The use of therapeutic hypothermia is not a new concept; its implementation can be found in literature dating back to the ancient Egyptians. The idea that cooling a person can slow biological processes and subsequently death was first described by Hippocrates (circa 450 B.C), who advised packing wounded soldiers in the snow. In the early 1800s, during the French invasion of Russia, a battlefield surgeon noticed that wounded soldiers placed closer to campfires died sooner than those placed in colder bunks. During this period, cryoanalgesia was also used for amputations, and surgeons noticed that hypothermia not only acted as an analgesic but also slowed bleeding. Clinical interest in the application of therapeutic hypothermia began in the 1930s with case reports on drowning victims who were resuscitated successfully despite prolonged asphyxia. In 1943, Temple Fay published one of the first scientific papers relating to therapeutic hypothermia. Fay observed improvement in outcomes after traumatic brain injury (TBI) when temperatures were lowered from 38.3 to 32.7 degrees Celsius. In the 1950s and 1960s, clinical trials using very deep hypothermia were started but abandoned soon after due to adverse effects. In the 1990s, mild hypothermia was implemented in three cases of cardiac arrest after successful resuscitation, and all three made a complete recovery without residual neurological damage. Therapeutic hypothermia began getting serious attention after two prospective randomized controlled trials published in the New England Journal of Medicine in 2002 found significant improvements in short and long-term survival, as well as neurological outcomes. Today, the term targeted temperature management (TTM) is used instead of therapeutic hypothermia. TTM can be used to prevent fever, maintain normothermia, or induce hypothermia.
Thermoregulation is the ability to maintain a steady-state core body temperature by balancing heat production and heat loss. Normal body temperature ranges from 36.1 to 37.2 degrees Celsius. The thermoregulatory center is located in the hypothalamus and constantly receives input from thermoreceptors located in the hypothalamus and the skin, which monitor the internal and external temperature, respectively. A decrease in temperature will activate various thermogenic and heat conserving responses.
The output from the hypothalamus is to the sweat glands, skin arterioles, and adrenal medulla via the sympathetic nervous system and skeletal muscles via motor neurons. Shivering thermogenesis is the primary means of heat production during hypothermia. Efferent motor nerve stimulation results in a rhythmic contraction of skeletal muscles, and since there is no work being performed, most of this energy is given off as heat. Sympathetic stimulation of superficial arteriole smooth muscle causes peripheral vasoconstriction, which limits convective heat loss and redirects warm blood to the core. Sympathetic stimulation also causes the release of epinephrine and norepinephrine from the adrenal medulla, which increases basal heat production. During prolonged hypothermia, the hypothalamus stimulates thyroid hormone production from the anterior pituitary gland.
Mechanism of Action
Targeted temperature management improves neurological outcomes and decreases mortality through multiple mechanisms that alter the cascade of deleterious metabolic, cellular, and molecular changes that occur following global ischemia. The three main temperature-dependent pathological processes that hypothermia acts on are ischemic brain injury, reperfusion injury, and secondary brain damage. Hypothermia decreases the metabolic rate by 5% to 7% per 1 C decrease in core body temperature. This is one of the main mechanisms underlying its protective effects since oxygen deprivation and the accumulation of lactate and other waste products of anaerobic metabolism are central to the progression of ischemic cerebral cell death. The accumulation of aspartate, glutamate, and other excitatory neurotransmitters also plays a significant role in neuronal death following cerebral ischemia. The severity of excitotoxicity and neuronal damage is proportional to the quantity of these neurotransmitters. In animal models, it was shown that the release of glutamate following global cerebral ischemia is temperature-dependent and that mild to moderate hypothermia is associated with the most profound reduction in glutamate levels when compared to severe hypothermia and hyperthermia . Hypothermia decreases free radical production and suppresses the various inflammatory processes that occur following global ischemia and reperfusion.
Reperfusion causes a massive increase in the production of free radicals such as hydrogen peroxide, superoxide, nitric oxide, and hydroxyl radicals. The high levels overwhelm the defensive antioxidant mechanisms throughout the body and cause the peroxidation of lipids, proteins, and nucleic acids, which contribute to neuronal damage. One study using an in vitro model of cerebral ischemia found that the neuroprotective effects of hypothermia were associated with a significant reduction in nitric oxide and superoxide formation when temperatures were reduced to 31 to 33 C. The inflammatory response that follows reperfusion has both beneficial and detrimental effects, with some mediators being transiently neuroprotective. However, this exaggerated response may last up to 5 days, and persistently high levels of cytokines are destructive over this protracted time course. Hypothermia suppresses the inflammatory cascade and, in turn, prevents the exacerbation of cerebral injury by inflammation.
