestic (E.N. Meshalkin, E.E. Litasova, A.I. Arutyunov) authors. Many sources of literature emphasize the effectiveness of this method of protecting the brain in post-hypoxic encephalopathy due to cardiac arrest, hypoxic ischemic encephalopathy of newborns, acute cerebrovascular accident (ACVA), brain and spinal cord injury. The exact mechanisms of action of therapeutic hypothermia (TH) still remain unclear. It is likely that the action of TH is associated with the interruption/modulation of metabolic, molecular and cellular damage chains leading to neuronal death.

The purpose of the review is to summarize the main mechanisms of the protective effect of TH and determine the niche of clinical use of the method.

Mechanisms of the protective effect of therapeutic hypothermia

Reduces brain oxygen consumption, protects metabolism and reduces lactic acid accumulation. The most important mechanism for the neuroprotective effect of TH is the reduction or delay of metabolic demands during damage to the central nervous system. Traditionally, it is believed that the decrease in oxygen consumption in the brain (CMO2) is 5% for every degree. In 2008, it was reported that the use of mild TH in patients with severe traumatic brain injury (TBI) resulted in a 5.9% reduction in energy requirements per degree degree. A direct strong correlation between body temperature and basal metabolism was also noted. TG reduces energy requirements, which has a beneficial effect on ATP reserves and the process of maintaining normal transmembrane gradients for ions and neurotransmitters. By limiting the consumption of oxygen and glucose by the brain, TG reduces the risk of energy deficiency,

which gives not only a therapeutic, but also a preventive effect.

Under normal conditions, cerebral blood flow is 50 ml per 100 g of tissue per minute. TG reduces it from 48 ml per 100 g of tissue per minute in normothermic animals to 21 and 11 ml per 100 g of tissue per minute at temperatures of 33 and 39 ° C, respectively. These figures can be confirmed by positron emission tomography parameters.

After brain injury, anaerobic lactate increases due to various reasons for inadequate oxygen transport. By preserving energy reserves, TG prevents the consistent accumulation of lactate with the development of acidosis. Moreover, mild TG reduces the rate of lactate accumulation in the cerebrospinal fluid and brain microdialysate. Although hypothermia is not able to reduce lactate accumulation and ATP consumption during prolonged ischemia, in the presence of short-term ischemia, TG is more effective in relation to the rate of macroenergetic phosphate consumption.

The mechanism of the influence of moderate TG on SMN02 is still not clear. Recent studies show that anesthesia in combination with TG safely reduces metabolism, but the mechanisms of this reduction vary. Anesthetics that cause a decrease in electrophysiological activity of the brain by reducing metabolic needs are not able to interrupt normal metabolic pathways; therefore, they are not able to cause full-fledged cerebral protection during hypoxia. Another study examined the effect of moderate TG on SMN02 and brain function in patients with increased intracranial pressure (ICP) and a simultaneous decrease in central pulse pressure. The study found that moderate TG improves oxygen balance by reducing the brain's energy demand.

Prevention of damage to the blood-brain barrier and correction of cerebral edema. The formation of cerebral edema after a period of injury is a consequence of increased permeability and disruption of the functional and morphological integrity of the blood-brain barrier (BBB), including tight junction proteins, transport proteins, basement membrane, endothelial cells, astrocytes, pericytes and neurons. Models of cerebral ischemia, traumatic brain injury (TBI), and intracranial hemorrhage have shown that TG moderately to profoundly protects the BBB and prevents the development of cerebral edema. This may explain the effectiveness of moderate TG on elevated ICP in TBI.

TH prevents the activation of proteases that are responsible for the degradation of the extracellular matrix, such as matrix metalloproteinases (MMPs),

capable of causing destruction of the BBB due to participation in matrix degradation. Moderate TG prevents damage to the BBB, reduces MMP expression and suppresses MMP activity. TG also prevents the development of cerebral edema by stabilizing the water balance of the brain. Aquaporins are a family of water channel proteins that control movement across the cell wall membrane. Moderate TG significantly reduces the overexpression of aquaporin 4 and protects the BBB, thereby reducing the severity of cerebral edema.

Effects of inflammatory mediators. Inflammation is an integral part of the body's defense complex. Autoaggression observed during inflammation may be a component of damage to organs and systems. After brain injury, activation of a cascade of pro- and anti-inflammatory cytokines is observed. The most significant pro-inflammatory cytokines are interleukin 1b, tumor necrosis factor a (TNFa), interleukin 6. The counterbalancing anti-inflammatory cytokines are transforming growth factor b and interleukin 10, however, correlate the presence of pro- and anti-inflammatory cytokines and their damaging effects on the brain is impossible, and cytokines with multidirectional types of action may have destructive (or protective) properties.

For example, TNF-α expressed in the striatum causes neurodegeneration effects, but if similar expression is realized in the hippocampus, then a protective effect occurs. There is an assumption that in the early phase of inflammation there is an aggressive effect of cytokines, and in the late phase of inflammation there is a reparative effect. It has also been suggested that soluble TNF-α (binding to receptor 2) is a signaling molecule for neuroprotection. It is believed that the protective effect of TNF-α can be realized depending on the activity of neuroglia, the time and severity of expression of receptors for TNF-α and the metabolic conditions of a particular region of the brain.

Under TG conditions, pro- and anti-inflammatory mediators exhibit different activities. Whether TG is a pro- or anti-inflammatory event is unclear. An in vitro study of human peripheral mononuclear cells showed that TH causes a shift in the balance of cytokines produced by leukocytes to the proinflammatory side. This suggests that there will be a state of excess inflammation, impaired host response, and an increased likelihood of infectious complications. The results of animal experiments show that moderate TG mitigates the inflammatory response and increases anti-inflammatory activity. Moderate TG further reduces mortality in experimental endotoxemia, but clinical studies have not provided such evidence.

Activated cells and their products can have a significant effect on secondary damage

tion of the brain, since some of the molecules of the inflammatory chain are involved in the repair process.

Inhibition of excitotoxic neurotransmitters. This mechanism of the positive neuroprotective effect of hypothermia is known quite well, primarily in relation to secondary brain damage. The greatest focus is on 2 neurotransmitters - excitatory amino acids (BAA) and nitric oxide (NO).

Exciting amino acids. The amount of BAK, including glutamine and aspartate, increases significantly after ischemia, hypoxia, trauma and poisoning. Activation of the corresponding receptors is the most important factor in the development of secondary damage after a primary stroke. The concentration of BAK correlates with the degree of neuronal damage.

Prevention of accumulation or release of glutamate by TG may be explained by the effect of cooling on metabolism, which maintains ATP levels at basal levels. ATP is required to maintain the ionic gradient and, if disrupted, will activate the entry of calcium ions into the cell, leading to increased glutamine concentrations outside the cell. Glutaminergic receptors (AMPA and NMDA) can also be modulated by TG, which can prevent the effects of excitotoxicity by limiting the entry of calcium ions through AMPA channels. Glutamate receptor 2, as a subunit of the AMPA receptor, is a likely point of application of hypothermia and is capable of limiting the incoming flow of calcium ions; turning off this receptor can lead to an excess flow of calcium ions.

There is an opinion that an increase in glutamine levels during cerebral ischemia occurs not only due to its excessive release, but also due to a violation of the reuptake of glutamine through the membrane. TG can increase the intensity of glutamine reuptake.

Maintaining a balance between BAK and inhibitory amino acids after brain injury is required. Moderate hypothermia effectively reduces the degree of damage to brain tissue by reducing the release of BAK and glycerol and increasing the concentration of inhibitory γ-aminobutyric acid. Inhibitory amino acids are antagonists of BAK, and TG restores the balance.

