Twenty-Four Hours of Mild Hypothermia in Unsedated Newborn Pigs Starting after a Severe Global Hypoxic-Ischemic Insult Is Not Neuroprotective

Abstract

Three to 12 h of mild hypothermia (HT) starting after hypoxiaischemia is neuroprotective in piglets that are anesthetized during HT. Newborn infants suffering from neonatal encephalopathy often ventilate spontaneously and are not necessarily sedated. We aimed to test whether mild posthypoxic HT lasting 24 h was neuroprotective if the animals were not sedated. Thirty-nine piglets (median weight 1.6 kg, range 0.8 -2.2 kg; median age 24 h, range 7-48 h) were anesthetized and ventilated and subjected to a 45-min hypoxic (FiO 2~6 %) global insult (n ϭ 36) or sham hypoxia (n ϭ 3). On reoxygenation, 18 were maintained normothermic (NT, 39.0°C) for 72 h, and 21 were cooled from 39 (NT) to 35°C (HT) for the first 24 h before NT was resumed (18 experimental, three sham hypoxia). Cardiovascular parameters and intermittent EEG were documented throughout. The brain was perfusion fixed for neuropathology and five main areas examined using light microscopy. The insult severity (duration in minutes of EEG amplitude Ͻ 7V) was similar in the NT and HT groups, mean Ϯ SD (28 Ϯ 7.2 versus 27 Ϯ 8.6 min), as was the mean FiO 2 (5.9 Ϯ 0.7 versus 5.8 Ϯ 0.8%) during the insult. Six NT and seven HT piglets developed posthypoxic seizures that lasted 29 and 30% of the time, respectively. The distribution and degree of injury (0.0 -4.0, normal-maximal damage) within the brain (hippocampus, cortex/white matter, cerebellum, basal ganglia, thalamus) were similar in the NT and HT groups (overall score, mean Ϯ SD, 2.3 Ϯ 1.5 versus 2.4 Ϯ 1.3) as was the EEG background amplitude at 3 h (13 Ϯ 3.5 versus 10 Ϯ 3.3 V).The HT animals shivered and were more active. The sham control group (n ϭ 3) shivered but had normal physiology and neuropathology. Plasma cortisol was significantly higher in the HT group during the HT period, 766 Ϯ 277 versus 244 Ϯ 144 M at 24 h. Mild postinsult HT for 24 h was not neuroprotective in unsedated piglets and did not reduce the number of animals that developed posthypoxic seizures. Cortisol reached 3 times the NT value at the end of HT. We speculate that the stress of shivering and feeling cold interfered with the previously shown neuroprotective effect of HT. Many studies on newborn animal models show that mild HT, which starts after an HI insult, is neuroprotective (1-5). The duration of HT in these studies varies from 3 to 72 h, and the reduction in body temperature varies between 3.5 and 6°C. Some studies, however, show only a minor beneficial effect (6), or the neuroprotection is temporary and not maintained (7).

Hypothermia for 24 Hours After Asphyxic Cardiac Arrest in Piglets Provides Striatal Neuroprotection That Is Sustained 10 Days After Rewarming

“…Unexpectedly, there was no benefit when the duration of hypothermia was extended to 24 h in the same model in piglets (16). These experiments differed from our protocol in that the piglets were not paralyzed or sedated during hypothermia.…”

“…Thus prolonged periods of hypothermia are presumably required to provide long-term neuroprotection. However, neuroprotection seen with 3 h of mild hypothermia after HI in piglets (15) was lost with 24 h of hypothermia, possibly because of the prolonged cold stress in unsedated piglets (16). Thus, larger postnatal animals may require sedation and muscle relaxation during hypothermia to reduce the potential adverse effects of cold stress.…”

Hypothermic neuroprotection

“…Further, it is of interest that in the piglet model of global hypoxia-ischemia neuroprotection and improved neurological function were seen only when the subjects were anaesthetized during the hypothermic period, suggesting a potentially important interaction between hypothermia and sedation / anesthesia. 168 A simple increase in protection is not the only useful outcome from combination treatment. For example, in the rat, repeated intraperitoneal doses of a glutamate antagonist substantially delayed the eventual development of neuronal loss in the hippocampus.…”

Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit

“…23 In our study, therapeutic dose of phenobarbital was routinely used in every enrolled patient. Thoresen et al 24 has shown that hypothermia alone without sedation was not effective in protecting the brain tissues of newborn piglets after a severe global hypoxicischemic insult. We speculate that the use of phenobarbital may help to reduce cerebral metabolism and oxygen consumption 25 and facilitate the hypothermia process, which might enhance the neuroprotection of head cooling for infants with perinatal asphyxia.…”