The 2015 recommendations for post-cardiac arrest care from the AHA include:
The 2015 International Consensus on CPR and Emergency Cardiovascular Care Science with Treatment Recommendations from the International Committee on Resuscitation (ILCOR) recommends:
Certain conditions may put patients at an increased risk of complications from therapeutic hypothermia. In such cases, targeted temperature management may still be used to achieve normothermia. Absolute contraindications to therapeutic hypothermia include hemorrhagic stroke, GCS > 8, uncontrolled bleeding, uncontrolled hemodynamically unstable rhythms, and cardiac arrest due to trauma. Relative contraindications to therapeutic hypothermia include thrombocytopenia (<50 K), coagulopathy, prolonged cardiac arrest (> 60 minutes), and refractory hypotension despite fluid and vasopressor support.
Prior to initiating targeted temperature management, the patient must be hemodynamically stable and have a secure airway with optimal oxygenation and ventilation. In addition, the baseline clinical status should be assessed, and hemodynamic monitoring should be in place. Ensure that the following are obtained prior to initiation of TTM
The process of targeted temperature management can divide into three phases: the induction phase, maintenance phase, and rewarming phase. The goal is to achieve a core temperature of 32 to 34 degrees Celsius as soon as possible, maintain this temperature for 12 to 24 hours, and then rewarm at a controlled rate of 0.2 to 0.5 C/hour.
Induction of hypothermia is the process in which a target core temperature of 32 to 34 degrees Celsius is reached as quickly as possible. This is achievable through several different external and internal cooling mechanisms. Hypothermia induction may be started in the ambulance or once the patient arrives at the hospital. Although it was thought that earlier cooling by paramedics en route to hospital would result in improved outcomes due to more rapid attainment of target temperature, this was not the case in some studies. One randomized controlled trial assigned 234 patients resuscitated from out of hospital cardiac arrest to either prehospital cooling or cooling after admission. The prehospital cooling was performed by paramedics using a rapid infusion of 2 liters of ice-cold (4 degrees C) lactated Ringers solution and was found to decrease core temperature by an average of 0.8 degrees C (P=0.01). However, the earlier achievement of target temperature was not associated with improved outcomes at hospital discharge. The RINSE trial (Rapid Infusion of Cold Normal Saline) found that out-of-hospital patients with cardiac arrest who received cold saline during CPR had reduced rates of ROSC, and provided no improvement in outcomes at hospital discharge. These results conflict with results from animal trials in which earlier cooling improved outcomes, raising questions as to when cooling should be commenced for optimal outcomes.
There are three main categories of cooling methods: conventional cooling techniques, surface cooling systems, and intravascular cooling systems.
Conventional Cooling Techniques
These consist of the use of cold saline infusions and ice packs and are the simplest and most cost-effective methods. The advantages of this method are that its availability is widespread; it is easy to use; it can be initiated by paramedics in the field, and is considered a safe method for hypothermia induction. It can also be used as an adjunct to more advanced cooling methods to augment the cooling rate. The disadvantage of using conventional methods is that they are very labor-intensive, often result in temperatures lower than the target temperature, and are not effective in maintaining the target temperature.
Surface Cooling Systems
Surface cooling systems use blankets or pads wrapped around the patient that circulate cold air or fluid. These devices are less labor-intensive and easier to use, with most being equipped with auto feedback mechanisms that alter the water or air temperature to maintain the set target temperature. Disadvantages include the rare risk of skin burns and irritation (mottling and redness), as well as the risk of overshooting the target temperature in the induction phase.
Core Cooling Systems
These currently consist mainly of intravascular catheters placed in a central vein that circulate cold saline. These devices have a high cooling rate, with rates between 2.0 and 4.5 degrees C/hour (depending on the size of the catheter and setting). They are considered the most reliable in all three phases of hypothermia treatment. Disadvantages of intravascular cooling devices are that they require an invasive procedure, there is a possibility of catheter-related thrombosis and infection, and they are relatively expensive. Other core cooling systems, such as the use of peritoneal lavage and extracorporeal circulation devices are not in widespread use yet.