Studies show that the penumbra and intact tissue are the areas in which TH has the greatest effect on the VAC. There are no such data regarding the core of damaged brain tissue. Therefore, with stroke, immediate cooling is necessary in order to preserve the maximum zone of intact brain and penumbra.

Nitric oxide. Oxidative stress damages body cells when the physiological balance between oxidants and antioxidants is disrupted. The key radical in brain damage is the superoxide anion, which produces

with the participation of xanthine oxidase and NADH oxidase. L-arginine is transformed into NO with the participation of three types of NO synthases (NOS): neuronal, endothelial and inducible (n, e, i). The level of these NOS increases during cerebral ischemia.

Under conditions of moderate TG, correction of NO and NOS levels are the most important mechanisms for protecting neurons. The protective effects were tested on experimental models of cerebral ischemia, intracranial hemorrhage, and TBI. NO accumulates in neurons immediately after damage, when there is an increase in the activity of its synthases. Moderate TG can reduce NO levels, suppress NOS activity and thereby protect neurons. Such activity is proven by the fact of a decrease in NO levels in the internal jugular vein. Research on the effects of TG on NO levels is contradictory: there is evidence that TG does not affect the production of NO by peripheral blood monocytes when stimulated by lipopolysaccharide.

In recent years, scientists have begun to actively compare the effects of TG on NOS species. TG actively affects the level of iNOS during ischemia, while after ischemia it affects the expression of nNOS. There is an opinion that moderate TG does not change the expression of nNOS, but significantly reduces its activity.

Moderate TG is able to inhibit NOS expression in the cortical penumbra, reducing the content of NO and metabolites, which is similar to the effect on VAC. The difference is that TG used for brain damage can also affect the core of the damage. It is believed that the effect of TH on iNOS is time-dependent; delayed TH also gives a therapeutic effect; only the points of application (nucleus and penumbra) will differ.

The relationships between the neurotransmitter complex are quite complex. Elevated levels of NO may only be part of a cascade of mediator activation. An increase in glutamate levels in the cortex can lead to an increase in extracellular NO and its metabolites (nitrites and nitrates); hypothermia can inhibit this process. Inhibition of iNOS may be part of the inhibition of nuclear factor kappaB by NF-kB. Due to cerebral ischemia, activation of nuclear factor leads to the expression of many inflammatory genes involved in the pathogenesis of cerebral inflammation. Moderate hypothermia prevents nuclear factor translocation and DNA binding by inactivating NF-κB kinase inhibitor (IKK). IKK exists to phosphorylate and degrade nuclear factor inhibitor; therefore, preventing NF-κB from entering the nucleus, which may cause increased expression of iNOS and TNF-α genes. Cerebral ischemia induces activation of calcium-calmodulin-dependent kinase II, which is involved in nNOS activity, which is also a target of TH.

Reducing the influx and toxic effect of calcium ions on neurons. Calcium plays

a leading role in the normal physiology of membranes and cells, as well as in the pathophysiology of cellular damage. Excessive calcium entering the cell can initiate a process of cell damage. Studies conducted in experiments on animals and in humans confirm the fact that calcium overload of cells after the action of various damaging factors occurs quite quickly, which is also due to the redistribution of calcium from cell mitochondria. Calcium overload has been implicated in the pathogenesis of epilepsy. Moderate TG is able to limit calcium overload, turning off the work of calcium ATPase, and conserve energy in mitochondria, thereby stabilizing the mitochondrial function of preserving calcium inside mitochondria. In recent years, in vitro experiments have confirmed these findings.

Calpain (calcium protease) is a calcium-dependent protease that is activated by calcium ions in vitro. The main “points of application” of calpain are cytoskeletal proteins, protein kinases and hormonal receptors. After brain injury, TH is able to “turn off” calpain activity by inhibiting calpain II activity and thereby reduce cytoskeletal degradation activity.

Effect on cell apoptosis. TG can influence the processes of cell apoptosis. Similar activity can be observed in the caspase-dependent and caspase-independent apoptotic pathway.

Moderate hypothermia can interact with the intrinsic pathway of apoptosis by changing the expression of proteins of the Bcl-2 family, reducing the release of cytochrome C and reducing caspase activity. In a model of global ischemia, TG leads to a reduction in proteins of the pro-apoptotic Bcl-2 family, such as BAX, and “turns off” the activity of anti-apoptotic processes.

The extrinsic apoptotic pathway can also be inactivated by TG. In this case, the families of proteins FAS and FASL are most often involved. Both of these proteins are inhibited by a decrease in their expression under the influence of TG.

The antiapoptotic activity of TH may be mediated by an effect on NF-kB. In the normal state, the nuclear factor is located in the cytoplasm, being associated with a number of inhibitory cytoplasmic proteins. In order to be activated-

However, IKK must phosphorylate these inhibitors to release nuclear factor and allow the latter to enter the cell nucleus and induce gene expression. Inhibition of such activation of nuclear factor can inactivate the process of expression of apoptotic genes. This process can be stopped by TG.

Electron microscopy made it possible to prove significant morphological changes in neurons of the cerebral cortex after ischemia/reperfusion, chromatin condensation, delimitation, changes in the appearance of the nucleus, reduction in cell size, concentration of cytoplasm and other confirmation of the morphology of apoptosis.

Technologies of therapeutic hypothermia. Devices for implementing TH can be divided into 3 large groups: traditional methods of cooling (and therefore warming or, if necessary, maintaining temperature balance), non-invasive systems for cooling and invasive (intravascular) systems.

Traditional cooling method. This cooling method is the easiest option for achieving hypothermia by using cold saline or ice, which can be done either by intravenous or intragastric administration of solutions, or by covering the human body or certain areas of the body with ice (projection of the great vessels, head). It is believed that this method is relatively safe, but its use is most applicable at the stage of prehospital care or in a non-specialized clinic. The authors note that this method is effective in inducing TG, but in the case of maintaining a certain level of temperature and warming, the traditional method is criticized for being uncontrollable and unpredictable, which explains the complementary nature of this type of TG. The greatest advantages are the absolute availability of this method of hypothermia and low cost.

Methods for cooling the body surface. Non-invasive devices for cooling the body surface are different from invasive devices. The cardinal difference between such devices is the rate at which the required temperature is reached and the exact “dosage”

Technical implementation of TG (cited by Storm S., 2012)

Manufacturer Device Option for achieving hypothermia Rate of achieving cooling, "R/h Feedback Possibility of reusing the device (cooling elements)

Philips (Netherlands) InnerCool RTx Catheter 4-5 Yes No

Zoll (USA) Thermogard XP Catheter 2-3 Yes No

CR Bard (USA) ArcticSun 5000 Surface adhesive pads 1.2-2 Yes No

CSZ (USA) Blanketrol III Blankets 1.5 Yes Yes

EMCOOLS (Austria) FLEX.PAD Surface adhesive pads 3.5 No No

MTRE (USA) CritiCool Blankets 1.5 Yes No

temperature maintenance and warming of the patient. Despite the adhesion effect of the material, no serious skin damage has been described. The Arctic Sun system has greater potential compared to other devices due to the ability to maintain normothermia.

Endovascular devices. Such devices have computer control with mandatory feedback; The temperature change is carried out by circulating water through a closed system with recirculation. The main advantage of using such devices is the ability to eliminate the periphery-core time gradient, which is invariably created during the cooling/warming process when using external devices. In such a situation, very careful temperature control is required, which is achieved through the use of direct sensors installed either in the lumen of the vascular bed or in the bladder. The combination of these features allows for the most optimal warming process and prevention of excessive cooling. The maximum duration of the procedure using this technique is not clear, but it is clearly less than it can be when using external devices.

