INTRODUZIONE
Mild therapeutic hypothermia (HT) was introduced into the clinical management of cardiac arrest survivors after the publication of the results of two clinical trials showing a benefit compared with standard treatment and has been included in the guidelines for post-cardiac arrest care from the American Heart Association and the European Resuscitation Council .
The protective effects of hypothermia are believed to be a consequence of a reduction in the cellular metabolism and the retardation of destructive enzymatic reactions and the concomitant oxygen needs, thus conserving ATP levels.More recently, the beneficial effects of hypothermia, when applied to prevent an ischemic episode, included a trigger level of RONS that can act as a mechanism for induction of signaling pathways and the modulation of the extrinsic and intrinsic pathways of apoptosis.
The implementation of HT into clinical practice was also supported by meta-analyses of these clinical trials. Recently, however, several authors presented a critical view of the current evidence for the protective role of HT in post-cardiac arrest syndrome. In analyses of the available randomized data, they showed that the evidence for the benefits of HT in cardiac arrest survivors remains inconclusive . Their criticisms were based on the small size of published trials, low-quality data and non-negligible risks of systematic and random errors . Furthermore, in the published studies, HT was compared with standard care without specific temperature management, ie, usually with spontaneously developed fever. The deleterious effects of fever and hyperthermia have been repeatedly observed in a wide population of critically ill patients as well as in cardiac arrest survivors . The relative lack of evidence regarding the benefits of mild therapeutic HT in cardiac arrest survivors has led to the establishment of a large multicenter randomized controlled trial comparing mild therapeutic HT with controlled normothermia (NT) in CA survivors (the Target Temperature Management trial), which is currently underway .
EARLY CLINICAL TRIALS :
1.Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. 2002
In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32 degrees C to 34 degrees C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days.
Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups.
CONCLUSIONS:
In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality
2.Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. 2002
Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans.
In this randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest.The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility.
The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome--that is, they were discharged home or to a rehabilitation facility--as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events.
CONCLUSIONS:
Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.
CHARACTERIZATION HYPOTHERMIA
Oxidative Stress and Antioxidant Activity in Hypothermia and Rewarming: Can RONS Modulate the Beneficial Effects of Therapeutic Hypothermia? 2013
Hypothermia is a condition in which core temperature drops below the level necessary to maintain bodily functions. The decrease in temperature may disrupt some physiological systems of the body, including alterations in microcirculation and reduction of oxygen supply to tissues. The lack of oxygen can induce the generation of reactive oxygen and nitrogen free radicals (RONS), followed by oxidative stress, and finally, apoptosis and/or necrosis. Furthermore, since the hypothermia is inevitably followed by a rewarming process, we should also consider its effects. Despite hypothermia and rewarming inducing injury, many benefits of hypothermia have been demonstrated when used to preserve brain, cardiac, hepatic, and intestinal function against ischemic injury. This review gives an overview of the effects of hypothermia and rewarming on the oxidant/antioxidant balance and provides hypothesis for the role of reactive oxygen species in therapeutic hypothermia.
Normal body temperature in humans is maintained near a constant level of 36.5–37.5°C through homeostatic processes of thermoregulation. The hypothalamus controls body temperature through the preoptic and the posterior nuclei. The posterior nucleus is especially important, since it acts in regulating the physiological responses that allow the control of body temperature, such as vasoconstriction, shivering or increased intake of food to warm-up, sweating, and vasodilation. Heat is mainly generated in muscle tissue, including other thermogenic organs such as the heart and the liver, while it is lost through the skin (90%) and lungs (10%) and its rate is influenced by the physics involved in the mechanisms of convection, conduction, evaporation, and radiation . In small mammals the brown adipose tissue (BAT) is known to act as a thermogenic organ allowing nonshivering thermogenesis. When the human body is exposed to cold and the homeostatic mechanisms are unable to compensate the heat that is being lost, there is a drop in body temperature. The symptoms and consequences of hypothermia may vary depending on the degree of hypothermia and have been associated according to the four degrees or stages of severity: mild 32–35°C; moderate, 28–32°C; severe, 20–28°C; and profound at less than 20°C .
