• -

  The optimum temperature level in TTM has not been defined.

• -

  There is greater evidence of a favorable effect with 33°C (32−34°C) than with the standard treatment without temperature control - though there are no significant differences among three core temperature targets, namely 32–33 and 34°C.12,14–16 There is general agreement that when a target temperature of 36°C is chosen, the latter is less strictly maintained.17

• -

  The study published by Nielsen et al. was designed to define a target temperature for TTM, and evidenced no differences between a temperature of 33°C versus 36°C.18 Posteriorly, the evidence showed the outcome to be poorer in patients receiving standard care in whom the target temperature was raised to 36°C.19,20 However, the appearance of fever in these patients (which worsens the prognosis) and the lax application of the hypothermia protocols are elements that do not allow us to firmly conclude that hypothermia target temperature is the factor that improves survival in the intervention group.

• -

  For these reasons, an international multicenter study (Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest [TTM2, ClinicalTrials.gov: NCT03114033]) has been designed to compare a TTM of 33°C versus normothermia and early fever treatment (≥ 38.7°C) - with results that have not yet been published.21

• -

  No trials are available on the effect of the rate of temperature reduction upon the patient prognosis. However, there are observational studies that have found no evidence indicating that the rate at which the target temperature is reached has any impact upon the clinical outcomes,22 even in those patients in which TTM is started in the pre-hospital setting.23

• -

  Post-resuscitation (ischemia-reperfusion) syndrome is characterized by brain edema that causes an increase in intracranial pressure, producing additional cerebral ischemia that worsens the neurological damage already caused. There is a critical time window in this syndrome, covering the period between the recovery of spontaneous circulation and triggering of the inflammatory response, in which a decrease in body temperature may have beneficial effects. It is believed that this window may be about 4–5 hours.24

• -

  The required duration of TTM is not clear. The only study in patients comparing the effect of TTM at 33°C during 24 versus 48h evidenced no superiority, though there was a tendency towards better outcomes with durations of over 24h.25

• -

  To date no studies have been made on how the return to normothermia should be made, and whether it should be spontaneous or controlled.

• -

  In general, when TTM is performed with the classical methods such as ice or insulating blankets, passive warming is used, since it is very difficult for warming to be made at an established rate.

• -

  When feedback-based control methods are used, a controlled warming rate is commonly employed, usually between 0.1 and 0.5°C per hour, in order to avoid rebounds. Controlled normothermia should be maintained beyond the period of hypothermia, since hyperthermia phenomena are common.

The infusion of cold saline solution is simple, inexpensive and widely used to induce TTM, though it is not effective in maintaining it. The technique generally involves the use of a pressure bag to increase the infusion rate. One liter of cold saline solution infused in 15min can reduce the core temperature by 1°C. Intravenous volumes of up to two liters are used, generally in the form of 0.9% saline solution. This technique poses a risk of adverse effects in the form of overcooling, and moreover can cause volume overload and acute lung edema. It is therefore not advisable in patients with heart failure, altered kidney function, respiratory distress syndrome or evidence of volume overload.

Cold traditionally has been applied with ice bags and, more recently, with carbon-based gel pads that afford temperature reductions of 3.5°C/hour (EMCOOLS® cooling system). This rate is faster than when cold saline infusions are used (approximately 2°C/hour). The technique is simple and rapid to perform, even in the out-hospital setting, but can cause skin burns and irritation, and is not the best choice method in the presence of skin lesions (e.g., exfoliative dermatitis or extensive burns). The appearance of patient trembling associated to the drop in temperature tends to be more frequent with this technique.

These techniques are based on the principle of thermal conductivity. Cold liquid or air is circulated through cooling sheets, vests or pads in contact with the body of the patient.30 These methods usually lower body temperature at a rate of 0.5−1°C/hour, though the time taken to reach the desired temperature depends on the device used.

Arctic Sun® (Medivance, Bard, Beckton Dickinson, Louisville, CO, USA) is a noninvasive percutaneous system for TTM allowing faster temperature regulation and control. It controls temperatures in a range of 32–38.5°C. The operating principle is based on the circulation of cold water within a series of pads adhered to the skin of the patient. Its electronic module is connected to the disposable pads that transfer the thermal energy directly over the skin, affording isolation from the environmental temperature. This is a servo-control system that monitors body temperature each second and compares it against the desired protocol, adjusting the temperature of the circulating water 30 times an hour.

These are regarded as invasive methods. Two devices are available on the market: Thermoguard XP® (Zoll, Chelmsford, MA, USA) and InnerCool RTx® with the Accutrol® catheter (Phillips). The former system uses different central venous catheters that can be placed via the subclavian, internal jugular or femoral vein. The target temperature is reached by circulating 0.9% saline solution within a closed circuit through the catheter balloon. InnerCool RTx® uses a single type of catheter equipped with a temperature sensor for precise control. These advanced cooling systems allow computerized temperature control with a servo-control mechanism.31 With these systems the overcooling rates are lower and failure to reach the target temperature is less likely. However, the results are no better than those obtained with other techniques, and there is an added risk of intravascular infections, venous thrombosis and local complications associated with insertion of the catheters.