Clinical testing and evidence collection

Heart failure. Both experimental models and clinical studies have proven the benefits of TH in restoring the functional integrity of the brain after the resumption of spontaneous circulation. To date, TG is included in a number of national and international guidelines for the treatment of patients in a coma after cardiac arrest and effective resuscitation measures. Key evidence for the effectiveness of TH in similar clinical situations was published in 2002, when the authors cooled their patients to 32-34oC for a period of 12-24 hours. The study focused on patients with prehospital cardiac arrest, primary ventricular fibrillation, and a known “cardiac” cause of cardiac arrest; other causes of cardiac arrest were excluded from the study. The small sample size of patients was critical, but due to a very clear design, possible erroneous conclusions and consequences were excluded. Attempts have been made to repeat similar studies in other cohorts of patients, but clear evidence has not been obtained in other groups of patients. Post-hoc analysis showed that there are a number of advantages in the group with normothermia (in comparison with hyperthermia), however, the method of hypothermic protection still has great advantages.

Traumatic brain injury. The most significant feature of all therapeutic strategies for TBI is the fact that there are still no methods with proven effectiveness. Usually the use of TG is delayed due to the need for

primary resuscitation measures and the necessary set of diagnostic procedures.

Eight meta-analyses were conducted that proved the ineffectiveness of TG in complex therapy for severe TBI. It was shown that there were no serious randomized studies, the studies differed in the treatment protocol, and the nature of the randomization was beyond any criticism. A 2009 Cochrane review found that there were several benefits to the use of hypothermia for severe TBI, with reduced mortality and severity of illness, but the rate of such studies was low and multicenter studies did not show similar benefits, notably showing no difference in incidence lethal outcome. All these studies were united by the fact of early (in the first 6 hours) use of TG to provide neuroprotection. In clinical practice, TG is usually used to reduce elevated ICP, but no evidence-based studies have been conducted on this thesis.

Acute cerebrovascular accident. At the moment, it has been unequivocally proven that thrombolysis and antiaggregation therapy will be effective in acute stroke. At the moment, TH can be a component of complex therapy, but is not opposed to thrombolysis; however, the use of TH as a neuroprotective strategy can improve the characteristics of local oxygen supply to the brain by reducing consumption and creating conditions for better recovery. In experimental models, the effectiveness of TH has been proven by reducing the volume of the affected area of ​​the brain by up to 40%. There are no studies that would determine clinical effectiveness and increased survival.

There are a number of features that must be taken into account when using TG for stroke. Thus, many patients have elements of consciousness and are not in a deep coma; therefore, they do not tolerate the process of induction and maintenance of TG poorly, in contrast to patients with cardiac arrest or severe TBI in a coma. The result is that muscle tremors increase basal metabolic rate and oxygen demand, requiring sedation and/or neuromuscular blockade.

Hypoxic ischemic encephalopathy of newborns. Based on the fact that hypoxic brain injury in preterm infants is a leading cause of disability in surviving infants, researchers have been quite active in trying to use TH to improve functional outcome. S. Shankaran et al. used the whole body TG method with cooling to 33.5°C in the first 6 hours from birth; the TG maintenance period was 72 hours. In addition, the results of exposure and different approaches to cooling on the whole body or only on the head were studied. Significant figures were obtained for reducing the severity of disability during long-term observation of patients in

group using general cooling, the effectiveness and safety of the neuroprotection method were also demonstrated.

Side effects

Shiver. This phenomenon is associated with an increase in the activity of the sympathetic nervous system and basal metabolism, which is critical for the patient, who requires the inverse relationship to the basal metabolism - suppression through the use of sedation and neuromuscular blockers.

Pneumonia. The only review regarding severe TBI did not note a significant increase in the incidence of pneumonia in patients after TH.

Instability of heart function. TG is associated with arterial hypotension and arrhythmias (bra-diarrhythmias), but the authors note that the effect, similar to that of P-blockers, has a positive effect on cardiac function in patients with cardiac arrest and the presence of ventricular fibrillation.

Hyperglycemia. The most common side effect of TG is hyperglycemia; there is evidence of a correlation with increased mortality.

Electrolyte disorders. The most common disorder is hypokalemia. Routine testing of potassium and sodium levels in the blood plasma allows an adequate response to these disorders.

Rebound syndrome in the form of increased ICP due to warming. This phenomenon has been described in many types of TG, which requires additional measures to correct the increase in ICP during warming.

1. Today there is a sufficient amount of knowledge about the mechanisms of action of therapeutic hypothermia.

2. The strategy of moderate therapeutic hypothermia is a promising way to protect the brain in critical conditions, which is proven primarily by experimental developments and less by clinical studies.

3. Further developments are substantiated in relation to a wide range of studies: patient selection, therapeutic “window” of initiation of therapeutic hypothermia, indicators of adequacy of protection (neurophysiological, biochemical, neuroimaging).

Research Institute of Complex Problems of Cardiovascular Diseases of the Siberian Branch of the Russian Academy of Medical Sciences

Grigoriev Evgeniy Valerievich - Dr. med. Sciences, prof., deputy Director for Scientific and Medical Work, Leading scientific co-workers lab. critical conditions; e-mail: [email protected]

Shukevich Dmitry Leonidovich - Dr. med. sciences, head lab. critical conditions. Plotnikov Georgy Pavlovich - Dr. med. Sciences, Ved. scientific co-workers lab. critical conditions. Kemerovo Cardiology Clinic

Tikhonov Nikolay Sergeevich - doctor of the intensive care unit.

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Received 03/24/14 Received 03/24/14

DIAGNOSTIC VALUE OF BIOMARKERS OF SYSTEMIC INFLAMMATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Budnevsky A.V., Ovsyannikov E.S., Chernov A.V., Drobysheva E.S.

GBOU VPO "Voronezh State Medical Academy named after. N.N. Burdenko" Ministry of Health of Russia, 394000 Voronezh

Chronic obstructive pulmonary disease (COPD) causes significant social and economic costs. Airway inflammation is a major component of the pathogenesis of COPD, which is present in the early stages of the disease and persists for many years after the cessation of the triggering factors. Over the past few years, there has been growing interest in biomarkers of inflammation in various diseases, including COPD. Biomarkers that have been studied in patients with COPD are associated with the pathophysiology of the disease and the inflammatory process in the lungs. However, only some of them have been shown to be significant. The purpose of this review is to summarize the currently available data on systemic biomarkers of inflammation in COPD, their possible role in assessing disease activity, severity and determining the phenotype of COPD. Most systemic biomarkers are not specific for COPD. In addition, the presence of concomitant diseases, most often cardiovascular diseases, causes certain difficulties in assessing the value of systemic biomarkers. Despite this, the results of studies involving a large number of COPD patients have provided information on the role of currently available biomarkers in determining disease activity, as well as the COPD phenotype with systemic inflammation. The inclusion of biomarkers in screening protocols for patients with COPD requires further study.

Key words: chronic obstructive pulmonary disease; biomarkers; systemic inflammation.

THE DIAGNOSTIC VALUE OF SYSTEMIC INFLAMMATION BIOMARKERS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Budnevsky A.V., Ovsyannikov E.S., Chernov A.V., Drobysheva E.S.

N.N. Burdenko Voronezh State Medical Academy, Russia

Chronic obstructive pulmonary disease (COPD) is a cause of appreciable social and economic losses. Airway inflammation is the main factor at the early stages of COPD pathogenesis and persists for many years after cessation of the action of provoking factors. In the last years, researchers have shown much interest in biomarkers associated with various diseases including COPD. Biomarkers of COPD are related to pathophysiology of the disease and inflammatory processes in the lungs. This review is designed to summarize the currently available data on systemic COPD biomarkers, their use for the assessment of activity of the disease and the possible role in the formation of COPD phenotype. Most systemic biomarkers are not specific for COPD. Moreover, evaluation of their significance encounters difficulties due to the presence of concomitant pathologies, in the first place cardiovascular diseases. However, studies involving a large number of patients with COPD provided information about the role of biomarkers in the activity of COPD and the formation of its phenotype with systemic inflammation. The introduction of biomarkers in protocols of examination of COPD patients needs further substantiation.