One prospective intervention study compared several different methods of hypothermia and normothermia induction. Patients were randomly assigned to conventional cooling, cooling with water circulating external cooling device, an air circulating external cooling device, water circulating external cooling device using self-adhesive gel-coated pads, or an intravascular heat exchange system. This study found that in the hypothermia group the speed of cooling was higher when using water circulating cooling devices (1.33 +/- 0.63 degrees C/h), the gel-coated external device (1.04 +/- 0.14 degrees C/hour), and the intravascular heat exchange system (1.46 +/- 0.42 degrees C/hour) compared to significantly lower rates with the air circulating devices (0.18 +/- 0.20 degrees C/hour) and conventional methods (0.32 +/- 0.24 degrees C/hour) (p < 0.05). Similar results were found in the normothermia group. In terms of maintaining the target temperature, intravascular cooling systems were found to be much more reliable than the other methods, with a mean temperature deviation of 0.24 +/- 0.14 degrees C in the hypothermia group compared to conventional cooling (0.48 +/- 0.3 degrees C), water circulating device (0.58 +/- 0.47 degrees C), air circulating device (0.67 +/- 0.36) and the gel-coated external system (0.45 +/- 0.42 degrees C). These results indicate that water circulating cooling devices, gel-coated external devices, and intravascular devices are equally efficient and better than conventional cooling and air circulating devices in inducing hypothermia and normothermia. Intravascular cooling systems are the most reliable method during the maintenance phase, with fewer fluctuations in temperature compared to the other cooling methods.
The application of therapeutic hypothermia requires constant monitoring of core body temperature. This is vital to achieving an accurate target temperature, preventing overcooling, assessing variations in temperature during the maintenance phase, and ensuring a steady, controlled increase in temperature during the rewarming phase. The ideal site to measure core temperature is one that will give an accurate, real-time measurement. The current gold standard is the measurement of the temperature of the blood using a pulmonary artery catheter. The most commonly used monitoring sites (bladder, rectum, esophagus, and tympanic membrane) exhibit a time lag between registered temperature and measured core temperature, especially during the induction phase in which there are large temperature changes over a short time. This may lead to overshooting the target temperature during induction. The esophageal temperature is the most rapid and accurate reflection of the gold standard, with an average lag time of 5 minutes (range, 3 to 10). The ideal depth of probe insertion is 32 to 38 cm; this minimizes the chance of downward dislocation into the stomach. A disadvantage of this method is the possibility of interfering with specific therapeutic and diagnostic procedures (transesophageal echocardiography, feeding tubes, etc.). The bladder temperature has an average lag time of 20 minutes when compared with the gold standard. It is relatively convenient and easy to insert the bladder probe as it is combined with catheter insertion, a procedure that will often be performed anyway. The accuracy of the bladder temperature depends on the rate of diuresis, which can be low in patients after cardiac arrest, making this a less reliable method of temperature measurement. The rectal temperature has an average lag time of 15 minutes. Rectal probe insertion is a quick and easy procedure; however, there is a high rate of dislocation. Peripheral sites are completely inaccurate and should never be used to guide hypothermia treatment.
In this phase, the core body temperature is gradually raised by 0.2 to 0.5 degrees C per hour until it is greater than 36 degrees C. A slower rate of rewarming is associated with fewer complications, and rapid rewarming may negate the benefits of therapeutic hypothermia. Upon reaching a temperature of 36 degrees C, cooling devices and medications used to control shivering can be discontinued. The rewarming phase starts 12 to 24 hours after the beginning of induction and can take up to 8 hours.
Targeted temperature management is associated with multiple physiologic changes, some of which may give rise to complications during treatment. The personnel involved in the care of patients undergoing therapeutic hypothermia be aware of and anticipate these potential complications, as taking preventative measures as well as early recognition and treatment of complications can improve the overall survival.
Most of the complications of targeted temperature management affect the cardiovascular system since the cardiac disease is in the background of approximately 80% of patients without hospital cardiac arrest. The decrease in core temperature activates certain thermoregulatory mechanisms, including sympathetic stimulation-induced peripheral vasoconstriction and increased catecholamine production, which may exacerbate preexisting cardiac dysfunction by increasing myocardial oxygen demand. Hypothermia may also cause coronary vasoconstriction, increasing the risk of myocardial infarction. Changed in hemodynamic parameters include a 25% decrease in cardiac output, an increase in blood pressure, an increase in peripheral vascular resistance, and sinus bradycardia. Fortunately, serious arrhythmias rarely occur at the temperatures used in targeted temperature management (32 to 34 degrees C). The risk of arrhythmias increases when the core body temperature decreases to 30 degrees C or less. Such low temperatures are rarely intentionally used in therapeutic hypothermia, but due to the time lag between measured and true core temperature measurement when using sites other than the blood directly, overshooting the target temperature is not uncommon.
Cold-induced diuresis is a significant concern in hypothermic patients. It is a diuretic response caused by a combination of increased venous return secondary to vasoconstriction, increased Atrial natriuretic peptide (ANP), decreased Antidiuretic hormone (ADH), and tubular dysfunction. Left untreated, this may cause hypovolemia, electrolyte disturbances, and hemoconcentration.
