Optimal temperature for whole-body hypothermia in the newborn: An in vitro study using foreskin mitochondrial oxygen consumption

Abstract

OBJECTIVES: Whole-body hypothermia (to 33.5 ± 0.5 • C) is a therapeutic modality that reduces risks of death and neurodevelopmental disability in neonates subjected to hypoxic-ischemic insults. This in vitro study was designed to determine changes in neonatal cellular metabolism with temperature. Its main aim was to compare the metabolic rate at ≤33 • C with that at ≥35 • C. STUDY DESIGN: Foreskin specimens were used as a source of neonatal tissue. Cellular respiration (mitochondrial O 2 consumption) was used as a surrogate biomarker for the metabolic rate. Foreskin specimens from healthy newborns were collected immediately after circumcision and processed within one hour for measuring the rate of O 2 consumption at various temperatures (±0.5 • C). O 2 consumption was determined as function of time from the phosphorescence decay of Pd (II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. RESULTS: In a vial sealed from air and containing foreskin specimen in phosphate-buffered saline supplemented with 5 mM glucose, [O 2 ] decreased linearly with time, confirming its zero-order kinetics. The rate of O 2 consumption (M O 2 .min −1 ), thus, was the negative of the slope of [O 2 ] vs. time. Cyanide inhibited O 2 consumption, confirming the oxidation occurred in the respiratory chain. Cellular respiration at ≤33 • C (n = 25) significantly differed from that at ≥35 • C (n = 24), p < 0.001. The rate (M O 2 .min −1 .mg −1 ) at 25 • C was 0.034 ± 0.006 (n = 11, p = 0.044), at 33 • C was 0.029 ± 0.008 (n = 14, reference temperature), at 35 • C was 0.062 ± 0.020 ( 2-fold higher, n = 18, p < 0.001), and at 37 • C was 0.061 ± 0.009 ( 2-fold higher, n = 6, p < 0.001). CONCLUSIONS: Neonatal foreskin cellular respiration is highly sensitive to critical temperatures (33 • C vs. 35 • C).

Effect of rewarming in oxygenation and respiratory condition after neonatal exposure to moderate therapeutic hypothermia

“…MTH reduces basal metabolic rate, decreasing oxygen consumption and CO 2 production. In vitro test of neonatal foreskin tissue during hypothermia showed a 50% decrease in oxygen consumption at 33.5 C. 9 Furthermore, it has been shown in vivo that cardiac output during MTH is 67% of cardiac output after rewarming. 10 Rewarming increases metabolic demands, oxygen consumption and CO 2 production.…”

“…11,12 It has been shown in adults that an increased cardiac output, increases extra-and intrapulmonary shunts. 13 Oxygen consumption will decrease during hypothermia, 9 raising mixed venous saturation and reducing cardiac output and blood flow through these shunts. The combination of both mechanisms would increase arterial oxygenation during hypothermia in addition to the above-mentioned increase in hemoglobin-oxygen affinity.…”

Noninvasive assessments of oxygen delivery from the microcirculation to skin in hypothermia-treated asphyxiated newborn infants

“…t herapeutic hypothermia (TH) has become the standard treatment for severe and moderate hypoxic-ischemic neonatal encephalopathy (HIE), as a means of reducing mortality and cerebral morbidity (1)(2)(3)(4). TH decreases the metabolic rate by 6-10% per degree celsius (°C) drop in core temperature (5,6).…”

Treatment of Neonatal Hypoxic Ischemic Encephalopathy with Hypothermia; the Window of Opportunity

“…Studies are ongoing to establish the optimal temperature for moderate hypothermia [58], and the duration of this therapy that produce maximum effects in improving long term outcomes in addition to finding the most effective adjunct therapy to potentiate the hypothermia effect in neuroprotection following HIE.…”