Key words: chronic obstructive pulmonary disease; biomarkers; systemic inflammation

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of disability and death and causes significant social and economic losses. In recent years, there has been an increase in the prevalence of the disease, and according to forecasts, the damage from COPD will increase, which is mainly due to the unfavorable environmental situation and continued exposure to risk factors. Despite the fact that the diagnosis of COPD, the choice of therapy, and the assessment of its effectiveness are based primarily

on the degree of airflow limitation, it is now recognized that forced expiratory volume in 1 s (FEV1) does not fully reflect the complex relationships of pathological processes present in COPD at the clinical, cellular and molecular levels. Airway inflammation is a major component of the pathogenesis of COPD, which is present in the early stages of the disease and persists for many years after the cessation of the action of the provoking factors, and persistent systemic inflammation

Therapeutic hypothermia- therapeutic effects on the patient’s body temperature in order to reduce the risk of ischemic tissue damage after a period of insufficient blood supply. Periods of insufficient blood supply can occur as a result of cardiac arrest or blockage of an artery due to embolism, as commonly occurs with a stroke. Therapeutic hypothermia can be administered by invasive methods, in which a special heat-exchange catheter is inserted into the patient's inferior vena cava through the femoral vein, or by non-invasive methods, which typically use a water-cooled blanket or vest on the torso and applicators on the legs, which are in direct contact with the body. patient's skin. Studies have shown that patients at risk of ischemic brain injury have better neurological outcomes when using therapeutic hypothermia.

Background

Hypothermia has been used as a therapeutic method since ancient times. The Greek physician Hippocrates (probably the only ancient doctor in the world whose views are supported in modern times) recommended covering wounded soldiers with snow and ice. Napoleon's surgeon, Baron Dominique Larrey, testified in writing that wounded officers who were kept closer to the fire were less likely to survive severe wounds than infantrymen who were not too pampered by such care. In modern times, the first medical article on hypothermia was published in 1945. This study focused on the effects of hypothermia on patients suffering from severe head injuries.

In the 1950s, hypothermia found its first medical use to create a bloodless surgical field during surgery for intracranial aneurysm. Most early studies focused on the use of deep hypothermia with body temperature in the range of 20–25 °C (68–77 F). This extreme reduction in body temperature generated a host of side effects, making the use of deep hypothermia impractical in most clinical situations. During the same period, isolated studies also appeared on milder forms of therapeutic hypothermia with a moderate decrease in body temperature to the range of 32–34 °C (90–93 °F). In the 1950s, Dr. Rosomoff demonstrated the beneficial effects of mild hypothermia following cerebral ischemia and traumatic brain injury in dogs. Additional animal studies in the 1980s demonstrated the ability of mild hypothermia to play a general neuroprotective role following blockade of blood flow to the brain. These animal findings were confirmed by two seminal human studies that were simultaneously published in 2002 in the New England Journal of Medicine. Both studies, one from Europe and the other from Australia, demonstrated the beneficial effects of moderate hypothermia after cardiac arrest. In response to these studies, in 2003 the American Heart Association (AHA) and the International Liaison Committee on Critical Care (ILCOR) mandated the use of therapeutic hypothermia after cardiac arrest. Today, an increasing number of clinics around the world are using AHA and ILCOR guidelines and have included hypothermic treatment as part of the standard care package for patients suffering from cardiac arrest. Some researchers have gone even further and argue that hypothermia provides better neuroprotection after blocking blood flow to the brain than medication.

GBOU HPE Kirov State Medical Academy

Department of Pediatric Surgery

Therapeutic hypothermia

Performed:

pediatric student

faculty 633 groups,

Malova E.N.

Head Department: Doctor of Medical Sciences,

Associate Professor Razin M.P.

Teacher:

Gulin A.V.

Kirov, 2014

1. Historical background

hypothermia neuroprotective craniocerebral medical

The first mention of the use of hypothermia as a therapeutic method is the recommendation of Hippocrates (460-377 BC) to cover wounded soldiers with ice and snow. Military surgeon Dominic Larrey (1766-1842) wrote that wounded officers who were kept close to the fire were less likely to survive severe wounds than infantrymen who were not kept warm. The effect of cold water on the human body was first studied by J. Curry in 1798. To find out the causes of death of sailors who were shipwrecked in winter, he immersed volunteers in water at a temperature of 9-10 ° C and studied the effects of artificial hypothermia. In the 1950s, deep hypothermia with a body temperature of 20-25°C was used to create a bloodless surgical field for heart surgery, but such cooling caused a lot of side effects. In 1968 at the Institute of Surgery named after. A.V. Vishnevsky, a group of scientists led by Academician A.A. Vishnevsky proved that with rapid cooling after death of warm-blooded animals, the possibility of returning to life is measured in hours, while without cooling it is measured in minutes. During the same period, studies of milder forms of therapeutic hypothermia with a moderate decrease in body temperature to the range of 32-34 ° C appeared, which demonstrated improved survival of patients with cerebral ischemia and traumatic brain injury. Additional animal studies in the 1980s demonstrated the ability of mild hypothermia to play a general neuroprotective role following blockade of blood flow to the brain.

2. The mechanism of the neuroprotective effect of hypothermia

Nervous tissue has the least energy reserve. The optimal cerebral blood flow is 0.6 ml/g/min. When blood flow decreases below 0.5 ml/g/min, protein synthesis stops, below 0.35 ml/g/min, the anaerobic cycle of glucose oxidation starts, below 0.15 ml/g/min, irreversible changes develop after 6 minutes. Cell death can occur through necrosis or apoptosis. When blood flow is stopped, a cascade of pathobiochemical changes develops (glutamate excitotoxicity, intracellular calcium accumulation, activation of intracellular enzymes, development of oxidative stress, expression of early response genes), leading to cell death through the mechanisms of necrosis and apoptosis with the formation of an infarct core and ischemic penumbra (penumbra). Transmembrane transport is disrupted, and an excess amount of Na+ and water enters the cell, which leads to edema, the severity of which depends on the size of the ischemic zone. This is accompanied by extracellular edema caused by cell death with the release of large amounts of under-oxidized products. There are no morphological changes in the penumbra zone, but due to a decrease in blood flow, functional disorders increase, which subsequently lead to cell death through apoptosis.

For a long time it was believed that the positive effect of hypothermia was associated only with the effect on cellular metabolism. Since cellular metabolism slows down by 5-7% when body temperature decreases by 1°C, a decrease in tissue oxygen demand is a neuroprotective effect of hypothermia. However, even a small decrease in body temperature has been shown to be clinically effective, and a decrease in temperature below 30°C is not advisable.

Cells need oxygen to synthesize ATP molecules, which are involved in the active transport of ions across the membrane and maintaining homeostasis. In the absence of ATP, the balance of electrolytes in the cytoplasm and intercellular environment is disrupted, which leads to cell death. However, even slight hypothermia of the environment reduces the permeability of the cell membrane, which slows down the development of electrolyte disturbances and allows the cell to survive in conditions of low energy production. Brain edema is relieved, intracranial pressure is reduced, which prevents death from brainstem herniation. Also, when the temperature decreases, glutamate neurotransmission is suppressed, excitotoxicity is reduced and the ischemic cascade slows down.

