39: Therapeutic Hypothermia

To reduce mortality in infants with perinatal hypoxia ischemia when initiated before 6 hours of age. It is indicated in the treatment of infants (36 0/7 weeks' gestation or greater, younger than 6 hours) who fulfill the criteria for the diagnosis of moderate to severe hypoxic ischemic encephalopathy (HIE). Cooling can be done by selective head (Olympic Cool-Cap System, Olympic Medical Corporation, Seattle, WA) or total-body cooling. This chapter discusses total body cooling.

Infants should be evaluated for eligibility by (step A) clinical and physiological criteria followed by (step B) complete neurological examination. Infants have to meet both physiologic and neurologic criteria. Eligibility criteria are for either whole-body cooling by blanket or mattress or head cooling by a fitted cap. For head cooling a step C is required, which includes an amplitude-integrated electroencephalogram (aEEG) (recording at least 20 minutes duration) that shows either moderately or severely abnormal aEEG background activity or seizures.

1. Step A: clinical and physiological criteria. All infants should be evaluated as follows:

   1. Blood gas (a cord blood gas or an arterial [preferred] or venous/capillary blood gas within the first hour of life): pH <7 or base deficit >16, proceed to step B.

   2. No blood gas or arterial/venous/capillary blood gas pH 7–7.15 or base deficit of 10–15.9 with an acute perinatal event (cord prolapse, abruption placenta, severe fetal heart rate [FHR] abnormality, variable or late decelerations; maternal trauma, hemorrhage, or cardiac arrest) plus either a or b (below), then proceed to step B.

      1. 10-minute Apgar ≤5.

      2. Continued need for ventilation initiated at birth and continued for at least 10 minutes.

2. Step B: complete neurologic examination. Once infant meets step A clinical and physiological criteria, perform a complete standardized neurologic examination. Moderate to severe encephalopathy is defined as seizures or the presence of one or more signs in 3 of the 6 categories in staging of HIE (level of consciousness, spontaneous activity, posture, tone, primitive reflexes, and autonomic system). The number of moderate or severe signs will determine the extent of encephalopathy; if signs were equally distributed, the designation is based on the level of consciousness.

   1. If seizures are documented or are occuring, the infant is automatically eligible for cooling.

   2. No seizures are reported, the infant has to have at least 3 out of the 6 neurologic signs in moderate or severe encephalopathy (Table 39–1) to be eligible for cooling.

3. Infant is eligible for cooling once criteria in step A and B are met.

Hyper-hypothermia machine used to raise or lower a patient's temperature to a target level through conductive heat transfer; infant-sized hyper-hypothermia blanket, single-patient use, able to provide both heating and cooling to maintain patient's target temperature; infant esophageal probe and cable for continuous monitoring of patient's core temperature; 2–3 gallons of distilled water for initial setup; drainage hose; open infant critical care bed with warming capability at the conclusion of the therapeutic hypothermia. Cooling device unit (eg, Blanketrol III with cooling blankets, Kool-Kit Neonate, Cincinnati Sub-Zero, Cincinnati, OH).

1. Confirm the eligibility for cooling as noted in Section II.

2. Gather equipment for cooling. Follow preparation instructions of the hyper-hypothermia machine per operation manual. The author's institution uses the Blanketrol III Model 233 hyper-hypothermia cooling device unit.

3. Pain management. No specific analgesics or anesthetics are recommended. Sedation throughout the procedure is based on needs for mechanical ventilation and/or seizure control. Most commonly used sedation is morphine.

4. Precool the blanket to 5°C for whole-body cooling to maintain an esophageal temperature of 33.5°C ± 0.5°C for neuroprotection. Lay infant supine on the pre-cooled blanket with occiput resting on the blanket. A single-layer thin blanket may be placed between the infant and the cooling blanket to prevent soiling of equipment (Figure 39–1).

5. Insert the esophageal temperature probe into an external naris. Probe may be softened by placing in warm water for a few minutes. The probe should be positioned in the lower third of the esophagus (desired length = distance from nares to ear to the mid-sternum minus 2 cm). Secure the probe by taping with adhesive to the side of the infant's nose. Connect the probe to the cooling unit and begin temperature monitoring straight away. Confirm probe placement with a radiograph but do not wait for a radiograph to initiate cooling.

6. Use an open critical care bed for optimal monitoring. Skin temperature will be monitored by skin temperature probe on the lower abdomen attached to the radiant warmer. The radiant warmer is set to “manual mode” with the heat turned off (allow continuous skin temperature monitoring without any heat output). Do not use any other source of exogenous heat.

7. Operate the cooling unit in automatic mode with a core temperature goal of 33.5°C ± 0.5°C. Follow your neonatal intensive care unit [NICU]-specific cooling device instruction manual.