The hypothermia induced diuresis, along with tubular dysfunction and intracellular ion shifts, resulting in a decreased serum concentration of several electrolytes, including magnesium, potassium, and phosphate. Regular measurement and correction (if necessary) should be performed. A study comparing electrolyte levels between normothermic patients and patients undergoing therapeutic hypothermia after severe head injury found that Mg levels decreased from 0.98+/-0.15 to 0.58+/-0.13 mmol/L (mean +/- standard deviation; p < 0.01), phosphate levels from 1.09+/-0.19 to 0.51+/-0.18 mmol/L (p < 0.01), Ca levels from 2.13+/-0.25 to 1.94+/-0.14 mmol/L (p < 0.01), and K levels from 4.2+/-0.59 to 3.6+/-0.7 mmol/L (p < 0.01) during the first 6 hours of cooling. In the normothermic electrolyte levels were unchanged. Hypomagnesaemia may cause cerebral and coronary vasoconstriction and can exacerbate reperfusion injury. Hypokalemia and hypophosphatemia may cause life-threatening tachyarrhythmias, as well as respiratory muscle weakness that can increase the risk of respiratory infections and wean from mechanical ventilation. Regular measurement of serum electrolytes and correction (if necessary) are crucial preventative measures that must be taken in these patients. It is also important to remember that high dose electrolyte supplementation is often necessary to correct these abnormalities.
The rewarming phase may also be associated with electrolyte disturbances. Hyperkalemia often occurs in this phase due to the release of intracellular potassium and may result in cardiac arrhythmias. Rewarming the patient at a slow and controlled rate can prevent this complication by giving the kidneys more time to excrete the excess potassium.
Hypothermia induces several changes in immune function, many of which are thought to contribute to the protective effects of hypothermia against brain injury. However, they may also increase the risk of infectious complications. Hypothermia inhibits various inflammatory responses. It impairs the secretion of pro-inflammatory cytokines and suppresses leukocyte migration and phagocytosis. Hyperglycemia and peripheral vasoconstriction that often occurs with hypothermia also contribute towards the increased risk of infections. The risk of infectious complications increases with prolonged hypothermia. A meta-analysis of randomized trials of therapeutic hypothermia which reported infectious complications found that the prevalence of all infections was not increased (rate ratio, 1.21 [95% confidence interval 0.95-1.54]), but the risk of pneumonia and sepsis was (risk ratio for pneumonia, 1.44 [95% CI, 1.10-1.90]; risk ratio for sepsis, 1.80 [95% CI, 1.04-3.10]). Most of the studies included in this trial lacked clear definitions of infectious complications and reported them with insufficient details. Therefore, to get a better understanding of the risk of infections with therapeutic hypothermia, further trials should be conducted where there is a more extensive report on the nature and incidence of these complications. Nevertheless, a high level of vigilance should be maintained, and certain measures should be taken in all therapeutic hypothermia patients for the prevention and early detection of infections. These include regular microbiological surveillance, timely catheter replacement, examining wounds and catheter insertion sites, and avoiding hyperglycemia.
Hypothermia causes a linear decrease in the metabolic rate by 5% to 7% per 1 degree Celsius decrease in core body temperature. A left shift in the oxygen hemoglobin dissociation curve reduces tissue oxygen availability and may contribute to the development of metabolic acidosis (Schubert (1995)). Oxygen consumption and CO2 production are equally decreased. If ventilator settings are not properly adjusted, decreased CO2 production may promote respiratory alkalosis and hypocapnia. This results in cerebral vasoconstriction increased cerebral vascular resistance, and decreased cerebral blood flow. Pharmacokinetic and pharmacodynamic alterations in drug metabolism can occur in patients receiving therapeutic hypothermia. These patients receive multiple drugs during their treatment course, including paralytics, anticonvulsants, sedatives, and cardiovascular drugs. Unanticipated drug toxicity may occur due to changes in metabolism, especially since many of these drugs have a narrow therapeutic window. The mechanisms involved in these changes are drug-specific and can occur in one or more of the different phases of drug metabolism, response, or elimination. Clinical studies evaluating the effect of hypothermia on the metabolism of specific drugs found that for many commonly used drugs such as propofol, vecuronium, rocuronium, midazolam, and phenytoin, there was an increase in serum concentration, decrease in clearance rate, and increase the duration of action. Metabolism gradually returned to baseline during the rewarming phase. This suggests that doses should be lowered to prevent toxicity. TH may be associated with decreased insulin sensitivity and decreased insulin secretion by pancreatic islet cells. It has been shown that hyperglycemia is associated with poor neurological outcomes and increased mortality. However, it is unclear whether the hyperglycemia is due to hypothermia or due to the initial stress of cardiac arrest and the resultant organ hypoperfusion. Some studies show that therapeutic hypothermia does not have an independent effect on glucose homeostasis, and when compared with normothermic patients, blood glucose levels only differs between the period of cardiac arrest and the initiation of hypothermia treatment. These conflicting results raise the question as to whether the hyperglycemia affects neurological outcome and survival directly, or simply that the glucose level is proportional to the severity of initial neurological damage, which would be associated with a less favorable outcome.