Another effect is a negative impact on immunoinflammatory processes. As a result of the ischemic cascade, the cellular elements that make up the blood-brain barrier die, which is accompanied by transendothelial migration of leukocytes into the brain tissue, which cause aseptic inflammation. Magnetic resonance spectroscopy has shown that the ischemic penumbra zone has the highest temperature. Reducing brain temperature slows down inflammatory reactions in this area, providing a neuroprotective effect.

Another positive effect of hypothermia occurs in the event of reperfusion. A sharp influx of oxygen accelerates oxidative reactions in living cells, which leads to increased acidosis and even greater accumulation of free radicals. The membrane-stabilizing effect, slowing down immune reactions, reducing intracranial pressure - all this can serve as a mechanism to combat the development of reperfusion syndrome.

Side effects of hypothermia

Human body temperature is controlled by higher centers in the hypothalamus through autonomic responses that affect peripheral blood flow volume, sweating, and shivering. When body temperature drops below a certain threshold (usually 36°C), the patient experiences tremors. Peripheral vasoconstriction causes an increase in cardiac preload, which is compensated by tachycardia and hypertension. All of this can cause discomfort in unsedated patients. To relieve these symptoms, pethidine and diphenhydramine are most often used in combination with a solution of magnesium sulfate. The administration of magnesium sulfate solution is also associated with another side effect of hypothermia - electrolyte disorders. Hypomagnesemia is noted, which leads to an increase in convulsive readiness. Prolonged hypothermia leads to hyponatremia and hyperkalemia, probably due to decreased function of the Na+ / K+ -ATPase pump of the cell membrane.

The sensitivity of tissues to insulin decreases, which leads to hyperglycemia. Therefore, when performing hypothermia, it is necessary to monitor and correct blood glucose levels by administering additional doses of insulin. It should be noted that hyperglycemia is insulin resistant at temperatures< 30°С. Длительная гипотермия приводит к гипогликемии из-за нарушения глюконеогенеза и снижения запасов гликогена в печени.

It was noted that during cooling, blood buffer bases, pCO2, the amount of protein and its fractions decrease.

When the temperature drops to 35°C, reversible platelet dysfunction occurs. At temperatures below 33°C, a decrease in coagulation and an increase in APTT and PT are recorded, which can provoke bleeding. For this reason, general hypothermia is contraindicated in patients at high risk of bleeding and with hemorrhagic stroke. However, there is evidence that mild hypothermia with a body temperature of ~ 35°C, started 12 hours after the development of symptoms, does not cause secondary hemorrhagic complications.

Hypothermia is a relative contraindication to thrombolytic therapy with tissue plasminogen activator. In vitro studies have shown that the lytic activity of tPA decreases by 5% with a decrease in temperature of 1°C. However, in vivo studies have not confirmed the effect of hypothermia on either the efficacy of thrombolytic therapy or mortality.

At body temperature<30°С возникает опасность возникновения электрической нестабильности сердца, снижения сердечного выброса, артериального давления. В связи с этим по современным стандартам температура тела пациента не должна быть меньше 32°С.

Hypothermia Methods

Therapeutic hypothermia can be carried out using invasive and non-invasive methods and is divided into general and local.

Invasive methods involve infusion of cooled saline into a central vein. The advantage of this technique is the controllability of hypothermia, which allows you to achieve a temperature value within ~ 1°C of the target, regulate the cooling rate and the warming rate. The main negative side of this method is the systematic nature of hypothermia, which provides a high probability of developing the above side effects. There is also a possibility of bleeding, thrombosis, and infectious complications, which are especially dangerous in conditions of hypothermia.

Non-invasive techniques involve cooling the patient's body through the outer covering. One option is a heat exchange blanket, which has multiple cooling and warming rates to achieve controlled general hypothermia of the entire body. A separate group is represented by methods of local surface cooling, one of which is craniocerebral hypothermia.

Craniocerebral hypothermia

Craniocerebral hypothermia (CCH) is cooling of the brain through the outer covering of the head in order to increase its resistance to oxygen starvation.

For this, various means were used: rubber or plastic bubbles filled with ice, cooling mixtures (snow with salt, ice with salt), rubber helmets with double walls kami, between which cooled liquid circulates, and bandages-fairings, air hypotherms with low circulation of cooled air. However, all these devices are imperfect and do not lead to the desired result. In 1964, in our country, the “Holod-2F” device was created (by O.A. Smirnov) and is currently being mass-produced by industry, which is based on the original jet method of cooling the head, and then the air-cooled “Fluido-Craniotherm” . CCG with the help of these devices has a number of advantages over general cooling, since first of all the temperature of the brain, especially the cortex, i.e. the structure most sensitive to oxygen starvation, decreases.

When the temperature of the upper layers of the brain adjacent to the cranial vault is 26-22°C, the temperature in the esophagus or rectum remains at 32-30°C, i.e. within limits that do not significantly affect cardiac activity. The "Holod-2F" and "Fluido-Craniotherm" devices allow you to urgently begin cooling during an operation without interrupting it or interfering with the surgeon's work; use hypothermia in the postoperative period for resuscitation purposes; automatically maintain the temperature of the coolant and the patient’s body during the cooling process; warm the patient; control the patient’s body temperature at four points simultaneously and the temperature of the coolant.

Obviously, it is possible to achieve a guaranteed uniform decrease in the temperature of brain tissue only with general hypothermia. The removal of heat from the surface of the head leads to cooling of the surface tissues, skull bones, and only after that - to a decrease in the temperature of the surface areas of the brain. At the same time, the central influxes of heat remain quite powerful, which forms a pronounced temperature heterogeneity of the brain, the role of which in pathology has not been studied. However, due to the listed side effects, the temperature and time limits of general hypothermia are strictly limited, which reduces the neuroprotective effect of this technique.

CCG is used:

· during operations accompanied by a short shutdown of the heart from the blood circulation, such as suturing a secondary atrial septal defect, valvuloplasty for pulmonary artery stenosis, valvuloplasty for aortic stenosis and, in some cases, for Fallot’s triad;

· when there is a danger of severe hypoxia due to the nature of the surgical intervention itself, for example, the application of interarterial anastomoses in “blue” patients, when eliminating coarctation of the aorta or reconstructive operations on the brachiocephalic branches of the aortic arch;

· in emergency neurosurgery. CCG is especially effective in patients with severe traumatic brain injury, accompanied by severe cerebral edema and disturbances of cardiac activity and breathing. When the temperature in the external auditory canal decreases to 31-30°C and the rectal temperature remains in the range from 34 to 35°C, there is a significant improvement in cardiac activity and respiration, which is explained by a decrease in cerebral edema, hypoxia and secondary changes;

· during resuscitation of patients (therapeutic hypothermia). CCG in clinical death can be decisive in the outcome of revival, as it prevents or reduces cerebral edema.

General anesthesia for CCG does not differ from that for general hypothermia. Cooling begins after induction of anesthesia and intubation. The patient's head is placed in a helmet equipped with numerous holes for streams of cold water or air. The optimal temperature of the coolant (water, air) should be considered 2°C. Lower temperatures are dangerous due to frostbite of the skin. The patient's body temperature is measured at several points (inside the ear canal at the level of the eardrum, in the nasopharynx, esophagus and rectum). Temperature inside the ear canal at the level of the eardrum ki corresponds to the temperature of the cerebral cortex at a depth of 25 mm from the internal vault of the skull; body temperature is judged by the temperature in the rectum. The rate of cooling of the brain using devices ranges from 7 to 8.3°C/min, and of the body - 4.3-4.5°C/min. Cooling is continued until the temperature in the rectum is not lower than 33-32°C, in the esophagus 32-31°C.