8. The infant's esophageal temperature will begin to decrease soon after the initiation of the cooling therapy. The cooling blanket system adjusts automatically to achieve 33.5°C in ∽90–120 minutes. Once stable at 33.5°C, some esophageal temperature fluctuation around the setpoint is to be expected, but should not be greater than ±0.5°C. Monitor and record esophageal, skin, and water temperatures, as well as all vital signs at 15-minute intervals during cooling (or follow unit-specific policy). Total period of cooling is 72 hours.

9. Gradual rewarming is done over 6 hours after completion of 72-hour cooling period. The automatic cooling unit setpoint temperature is increased by 0.5°C every hour to a maximum setpoint of 36.5°C. The goal is to slowly increase the temperature 0.5°C per hour to reach normothermia by the end of 6 hours. Monitor vital signs (especially temperature) throughout the rewarming period. Hyperthermia must be avoided at all cost.

10. At the end of 6-hour rewarming period, turn off hyper-hypothermia unit and remove cooling blanket and esophageal probe. Follow cooling unit maintenance per local NICU protocol.

11. During the cooling and rewarming process, the infant should receive routine clinical care appropriate for the level of acuity, including laboratory blood studies for surveillance of respiratory, cardiovascular, hematologic, and renal dysfunction. Blood gas measurements must be corrected for body temperature during hypothermia.

The following is a list of potential complications and may include others not noted here.

1. Cardiovascular and respiratory

   1. Arrhythmia. Hypothermia can decrease depolarization of cardiac pacemaker cells, causing bradycardia (most common cardiovascular complication). Maintain infant's temperature within target of 33.5°C ± 5°C to prevent more severe arrhythmias.

   2. Hypotension. Decreases in stroke volume and heart rate may contribute to decreased cardiac output and hypotension. The requirement for inotropes for pressure support during cooling are more related to physician behavior.

      1. Pulmonary hypertension. Increased pulmonary vascular resistance has been reported in hypothermic infants; however, the number of hypoxic-ischemic infants with persistent pulmonary hypertension in large clinical trials were similar between cooled and noncooled infants.

      2. Blood gases. Hypothermia decreases O₂ consumption and CO₂ production; therefore, ventilator settings need to be monitored and adjusted to avoid hyperventilation that can cause cerebral vasoconstriction. Blood gas values are temperature dependent, and if blood samples are warmed to 37°C before analysis (as is common in most laboratories), Po₂ and Pco₂ will be overestimated and pH underestimated in hypothermic patients. For accurate interpretation, samples should be analyzed at the patient's real temperature. If this is not possible, Polderman suggests blood gas values assayed at 37°C can be estimated as follows:

         1. Subtract 5 mm Hg Po₂ per 1°C that the patient's temperature is <37°C;

         2. Subtract 2 mm Hg Pco₂ per 1°C that the patient's temperature is <37°C;

         3. Add 0.012 pH units per 1°C that the patient's temperature is <37°C.

2. Dermatologic

   1. Skin breakdown. Vasoconstriction during extreme cold can lead to decreased blood flow, and localized damage is caused to skin and other tissues. Regular inspection of the infant's skin is part of routine care during cooling.

   2. Subcutaneous fat necrosis. Cause is unknown and is associated with perinatal asphyxia. Hypothermia causes vasocontriction that worsens skin perfusion that has already been compromised by asphyxia, thereby leading to fat necrosis. Most of the reported cases occurred after completion of cooling. Serum calcium levels should be monitored in affected infants due to risk of hypercalcemia (Plate 9).

3. Hematologic. Serial follow-up of hematologic parameters is an important part of surveillance during cooling.

   1. Hypothermia-induced thrombocytopenia is due to increased platelet destruction (platelet sequestration in the liver and spleen) and disseminated intravascular coagulation (DIC), resulting in early thrombocytopenia and bone marrow suppression with reduced platelet production.

   2. Coagulopathy induced by mild hypothermia with the risk for severe bleeding associated with therapeutic cooling is relatively small.

4. Metabolic

   1. Metabolic acidosis. Decreased cardiac output leading to reduced clearance of lactic acid.

   2. Altered glucose metabolism. Hypothermia decreases insulin sensitivity and secretion, leading to hyperglycemia; higher doses of insulin may be needed. During rewarming process, infants treated with insulin may be at risk for hypoglycemia as sensitivity to insulin is restored.

   3. Drug metabolism and excretion of drugs and metabolites might be modified by cooling, as well as the presence of hepatocellular and renal impairment complicating HIE. Metabolism of drugs such as phenobarbital, morphine, and vecuronium are slowed by effects of the temperature-dependent hepatic cytochrome P450 system. Potentially toxic levels of drugs can accumulate in the system if metabolism and excretion are impaired.

5. Infections. Cooling has immunosuppressive and anti-inflammatory effects. Meta-analysis of large trials did not show any increased incidence of infection in cooled infants.