Shivering is a thermoregulatory response to hypothermia that occurs when the core body temperature decreases below 36.5 degrees C. Shivering produces heat through the rhythmic contraction and relaxation of skeletal muscle, which increases oxygen consumption, energy expenditure, and induction time. These changes counteract many of the beneficial effects of therapeutic hypothermia; therefore, shivering must be suppressed to ensure maximal benefit from hypothermia. This is achievable through various pharmacologic and non-pharmacologic interventions.
Rewarming is associated with several complications, the most important of which are electrolyte disturbances and hemodynamic instability. The intracellular shift of electrolytes that occurs during cooling is reversed in this phase, and the resultant increase in extracellular ions, especially potassium, can lead to fatal cardiac arrhythmias. To prevent hyperkalemia, rewarming should occur at a slow and controlled rate, and this allows the kidneys to excrete the excess potassium more efficiently. Renal replacement therapy should be initiated in oliguric patients before rewarming. Besides, potassium-containing fluids should be discontinued before the initiation of rewarming in all patients. Rewarming causes peripheral vasodilation and redistribution of blood that may result in hypotension and consequently reduced tissue oxygen delivery. This can be prevented by volume loading with normal saline 4 to 8 hours before rewarming. It is essential to closely monitor hemodynamics during this phase, with a routine assessment of blood pressure, urine output, and serum lactate.
Randomized Controlled Trials
Treatment of Comatose Survivors of Out-of-Hospital Cardiac arrest with Induced Hypothermia
This trial was one of the first randomized controlled studies evaluating the effects of therapeutic hypothermia on comatose survivors of out-of-hospital cardiac arrest. This trial, along with the HACA trial, was pivotal to hypothermia establishing its place in resuscitation guidelines. The study was performed in Melbourne, Australia, between September 1996 and June 1999. Seventy-seven patients were enrolled based on specific criteria, including the initial rhythm of ventricular fibrillation, the successful return of spontaneous circulation (ROSC), and persistent coma after resuscitation. Patients with cardiac arrest of presumed noncardiac etiology were excluded, along with patients with cardiogenic shock, males under the age of 18, and females under the age of 50.
Patients were randomly assigned to either the hypothermia group (temperature of 33 degrees C) or the normothermia group (temperature of 37 degrees C). The cooling process for the hypothermia group began in the ambulance with the use of external cooling devices. Once these patients arrived at an emergency department, they underwent more vigorous cooling, also through the use of external cooling methods. Core temperature was initially measured using the tympanic or bladder temperature until a pulmonary artery catheter was placed. Once the target temperature of 33 degrees C was reached, it was maintained for 12 hours after arrival to the hospital. Patients were actively rewarmed after 18 hours, for 6 hours using a heated air blanket.
The primary outcome measure for this study was survival to hospital discharge with a sufficiently good neurological function to be sent home or to a rehab facility. 21 of the 43 (49%) hypothermia group patients were found to have a good outcome, as compared with 9 of the 34 normothermia patients (26%, P=0.046). Time from collapse to ROSC and age were found to decrease the likelihood of a good outcome. After adjustment for these variables, the odds ratio for a good outcome in the hypothermia vs. normothermia group was 5.25 (95% CI, 1.47 to 18.76; P=0.011). These results indicate that there is a significant improvement in outcomes when therapeutic hypothermia is used on comatose patients after out of hospital cardiac arrest. Therapeutic hypothermia was also found to be safe, with clinically non-significant changes in hemodynamic and laboratory (potassium and glucose) parameters. Previous studies were associated with several complications. The observed difference in this study is thought to be due to the shorter duration and milder degree of hypothermia used.
Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest
This randomized controlled trial took place in nine centers in five European countries between March 1996 and January 2001 (enrollment stopped in July 2000 due to enrollment rate being less than expected and funding ending at this date). Like other RCTs on therapeutic hypothermia, assessment of outcome was blinded, but the personnel involved in the initial care of the patient were not. The inclusion criteria were: witnessed cardiac arrest of presumed cardiac origin, the initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia, age between 18 and 75, the interval from collapse to initial resuscitation attempts between 5 and 10 minutes, and a collapse to ROSC interval less than one hour.
A total of 275 patients were enrolled, with 137 randomly assigned to the hypothermia group and 138 patients assigned to the normothermia group. In the hypothermia group, cooling was initiated on admission with the use of external cooling devices, to a temperature between 32 degrees C and 34 degrees C. The target time to achieve this temperature was 4 hours, with additional external cooling methods used if the target was not achieved by 4 hours. Temperature measurements were made with a bladder temperature probe. Cooling was maintained for 24 hours, followed by passive rewarming to a temperature of 36 degrees C. The primary outcome in this study was a favorable neurologic outcome within six months. A favorable neurological outcome was defined as a Pittsburgh cerebral performance category of 1 or 2 out of 5. Secondary outcomes included overall mortality at six months and the rate of complications during the first week after cardiac arrest. Fifty-five percent of the normothermia group met the criteria for a favorable neurologic outcome at six months, compared to 39% of the normothermia group (RR, 1.40; 95% CI, 1.08 to 1.81). Mortality at six months was 55% for the normothermia group and 41% for the hypothermia group (RR for hypothermia group, 0.74; 95% CI, 0.58-0.95; P=0.02). Based on the risk of death difference between the two groups, seven patients need to be treated with hypothermia to prevent one death.
These results show that therapeutic hypothermia increases the chance of a favorable neurological outcome and decreases mortality in patients resuscitated after out of hospital cardiac arrest. Complication rates in the hypothermia group in this study were greater than the study by Bernard et al., particularly the rate of infectious problems; this may be due to the longer duration of hypothermia. The results of this study might have been more profound if cooling was attained earlier. The median interval to reach the target temperature was 8 hours (interquartile range, 4 to 16), which was double the initial target time. Theoretically, we can assume that a faster cooling rate should be associated with a more favorable outcome since earlier hypothermia should mean earlier retardation of deleterious enzymatic reactions, a lower rate of free radical production, and acidosis, and a lower concentration of excitatory neurotransmitters. However, the ideal time to achieve hypothermia is not known, with some studies showing that a shorter time to achieve systemic cooling is associated with unfavorable neurologic outcome. Whether this observation is due to detrimental effects of rapid cooling or the dysfunction of homeostatic processes, including thermoregulation in patients with more severe initial brain damage is not known.
The Target Temperature Management 33 degrees C versus 36 degrees C after Out-of-Hospital Cardiac Arrest (TTM) trial
This randomized controlled trial recruited 950 patients in 36 intensive care units in Europe and Australia. It is the most extensive trial on the use of therapeutic hypothermia after cardiac arrest. Patients included in this trial were those resuscitated after out-of-hospital cardiac arrest of presumed cardiac etiology. Unlike previous trials, patients with both shockable and non-shockable initial rhythms were included. Patients were randomly assigned to receive therapeutic hypothermia with a target temperature of either 33 degrees C or 36 degrees C. Cooling was achieved using an intravascular cooling catheter in 24% of patients, and surface cooling systems were used in 76% of patients. Gradual rewarming commenced after 28 hours in both groups, and patients were rewarmed to 37 degrees C at a rate of 0.5 degrees C/hour. All surviving patients were followed until 180 days after enrollment of the last patient. The primary outcome was all-cause mortality, and the secondary outcome was a composite of poor neurologic function or death, defined as a Cerebral Performa degrees C group had died, and 48% in the 36 degrees C group (HR in the 33 degrees C group, 1.06; 95% CI, 0.89 to 1.28; P=0.51). There was no significant difference in composite outcome of neurologic function or death between the two groups (RR for a CPC of 3 to 5 in 33 degrees C group, 1.02; 95% CI, 0.88 to 1.16; P=0.78; RR for a score of 4 to 6 on the modified Rankin scale in 33 degrees C group, 1.01; 95% CI,0.89 to 1.14; P=0.87)
This trial showed that there was no significant difference between a target temperature of 33 degrees C and 36 degrees C. These results, however, may indicate that preventing fever alone, or targeted normothermia may be sufficient to provide the beneficial effects of therapeutic hypothermia seen in other studies. Both groups in this study were intervention groups; the inclusion of a third non-intervention group would have clarified the role of therapeutic hypothermia or therapeutic normothermia in these patients. When compared to the control group in the HACA trial in 2002, the 33 degrees C and the 36 degrees C groups in the TTM trial had lower mortality rates.