CCG causes a gradual decrease in blood pressure and a decrease in heart rate. ECG changes depend on the nature of the surgical intervention and the duration of exclusion of the heart from the circulation. Studies of the bioelectrical activity of the brain do not reveal any significant changes when cooled in this manner to a temperature of 25°C in the external auditory canal. During cooling, a decrease in blood buffer bases and pCO2 is observed, a decrease in the amount of protein and its fraction, a decrease in fibrinogen and an increase in fibrinolytic activity. However, these changes are reversible and return to normal when the patient is warmed to the original temperature.

The patient is warmed using electric heating pads, which are placed on the operating table under the patient's back. After the operation is completed, warming is continued using a polyethylene cape, under which warm air is pumped by a thermostat.

Problems of using craniocerebral hypothermia at the prehospital stage of medical care

Taking into account the pathogenesis of the development of ischemic brain damage and research results, neuroprotective therapy should be started as early as possible from the onset of acute ischemic pathology. Since drug methods of neuroprotection used in the prehospital stage have not proven their effect on the outcome of the disease, it is necessary to consider the use of new techniques, one of which may be craniocerebral hypothermia. However, when assessing the possibility of using CCH at the prehospital stage of medical care, a number of problems arise.

Modern diagnostic methods at the prehospital stage do not allow one to reliably exclude the hemorrhagic nature of cerebrovascular accidents; accurate diagnosis of the nature of a stroke is clinically possible only in 70% of cases (according to Evzelman M.A., 2003). The main question remains the effect of craniocerebral hypothermia on the prognosis of patients with hemorrhagic stroke. Although theoretical models of localized superficial hypothermia do not predict the development of bleeding disorders, modest non-randomized data are insufficient to provide guidance and risk/benefit ratios for the use of CCH in patients with a hemorrhagic component of stroke.

Another equally important problem is the effect of CCH on the width of the therapeutic window and the effectiveness of thrombolytic therapy. Thrombolysis in acute ischemic stroke is limited by the survival time of nerve cells exposed to total ischemia. If these periods are exceeded, the risks of side effects exceed the positive impact on the outcome of the disease. Considering the mechanisms of the neuroprotective effect of hypothermia, it is necessary to study the effect of CCH in the early stages of ischemic injury on the width of the therapeutic window of thrombolytic therapy. Studies conducted during general hypothermia in vivo are not enough to judge the nature of the effect of CCH on the lytic activity of tissue plasminogen activator. The positive effect of CCH on the relief of reperfusion syndrome also indicates the relevance of including this method in the treatment of ischemic brain damage.

The third significant problem is the development of portable devices and guidelines for craniocerebral hypothermia at the prehospital stage. Taking into account the time frame for providing medical care, it is necessary to develop tactics for inducing craniocerebral hypothermia in an emergency room with its continuation in a hospital setting.

Conclusion

Taking into account all the available data on the neuroprotective effect of hypothermia, we can judge the advisability of using craniocerebral hypothermia at the prehospital stage of medical care for the following conditions:

Acute ischemic stroke.

Transient ischemic attack.

Injuries of the central system, incl. closed head injury and spinal cord injury.

Posthypoxic encephalopathy.

Hyperthermia of central origin.

Coma of unknown origin.

Literature

1. Litasova E.E., Vlasov Yu.A., Okuneva G.N. et al. Clinical physiology of artificial hypothermia / ed. E.N. Meshalkina. Novosibirsk

Litasov E.E., Lomivorotov V.M., Postnov V.G. Non-perfusion in-depth hypothermic protection / ed. E.N. Meshalkina. Novosibirsk

Usenko L.V., Tsarev A.V. Artificial hypothermia in modern resuscitation // General resuscitation. 2009.

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Hypothermia (as a method) is an artificial decrease in the temperature of the body (or part of the body) by cooling. It is used as an independent or auxiliary remedy. There are local (local) and general hypothermia.

Local hypothermia of the stomach is performed using a special device LGZh-1 for bleeding ulcers of the duodenum, less often the stomach, erosive and a number of inflammatory diseases (for example,). A probe with a thin-walled balloon shaped like a stomach is inserted into the patient. The cylinder receives coolant (50% alcohol t° 4-5°), constantly circulating through the apparatus. The duration of hypothermia is 3-4 hours. Blood is transfused at the same time. Local hypothermia of the brain is performed using the Hypotherm apparatus, from which a stream of cold water or cooled air flows around the scalp. Used for severe cerebral edema (trauma, impaired blood supply to the brain). The duration of hypothermia is 2-4 hours; in this case, simultaneous intravenous infusion of hypertonic solution and plasma is indicated. Local hypothermia of the extremities is used as an anesthetic for amputation in seriously ill patients. The limb is covered with bags of ice, having previously applied it (for 2-3 hours; for 1-2 hours).

General hypothermia is used in operations that require temporary cessation of blood circulation (open - “dry” operations, surgeries, etc.). When body temperature drops to 25°, cessation of blood circulation is possible for 10-15 minutes, when cooling below 20° - for 45 minutes. and even more. Hypothermia is obtained by two methods.
1. External cooling (bath t° 3-5°, covering with bags of ice, hypotherm devices in the form of a system of tubes through which cold circulates). The patient is given endotracheal anesthesia with muscle and controlled breathing. When the depth is reached (see Anesthesia), the patient is placed in a cold bath. Monitor the temperature in the esophagus or with a special thermometer. In 30-60 minutes. the temperature drops to 32-30°. The patient is taken out of the bath, dried and placed on. Within 30 min. the temperature continues to decrease on its own by 2-5°. Muscle tremors at the beginning of cooling are relieved with an additional injection of a relaxant.

After the operation is completed, having applied a sticker to the wound, the patient is placed in a bath at a temperature of 40-45° and warmed to a temperature of 33-35°, then transferred to a bed and covered with a blanket. Then it rises on its own. Hypothermia reduces the sensitivity of tissues to oxygen starvation, which allows the brain to tolerate decreased blood circulation without harm.

The general rules for hypothermia using a machine or applying ice bags are the same.

2. Extracorporeal (extracorporeal) cooling; blood is drained from the patient’s vein through a system of tubes into a cooling apparatus, and then poured into a large artery.

Hypothermia below 20° requires artificial circulation (see). The main danger of hypothermia is cardiac fibrillation. The frequency of this complication increases as the temperature drops below 28°. If cardiac fibrillation occurs, defibrillation should be performed (see).

Hypothermia (from the Greek hypo - lower and therme - warmth; synonym general cooling) is an artificial decrease in body temperature, achieved under anesthesia, using physical influence (cold water, ice, chilled air, etc.). Hypothermia reduces the body's need for oxygen, increases its resistance to hypoxia (see), reduces or even eliminates the danger of temporary cerebral ischemia. Hypothermia is indicated for surgical interventions on a “dry” heart, during which it is turned off for 10 minutes. or longer (cerebral ischemia outside of hypothermia is tolerated without dangerous consequences for only 3 minutes), during operations requiring clamping of the aorta and turning off blood flow through the pulmonary artery. In neurosurgery, hypothermia is used in operations for cerebral aneurysms and brain tumors. Hypothermia has proven effective in thyrotoxic crisis. In patients with severe thyrotoxicosis and a significant increase in the level of metabolic processes, it is advisable to use moderate hypothermia in combination with neurovegetative blockade and endotracheal anesthesia. Hypothermia is also used during major operations in seriously ill patients, whose compensatory forces are depleted before surgery (I. S. Zhorov). In the postoperative period, hypothermia is indicated for hypoxic cerebral edema, intoxication and injuries to the central nervous system (A.P. Kolesov).

The combination of anesthesia (see) with hypothermia is the most complex, technically difficult type of combined anesthesia. At the same time, the danger of severe complications forces one to resort to hypothermia only when the danger due to the severity of the patient’s condition or the complexity of the intervention exceeds the risk associated with hypothermia itself.