Symptoms of mild hypothermia may be vague and some physiological responses to preserve heat can be observed with sympathetic nervous system excitation provoking shivering, hypertension, tachycardia, tachypnea, and vasoconstriction. Additional symptoms that may be present are cold diuresis, mental confusion, hepatic dysfunction, and hyperglycemia due to the decrease in glucose uptake by cells, a decrease in insulin secretion, and impaired tissue sensitivity to insulin .
Moderate low body temperature results in a stronger shivering. Due to a slower speed in nervous transmission and lower brain blood flow, mild confusion, impaired mental skills, and muscle misscoordination become apparent, and movements are slow and labored . Skin blood vessels contract further as the body focuses its remaining resources on keeping the vital organs warm. Microcirculation alterations cause a reduction of blood flow, red cell sedimentation, and an increase in blood viscosity (2% per degree heat loss), which increases the reduced availability of oxygen in the tissues leading to a hypoxic situation and acidosis .
Severe hypothermia occurs with decreasing temperature, and other physiological systems begin to fail: heart rate, breathing rate, and blood pressure decrease all. The hypothalamus is not controlling anymore the thermoregulation. This results in a heart rate of about 30 beats per minute with a temperature of 28°C in humans . Mental skills and motor coordination are still more impaired with a difficulty in speaking, sluggish thinking, incoherent behavior, and amnesia starting to appear; lack of skill in using hands, poor muscle coordination, difficulties in walking, and stumbling are also usually present.
Mild to moderate hypothermia (35 to 32°C) appears to be useful in preventing tissue damage, cell protection, and survival . Several international organizations such as the American Health Association and the International Liaison Committee on Resuscitation have recommended the use of therapeutic hypothermia in patients with cardiac pathologies among others . In the European Resuscitation Council Guidelines , induced hypothermia is included in the standard recommendations after cardiopulmonary resuscitation.
Equipment review: Cooling catheters to induce therapeutic hypothermia? 2006
Various cooling systems are currently available, each with specific advantages and disadvantages . These can be roughly divided into invasive methods and noninvasive methods, with infusion of cold fluid as a separate technique that can be used as an accessory tool in the induction phase of hypothermia . This review covers the properties of one of these cooling devices, namely the CoolGard. This core cooling device uses an indwelling central venous catheter , which can be placed in the femoral vein (larger catheter with three cooling balloons) or the subclavian or jugular vein (smaller catheter with two cooling balloons). Sterile saline is refrigerated (to a minimum temperature of 4–5°C) in the external device and then pumped through the balloons coaxially mounted on the catheter, enabling direct cooling of the blood. The catheter contains a temperature probe enabling a 'closed loop' temperature control system; the temperature is set at the desired level (the range of the device is 28–38°C, which may vary according to the installed software), after which the device cools the patient down to this level by decreasing or increasing the temperature of the circulating saline. The core temperature is then maintained at the desired level for as long as the attending physician deems necessary.
THE GENERATION OF RONS AND THERAPEUTIC HYPOTHERMIA
Status of Systemic Oxidative Stress during Therapeutic Hypothermia in Patients with Post-Cardiac Arrest Syndrome 2013
The protective effects of hypothermia are believed to be a consequence of a reduction in the cellular metabolism and the retardation of destructive enzymatic reactions and the concomitant oxygen needs, thus conserving ATP levels.More recently, the beneficial effects of hypothermia, when applied to prevent an ischemic episode, included a trigger level of RONS that can act as a mechanism for induction of signaling pathways and the modulation of the extrinsic and intrinsic pathways of apoptosis . Hypothermia does not simply block cell signaling pathway of apoptosis and necrosis but selectively upregulates some protective genes after ischemia . Many experimental assays showed that when hypothermia is applied during an ischemia or hypoxia episode, it is able to inhibit proapoptotic molecules and to induce an increase in antiapoptotic ones in ischemic tissues.