Effective use of targeted temperature management requires an interprofessional team of healthcare professionals working in a coordinated and efficient manner. This starts with emergency medical technicians (EMTs) performing timely and efficient CPR, followed by emergency physicians and nurses initiating the institutions' TTM protocol, and finally, the team in the ICU who continue the TTM protocol and manage any complications that may arise. Other specialists may be involved in the care of these patients, such as cardiologists for PCI or neurologists for neurological prognostication. Early door to TTM initiation time has been shown to be associated with improved neurological outcomes. There are multiple reasons why the initiation of TTM may be delayed. These include lack of familiarity with the institutions TTM protocol, transport to institutions unfamiliar with postarrest care, unclear etiology of cardiac arrest, and others. Improved outcomes in patients undergoing TTM post-cardiac arrest may be achieved with better communication between health care professionals, transfer of postarrest patients to centers experienced with post-arrest care (particularly those with PCI capabilities), and remaining up to date and familiar with the institutions TTM protocol.
Induced hypothermia is associated with several physiologic derangements, and frequent monitoring is essential for the early detection and management of complications. Below is a summary of the essential patient care considerations.
Drugs can suppress shivering through several different mechanisms involving a variety of receptor types that result in the lowering of the shivering threshold, peripheral vasodilation, and/or neuromuscular blockade. The most commonly used medications are opioids, short-acting benzodiazepines, and paralytics. However, there have been studies on multiple different drug classes showing different degrees of efficacy. Many protocols advocate for the routine use of sedatives, analgesics, and paralytics. However, one study found that a combination of non-pharmacological measures and non-sedating medications were sufficient to manage to shiver in 18% of patients, without the need for oversedation and paralysis.
An optimal approach to the suppression of shivering has not been established, and there is likely no approach that will be ideal for all patients, as the threshold and severity of shivering, response to different therapies, and the variations in pharmacodynamics and pharmacokinetics of these drugs vary between patients. These variations are due to differences in age, gender, body surface area, baseline neurological injury, and other factors. This outlines the need for an algorithm that treats shivering based on severity and includes routine assessments and treatment modification. An example of this is the Columbia Anti-Shivering Protocol, this is an algorithm that uses a stepwise approach to the treatment of shivering based on hourly BSAS scores, starting with baseline, noninvasive measures for a score of 0, to neuromuscular blockade for a score of 4.
|||Vaity C,Al-Subaie N,Cecconi M, Cooling techniques for targeted temperature management post-cardiac arrest. Critical care (London, England). 2015 Mar 16; [PubMed PMID: 25886948]|
|||Yamashita C,Nakagiri K,Yamashita T,Matsuda H,Wakiyama H,Yoshida M,Ataka K,Okada M, Mild hypothermia for temporary brain ischemia during cardiopulmonary support systems: report of three cases. Surgery today. 1999; [PubMed PMID: 10030747]|
|||Bernard SA,Gray TW,Buist MD,Jones BM,Silvester W,Gutteridge G,Smith K, Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. The New England journal of medicine. 2002 Feb 21; [PubMed PMID: 11856794]|
|||Schmitt KR,Tong G,Berger F, Mechanisms of hypothermia-induced cell protection in the brain. Molecular and cellular pediatrics. 2014 Dec; [PubMed PMID: 26567101]|
|||Schubert A, Side effects of mild hypothermia. Journal of neurosurgical anesthesiology. 1995 Apr; [PubMed PMID: 7772968]|
|||Globus MY,Busto R,Dietrich WD,Martinez E,Valdes I,Ginsberg MD, Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobutyric acid studied by intracerebral microdialysis. Journal of neurochemistry. 1988 Nov; [PubMed PMID: 2902196]|
|||Illievich UM,Zornow MH,Choi KT,Scheller MS,Strnat MA, Effects of hypothermic metabolic suppression on hippocampal glutamate concentrations after transient global cerebral ischemia. Anesthesia and analgesia. 1994 May; [PubMed PMID: 8160988]|