Hypothermia can be general and local. With local hypothermia according to Allen, the limb, tied with a tourniquet, is covered with crushed ice (new ice is added as it melts). After 60-150 minutes. the temperature of the cooled tissues drops to 6-8°, which reduces their need for oxygen and causes an analgesic effect. In elderly patients in serious condition, the use of local hypothermia for amputations due to atherosclerotic or diabetic gangrene has proven to be very effective.

In case of general hypothermia, endotracheal anesthesia is required, which provides the possibility of controlled breathing and the use of muscle relaxants (see). Changes during general cooling are cyclic (phase) in nature. The 1st phase of hypothermia - “adrenergic” - is characterized by a decrease in the temperature of the heart and esophagus to 34° (initial, or mild, hypothermia). Under the influence of the release of adrenaline, arterial and venous pressure increases, pulse and respiration become more frequent, and the arteriovenous difference in oxygen content increases. Hyperglycemia, hyperkalemia, and increased flow of thyroxine into the blood are noted.

The 2nd phase occurs when the temperature drops to 28° (moderate hypothermia). At the end of this phase, there is a significant depression of all body functions. Muscle stiffness, a drop in arterial and venous pressure are noted, the pulse drops to 40 beats, cardiac output and arteriovenous difference (arteriolization of venous blood) decrease, and intracranial pressure decreases. Endocrine functions are suppressed. The patient loses consciousness. From this point on, the doses of narcotic substances should be significantly reduced; it is even recommended to switch to 100% oxygen insufflation. In this phase, the heart can be switched off for 10 minutes.

The 3rd phase, which occurs when cooling is below 28°, is characterized by complete depletion of the endocrine functions of the pituitary gland, thyroid gland and adrenal glands. The stiffness of the muscles is replaced by their relaxation. Cardiac fibrillation often occurs, which threatens death, but if you maintain a superficial level of anesthesia, then at a temperature not lower than 21°, neither respiratory nor cardiovascular reflexes will disappear, although they will gradually decrease. T. M. Darbinyan identifies the phase of cooling the body from 27° to 20° as intermediate hypothermia.

Deep hypothermia should be considered cooling below 20°, which requires the use of extracorporeal circulation devices. Drew, Keen and Benazon (S.E. Drew, G. Keen, D.B. Benazon) proved that at a temperature of 13°, cerebral ischemia is tolerated within 45 minutes. with complete subsequent restoration of all functions. S. A. Kolesnikov et al. cooling was carried out to 9-15.6° with circulatory arrest for 7-45 minutes. However, clinical experience with deep hypothermia is still limited. Mortality with it is still very high due to the often developing decortication syndrome.

The final stage of hypothermia is the period of rewarming. It must ensure that the supply of oxygen to the tissues prevails over its consumption. Active slow rewarming (warm water, warm air, diathermy, etc.) in combination with sufficient anesthesia is recommended.

In the initial phase of hypothermia, the body responds to a decrease in temperature with trembling, and oxygen consumption does not decrease, but, on the contrary, increases 2-7 times. To suppress this reaction, curarization with non-depolarizing relaxants in combination with shallow anesthesia is successfully used. When trembling occurs, intravenous administration of 10-25 mg of aminazine and 20 mg of promedol is recommended.

Respiratory impairment that occurs during hypothermia leads to acidosis, and acidosis and myocardial hypoxia provoke cardiac fibrillation. To combat respiratory acidosis, hyperventilation is recommended. When fibrillation occurs, defibrillation with a capacitor discharge is most effective (V. A. Negovsky, N. L. Gurvich).

To improve coronary circulation, it is advisable to compress the thoracic aorta (see Revitalization of the body).

To achieve hypothermia, methods of external cooling, cooling of body cavities and extracorporeal circulation are used. Cooling is controlled by thermometry in the rectum or esophagus (a special thermometer).

External cooling is achieved by covering the patient with ice packs, immersing him in a bath of water at a temperature of 3-5°, and wrapping him in a blanket through which cold water is passed through tubes. For external cooling, special refrigerators are most convenient, for example the Autohypotherm apparatus (Swedish production).

With any method of external cooling, it is necessary to stop it when the temperature of the blood circulating through the cooled surface tissues decreases by 2/3 of the planned cooling: after cooling is completed, the temperature continues to fall, and if this is not taken into account, its decrease will exceed the set level of hypothermia.

Hypothermia using the method of cooling cavities - washing the open chest with cold water (1954), introducing a balloon with ice water circulating in it into the stomach cavity, etc. - has not received sufficient distribution. With extracorporeal cooling, venous blood from the vena cava enters the refrigeration system and then returns to the body through the femoral artery. A. A. Vishnevsky and T. M. Darbinyan et al. developed a method of combined regional perfusion of the brain and heart, which allows open-heart surgery under conditions of moderate hypothermia for 9-29 minutes. The method of regional hypothermia of the head using external cooling, due to the speed and ease of implementation, began to be used in a complex of resuscitation measures (see Revitalization of the body).

RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2014

Other thermoregulatory disorders in the newborn (P81)

Neonatology

general information

Short description

Approved by the Expert Commission

On health development issues

Ministry of Health of the Republic of Kazakhstan

Moderate therapeutic hypothermia- controlled induced decrease in the patient’s central body temperature to 32-34°C, in order to reduce the risk of ischemic damage to brain tissue after a period of circulatory disorders

Hypothermia has been proven to have a pronounced neuroprotective effect. At the moment, therapeutic hypothermia is considered as the main physical method of neuroprotective protection of the brain, since there is not a single method of pharmacological neuroprotection, from the standpoint of evidence-based medicine. Therapeutic hypothermia is included in the treatment standards of: the International Liaison Committee on Resuscitation (ILCOR), the American Heart Association (AHA), as well as the clinical recommendation protocols of the Association of Neurosurgeons of Russia.

The use of moderate therapeutic hypothermia, to reduce the risk of irreversible changes in the brain, is recommended for the following pathological conditions:

Encephalopathies of newborns

Heart failure

Strokes

Traumatic lesions of the brain or spinal cord without fever

Brain injury with neurogenic fever

I. INTRODUCTORY PART

Protocol name: Hypothermia (therapeutic) of a newborn

Protocol code:

ICD-10 code(s):

P81.0 Neonatal hypothermia due to environmental factors

P81.8 Other specified disorders of thermoregulation in the newborn

P81.9 Disturbance of thermoregulation in the newborn, unspecified

Abbreviations used in the protocol:

HIE - hypoxic-ischemic encephalopathy

CP - clinical protocol

CFM - monitoring of cerebral functions by αEEG

EEG - electroencephalography

αEEG - amplitude-integrated EEG

NMR - nuclear magnetic resonance

Date of development of the protocol: year 2014

Protocol users: neonatologists, anesthesiologists-resuscitators (children), pediatricians, general practitioners

Classification

Clinical classification:

Therapeutic hypothermia of newborns is a method of controlled cooling of the child's body. There are:

Systemic hypothermia;

Craniocerebral hypothermia;

Therapeutic hypothermia is given to children with a gestational age of more than 35 weeks and a body weight of more than 1800 g.

Therapeutic hypothermia reduces mortality and the incidence of neurological disorders in children with hypoxic-ischemic brain damage

Diagnostics

II. METHODS, APPROACHES AND PROCEDURES FOR DIAGNOSIS AND TREATMENT

List of basic and additional diagnostic measures

Basic (mandatory) diagnostic examinations performed on an outpatient basis: no.

Additional diagnostic examinations performed on an outpatient basis: no.

Minimum list of examinations that must be carried out when referring for planned hospitalization: none.

Basic (mandatory) diagnostic examinations carried out at the hospital level:

Methodology of therapeutic hypothermia

Before initiating hypothermia treatment, pharmacological agents should be administered to control shivering.