• –Other methods include: extracorporeal cooling techniques, continuous renal replacement therapy, and bladder and esophageal cooling.30 There are concrete scenarios in which techniques other than those commented above may be chosen, depending on the patient needs and clinical condition. However, many of them are still in the early investigational stages, and adequate and larger-scale clinical studies are needed before their use can become generalized (Table 3). Esophageal cooling has been shown to be an effective maintenance option.32 Intranasal cooling in turn has been successfully used for the induction phase, though it has not improved the outcomes in terms of patient survival or neurological prognosis.33

• –Some experts advise that the delay in starting treatment should be no more than 6−12h from CA onset, though others suggest that TTM should be performed as soon as possible, without specifying any concrete time limit.

• –Controlled methods are the recommended option for the entire TTM procedure. Accordingly, non-controlled methods would be useful as adjuncts only in the induction of TTM – not in maintenance.

• –It is advisable to maintain TTM for at least 24h in situations of hypothermia and up to 72h from the time of the event in controlled normothermia.4,18,34

• –The return to normothermia should be made in a controlled and active manner, with a warming rate of between 0.2°C/h and 0.5°C/h,34 and a target temperature of 36.5−37°C35 The latest European recommendations for the application of TTM advise a slow warming rate of 0.15−0.25°C/h.36

Patient monitoring should include6:

• a

  Invasive blood pressure monitoring with an arterial catheter and the maintenance of mean blood pressure (MBP) values ensuring a cerebral perfusion pressure > 60mmHg (in most cases the value is in the order of 80mmHg, as is applied in the general management of neurocritical patients). Cerebral autoregulation status should be taken into account.

• b

  Pulsioximetry. A value of 94-98% should be maintained in order to avoid hyperoxemia.6,37

• c

  Bispectral index (BIS): monitoring of patient waking state – this being particularly useful in patients subjected to muscle relaxation.

• d

  Continuous ECG monitoring to control rhythm and ensure the early detection of any alteration.

• e

  Continuous EEG monitoring, recommended especially in patients subjected to neuromuscular block, in order to detect possible myoclonus.

Hypothermia increases the risk of bleeding and the need for blood transfusions, due to alteration of the coagulation parameters that occurs from a 0.5°C drop in temperature.39

Infectious complications are frequent (seen in up to 70% of all cases) and are favored by post-CA inflammatory syndrome and the attenuated immune response secondary to hypothermia. The absence of fever impedes the early diagnosis of infection; the incidence of sepsis is therefore almost two-fold higher in the presence of hypothermia (13% versus 7%).14 Pneumonias are the most common processes (85%). They are generally not associated to increased mortality.39

Sympathetic tone rises during hypothermia, resulting in vasoconstriction and the reduction of organ perfusion. This in turn favors the development of metabolic acidosis, with a decrease in pH (from 7.37 to 7.31) and an increase in lactate concentration. The decrease in metabolic demand3,39 can imply an increase in CO2 and ventilation changes during the warming phase that could cause cerebral vasoconstriction.

Hyperglycemia is common as a result of diminished insulin output,41 though treatment is not advised in the presence of glycemia values of under 180mg/dl, in order to avoid hypoglycemia.

Hypopotassemia and hypomagnesemia are observed during cooling, and this in turn favors the appearance of potentially fatal ventricular arrhythmias. Both ions therefore require monitoring.31

Hypothermia has direct effects upon the heart, such as ECG alterations (prolongation of the PR interval, widened QRS and QTc) and the appearance of arrhythmias. Heart rate may also be seen to increase (at the start of TTM), followed by sinus bradycardia (40–45 bpm) that lowers cardiac output by 25-40%.39,41 However, there have been no reports of hemodynamic instability as a direct consequence of hypothermia.42

Shivering is one of the most common phenomena seen during the induction of TTM. It is a normal physiological response to lowered body temperature, seeking to produce warmth, and is associated to an increase in oxygen consumption of 50-400%. Shivering appears mainly when the temperature falls to between 35−37°C; once the target temperature of 32−34°C is reached, it becomes less frequent.43 Shivering is accompanied by hypertension, an increased heart rate and vasoconstriction, and complicates the cooling phase.39

Shivering should be prevented on an early basis. The treatment options in this regard include44: antipyretic / antiinflammatory drugs, vasodilators, opioids, alpha-agonists (dexmedetomidine), anesthetics and sedatives, serotonin agonists and neuromuscular relaxants.

The administration of magnesium sulfate at a dose of 0.5−1mg/h via the intravenous route (serum target concentration: 3−4mg/dl)45 increases the cooling rate and is convenient when percutaneous controlled methods are used – reducing smooth muscle tone and subsequent vasodilatation, with a decrease in shivering. As an added benefit, magnesium sulfate offers neuroprotective properties as an N-methyl-D-aspartate (NMDA) agonist. Although shivering control with magnesium sulfate is usually less pronounced than that afforded by sedatives or opioids, its few adverse effects make it an attractive option for use.

Opioids are the most widely used drugs (e.g., fentanil, morphine, meperidine). Meperidine is possibly the most effective option and exerts synergistic action with buscapine in suppressing shivering. However, the possible appearance of seizures or kidney damage associated to the combined use of these two drugs must be monitored.44,45 Alpha-agonists such as dexmedetomidine reduce the appearance of shivering, though their use is limited by the induction of bradycardia and hypotension.

Sedatives in combination with opioids are usually required, titrating the dose according to the suppression of shivering. The options in this regard include propofol and benzodiazepines. Neuromuscular relaxants can be used in severe cases. However, it must be taken into account that relaxants can mask the appearance of seizures, which often manifest post-CA patients.