|||Polderman KH, Mechanisms of action, physiological effects, and complications of hypothermia. Critical care medicine. 2009 Jul; [PubMed PMID: 19535947]|
|||McManus T,Sadgrove M,Pringle AK,Chad JE,Sundstrom LE, Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices. Journal of neurochemistry. 2004 Oct; [PubMed PMID: 15447666]|
|||Hunter BR,Ellender TJ, Targeted temperature management in emergency medicine: current perspectives. Open access emergency medicine : OAEM. 2015; [PubMed PMID: 27147892]|
|||Bernard SA,Smith K,Cameron P,Masci K,Taylor DM,Cooper DJ,Kelly AM,Silvester W, Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010 Aug 17; [PubMed PMID: 20679551]|
|||Hoedemaekers CW,Ezzahti M,Gerritsen A,van der Hoeven JG, Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Critical care (London, England). 2007; [PubMed PMID: 17718920]|
|||Li H,Yang Z,Liu Y,Wu Z,Pan W,Li S,Ling Q,Tang W, Is Esophageal Temperature Better to Estimate Brain Temperature during Target Temperature Management in a Porcine Model of Cardiopulmonary Resuscitation? BioMed research international. 2017; [PubMed PMID: 29423402]|
|||Soleimanpour H,Rahmani F,Golzari SE,Safari S, Main complications of mild induced hypothermia after cardiac arrest: a review article. Journal of cardiovascular and thoracic research. 2014; [PubMed PMID: 24753824]|
|||Polderman KH,Peerdeman SM,Girbes AR, Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. Journal of neurosurgery. 2001 May; [PubMed PMID: 11354399]|
|||So HY, Therapeutic hypothermia. Korean journal of anesthesiology. 2010 Nov; [PubMed PMID: 21179289]|
|||Geurts M,Macleod MR,Kollmar R,Kremer PH,van der Worp HB, Therapeutic hypothermia and the risk of infection: a systematic review and meta-analysis. Critical care medicine. 2014 Feb; [PubMed PMID: 23989182]|
|||Tortorici MA,Kochanek PM,Poloyac SM, Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Critical care medicine. 2007 Sep; [PubMed PMID: 17855837]|
|||Nurmi J,Boyd J,Anttalainen N,Westerbacka J,Kuisma M, Early increase in blood glucose in patients resuscitated from out-of-hospital ventricular fibrillation predicts poor outcome. Diabetes care. 2012 Mar; [PubMed PMID: 22279029]|
|||Müllner M,Sterz F,Binder M,Schreiber W,Deimel A,Laggner AN, Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1997 Apr; [PubMed PMID: 9143225]|
|||Ettleson MD,Arguello V,Wallia A,Arguelles L,Bernstein RA,Molitch ME, Hyperglycemia and insulin resistance in cardiac arrest patients treated with moderate hypothermia. The Journal of clinical endocrinology and metabolism. 2014 Oct; [PubMed PMID: 25033067]|
|||Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. The New England journal of medicine. 2002 Feb 21 [PubMed PMID: 11856793]|
|||Haugk M,Testori C,Sterz F,Uranitsch M,Holzer M,Behringer W,Herkner H, Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest. Critical care (London, England). 2011 [PubMed PMID: 21439038]|
|||Nielsen N,Wetterslev J,Cronberg T,Erlinge D,Gasche Y,Hassager C,Horn J,Hovdenes J,Kjaergaard J,Kuiper M,Pellis T,Stammet P,Wanscher M,Wise MP,Åneman A,Al-Subaie N,Boesgaard S,Bro-Jeppesen J,Brunetti I,Bugge JF,Hingston CD,Juffermans NP,Koopmans M,Køber L,Langørgen J,Lilja G,Møller JE,Rundgren M,Rylander C,Smid O,Werer C,Winkel P,Friberg H, Targeted temperature management at 33°C versus 36°C after cardiac arrest. The New England journal of medicine. 2013 Dec 5 [PubMed PMID: 24237006]|
|||Stanger D,Kawano T,Malhi N,Grunau B,Tallon J,Wong GC,Christenson J,Fordyce CB, Door-to-Targeted Temperature Management Initiation Time and Outcomes in Out-of-Hospital Cardiac Arrest: Insights From the Continuous Chest Compressions Trial. Journal of the American Heart Association. 2019 May 7 [PubMed PMID: 31055981]|
|||Mody P,Kulkarni N,Khera R,Link MS, Targeted temperature management for cardiac arrest. Progress in cardiovascular diseases. 2019 May - Jun; [PubMed PMID: 31078561]|
|||Choi HA,Ko SB,Presciutti M,Fernandez L,Carpenter AM,Lesch C,Gilmore E,Malhotra R,Mayer SA,Lee K,Claassen J,Schmidt JM,Badjatia N, Prevention of shivering during therapeutic temperature modulation: the Columbia anti-shivering protocol. Neurocritical care. 2011 Jun; [PubMed PMID: 21210305]|
|||Kilgannon JH,Jones AE,Shapiro NI,Angelos MG,Milcarek B,Hunter K,Parrillo JE,Trzeciak S, Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA. 2010 Jun 2; [PubMed PMID: 20516417]|