The patient's body temperature drops to 32-34°C and is maintained at this level for 24 hours. Clinicians should avoid reducing the temperature below the target value. Accepted medical standards state that the patient's temperature should not fall below a threshold of 32°C.

The body temperature is then gradually raised to normal levels over 12 hours, under the control of the cooling/warming system control unit computer. Warming of the patient should occur at a rate of at least 0.2-0.3 ° C per hour to avoid complications, namely: arrhythmia, lowering the coagulation threshold, increasing the risk of infection and increasing the risk of electrolyte imbalance.

Methods for implementing therapeutic hypothermia:

Invasive method

Cooling is carried out through a catheter inserted into the femoral vein. The fluid circulating in the catheter removes heat outside without entering the patient. The method allows you to control the cooling rate and set body temperature within 1°C of the target value.

The procedure should only be performed by a well-trained doctor who knows the technique.

The main disadvantage of the technique is serious complications - bleeding, deep vein thrombosis, infections, coagulopathy.

Non-invasive method

The non-invasive method of therapeutic hypothermia today uses specialized devices consisting of a water-based cooling/warming system unit and a heat exchange blanket. Water circulates through a special heat transfer blanket or a tight-fitting vest on the torso with applicators on the legs. To reduce temperature at an optimal rate, it is necessary to cover at least 70% of the patient's body surface area with heat transfer blankets. A special helmet is used to locally reduce brain temperature.

Modern cooling/warming systems with microprocessor control and patient feedback provide controlled therapeutic hypo/hyperthermia. The device monitors the patient’s body temperature using an internal temperature sensor and corrects it, depending on the specified target values, by changing the temperature of the water in the system.

The principle of patient feedback ensures high precision in achieving and controlling the temperature of the patient's body first, both during cooling and during subsequent rewarming. This is important to minimize the side effects associated with hypothermia.

Therapeutic hypothermia of newborns cannot be performed without a tool for long-term dynamic analysis of brain activity, which effectively complements the vital sign monitoring system.

The dynamics of changes in the brain activity of a newborn, which cannot be tracked during a short-term EEG study, is clearly presented during long-term EEG monitoring with the display of amplitude-integrated EEG (aEEG) trends, a compressed spectrum and other quantitative indicators of the central nervous system, as well as the initial EEG signal in a small number EEG leads (from 3 to 5).

AEEG patterns have a characteristic appearance corresponding to various normal and pathological conditions of the brain.

aEEG trends display the dynamics of changes in EEG amplitude during multi-hour studies in a compressed form (1 - 100 cm/hour) and allow you to assess the severity of hypoxic-ischemic disorders, sleep patterns, identify convulsive activity and predict the neurological outcome, as well as monitor aEEG changes in conditions leading to brain hypoxia in newborns and observe the dynamics of the patient’s condition during therapeutic interventions.

Additional diagnostic examinations carried out at the hospital level:

AEEG is carried out after 3 hours and 12 hours during the therapeutic hypothermia procedure.

Table 1. Typical options for EEG lead circuits for monitoring cerebral functions

table 2. Examples of aEEG patterns

Diagnostic measures carried out at the emergency stage: no.

Diagnostic criteria

Complaints and anamnesis: see CP “Asphyxia of a newborn.”

Physical examination: see CP “Asphyxia of the newborn”.

Laboratory tests: see CP “Asphyxia of a newborn.”

Instrumental studies: see CP “Asphyxia of a newborn.”

Indications for consultation with specialists:

Consultation with a pediatric neurologist to assess the dynamics of the newborn’s condition before and after therapeutic hypothermia.

Differential diagnosis

Differential diagnosis: no.

Treatment abroad

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Treatment

Treatment goals:

Reducing the incidence of severe complications in the newborn from the central nervous system after asphyxia and hypoxia during childbirth.

Treatment tactics

Non-drug treatment:

The level of cooling during craniocerebral hypothermia is 34.5°C±0.5°C.

The cooling level during systemic hypothermia was 33.5°C (Fig. 3).

Maintain rectal temperature 34.5±0.5°C for 72 hours.

The duration of the procedure is 72 hours.

The warming rate should not exceed 0.5°C/hour

Drug treatment: no.

Other treatments: no.

Surgical intervention: no.

Further management:

Monitoring the condition of a child in the ICU/NICU.

Follow-up with a neurologist for 1 year.

Immunization with preventive vaccinations according to indications.

Indicators of treatment effectiveness and safety of diagnostic and treatment methods described in the protocol:

Hypothermia in the treatment of HIE is associated with less damage to the gray and white matter of the brain.

More children treated with hypothermia have no changes on MRI;

General hypothermia at the time of resuscitation reduces the incidence of deaths and moderate and severe disturbances in psychomotor development in newborns with hypoxic-ischemic encephalopathy due to acute perinatal asphyxia. This has been confirmed in a number of multicenter studies in the USA and Europe;

Selective head cooling soon after birth can be used to treat children with moderate to mild perinatal encephalopathy to prevent the development of severe neurological pathology. Selective head cooling is ineffective in severe encephalopathy.

Hospitalization

Indications for hospitalization indicating the type of hospitalization*** (planned, emergency):

Group A criteria:

Apgar score ≤ 5 at 10 minutes or

Continued need for mechanical ventilation at 10 minutes of life or

In the first blood test taken during the first 60 minutes of life, (umbilical cord, capillary or venous) pH<7.0 или

The first blood test taken within 60 minutes of life (umbilical cord, capillary or venous) shows a base deficit (BE) of ≥16 mol/L.

Group “B” criteria:

Clinically significant seizures (tonic, clonic, mixed) or

Muscular hypotonia and hyporeflexia or

Severe hypertonicity and hyporeflexia or

Disorders of the pupillary reflex (narrowed and does not respond to darkening, dilated and does not respond to light, weak reaction of the pupil to changes in lighting).

Group “C” criteria based on CFM results

The upper edge of the curve teeth is more than 10 µV, the lower edge of the curve teeth is less than 5 µV. The curve may be interrupted by peaks or series of peaks greater than 25 µV or

The upper edge of the waves is less than 10 µV, the curve is interrupted and periodically appears as an isoline and/or is interrupted by a series of peaks less than 10 µV or

Continuous series of peaks with a voltage greater than 25 µV or

1. 1) Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischemic encephalopathy. Cochrane Database Syst Rev 2007;(4):CD003311. 2) Hypothermia for newborns with hypoxic ischemic encephalopathy A Peliowski-Davidovich; Canadian Paediatric Society Fetus and Newborn Committee Paediatr Child Health 2012;17(1):41-3). 3) Rutherford M., et al. Assessment of brain tissue after injury moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy: a nested substudy of a randomized controlled trial. Lancet Neurology, November 6, 2009. 4) Horn A, Thompson C, Woods D, et al. Induced hypothermia for infants with hypoxic ischemic encephalopathy using a servo controlled fan: an exploratory pilot study. Pediatrics 2009;123:e1090-e1098. 5) Sarkar S, Barks JD, Donn SM. Should amplitude integrated electroencephalography be used to identify infants suitable for hypothermic neuroprotection? Journal of Perinatology 2008; 28: 117-122. 6) Kendall G. S. et al. Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy Arch. Dis. Child. Fetal. Neonatal. Ed. doi:10.1136/adc. 2010. 187211 7) Jacobs S. E. et al. Cochrane Review: Cooling for newborns with hypoxic ischemic encephalopathy The Cochrane Library. 2008, Issue 4. 8) Edwards A. et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340:c363


Indication of the conditions for reviewing the protocol: Review of the protocol after 3 years and/or when new diagnostic/treatment methods with a higher level of evidence become available.




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