The generation of RONS is a typical feature of hypothermia and more prominent in rewarming. There is increasing evidence showing that the beneficial effects of hypothermia included a trigger level of RONS that can act as a mechanism for induction of signaling pathways and the modulation of apoptosis.
Modulation of apoptosis by hypothermia. After a serious insult the cell can trigger apoptosis, a highly regulated cell death mechanism. Intrinsic Pathway. Hypothermia increases ATP stores and slows ion channels then maintaining the integrity of the membranes. Hypothermia applied together or immediately after injury decreases the production of ROS. These events limit the rupture of the outer mitochondrial membrane and the release of proapoptotic molecules like cytochrome c into the cytosol. The hypothermia-induced increase in nitric oxide also avoids cytochrome c release and it is even reported that early NO production can exert a negative feedback regulation of iNOS . Moreover, iNOS transcription activated by NFκB was diminished after hypothermia . Since catalase is absent in mitochondria, maintaining GSH redox cycle is critical to avoid H2O2 accumulation. There is abundant evidence that hypothermia keeps GSH pool. Extrinsic Pathway. It was found that hypothermia decreases the affinity of the death ligands-death receptors, with the consequent inhibition of the initiator caspases like caspase-8 or the NFκB-family molecules.
HYPOTHERMIA AND NORMOTHERMIA
Mild therapeutic hypothermia is superior to controlled normothermia for the maintenance of blood pressure and cerebral oxygenation, prevention of organ damage and suppression of oxidative stress after cardiac arrest in a porcine mode 2013
Mild therapeutic hypothermia (HT) has been implemented in the management of post cardiac arrest (CA) syndrome after the publication of clinical trials comparing HT with common practice (ie, usually hyperthermia). Current evidence on the comparison between therapeutic HT and controlled normothermia (NT) in CA survivors, however, remains insufficient.
Mikulas Micek has compared eight female swine (sus scrofa domestica; body weight 45 kg) were randomly assigned to receive either mild therapeutic HT or controlled NT, with four animals per group. Veno-arterial extracorporeal membrane oxygenation (ECMO) was established and at minimal ECMO flow (0.5 L/min) ventricular fibrillation was induced by rapid ventricular pacing. After 20 min of CA, circulation was restored by increasing the ECMO flow to 4.5 L/min; 90 min of reperfusion followed. Target core temperatures (HT: 33°C; NT: 36.8°C) were maintained using the heat exchanger on the oxygenator. Invasive blood pressure was measured in the aortic arch, and cerebral oxygenation was assessed using near-infrared spectroscopy. After 60 min of reperfusion, up to three defibrillation attempts were performed. After 90 min of reperfusion, blood samples were drawn for the measurement of troponin I (TnI), myoglobin (MGB), creatine-phosphokinase (CPK), alanin-aminotransferase (ALT), neuron-specific enolase (NSE) and cystatin C (CysC) levels. Reactive oxygen metabolite (ROM) levels and biological antioxidant potential (BAP) were also measured.
Significantly higher blood pressure and cerebral oxygenation values were observed in the HT group (P<0.05). Sinus rhythm was restored in all of the HT animals and in one from the NT group. The levels of TnI, MGB, CPK, ALT, and ROM were significantly lower in the HT group (P<0.05); levels of NSE, CysC, and BAP were comparable in both groups.
In conclusion the results from animal model of cardiac arrest indicate that HT may be superior to NT for the maintenance of blood pressure, cerebral oxygenation, organ protection and oxidative stress suppression following CA.
TRIALS CURRENTLY UNDERWAY
Target Temperature Management after out-of-hospital cardiac arrest--a randomized, parallel-group, assessor-blinded clinical trial--rationale and design. 2012
The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm.
