Xun Liu

Effect of Hypothermia on Amplitude-Integrated Electroencephalogram in Infants With Asphyxia

OBJECTIVES: Amplitude-integrated electroencephalogram (aEEG) at <6 hours is the best single outcome predictor in term infants with perinatal asphyxia at normothermia. Hypothermia has been used to treat those infants and proved to improve their outcome. The objectives of this study were to compare the predictive value of aEEG at <6 hours on outcomes in normothermia- and hypothermia-treated infants and to investigate the best outcome predictor (time to normal trace or sleep–wake cycling [SWC]) in normothermia- and hypothermia-treated infants. METHODS: Seventy-four infants were recruited by using the CoolCap entry criteria, and their outcomes were assessed by using the Bayley Scales of Infant Development II at 18 months. The aEEG was recorded for 72 hours. Patterns and voltages of aEEG backgrounds were assessed. RESULTS: The positive predictive value of an abnormal aEEG pattern at the age of 3 to 6 hours was 84% for normothermia and 59% for hypothermia. Moderate abnormal voltage background at 3 to 6 hours of age did not predict outcome. The recovery time to normal background pattern was the best predictor of poor outcome (96.2% in hypothermia, 90.9% in normothermia). Never developing SWC always predicted poor outcome. Time to SWC was a better outcome predictor for infants who were treated with hypothermia (88.5%) than with normothermia (63.6%). CONCLUSIONS: Early aEEG patterns can be used to predict outcome for infants treated with normothermia but not hypothermia. Infants with good outcome had normalized background pattern by 24 hours when treated with normothermia and by 48 hours when treated with hypothermia.

Time Is Brain: Starting Therapeutic Hypothermia within Three Hours after Birth Improves Motor Outcome in Asphyxiated Newborns

Objective: Therapeutic hypothermia (HT) is the standard treatment for newborns after perinatal asphyxia. Preclinical studies report that HT is more effective when started early. Methods: Eighty cooled newborns were analyzed and grouped according to when cooling was started after birth: early (≤180 min) or late (>181 min). For survivors we analyzed whether starting cooling early was associated with a better psychomotor or mental developmental index (PDI or MDI, Bayley Scales of Infant Development II) than late cooling. Results: Forty-three newborns started cooling early and 37 started late. There was no significant difference in the severity markers of perinatal asphyxia between the groups; however, nonsurvivors (n = 15) suffered more severe asphyxia and had significantly lower centiles for weight (BWC; p = 0.009). Of the 65 infants that survived, 35 were cooled early and 30 were cooled late. There was no difference in time to start cooling between those who survived and those who did not. For survivors, median PDI (IQR) was significantly higher when cooled early [90 (77-99)] compared to being cooled later [78 (70-90); p = 0.033]. There was no increase in cardiovascular adverse effects in those cooled early. There was no significant difference in MDI between early and late cooling [93 (77-103) vs. 89 (76-106), p = 0.594]. Conclusion: Starting cooling before 3 h of age in surviving asphyxiated newborns is safe and significantly improves motor outcome. Cooling should be initiated as soon as possible after birth in eligible infants.

Xenon Enhances Hypothermic Neuroprotection in Asphyxiated Newborn Pigs

To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone.

Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

Background and Purpose— Hypothermia (HT) for neonatal hypoxic-ischemic encephalopathy is advised to start within the first 6 hours after birth. There is some clinical evidence that HT is more effective against moderate than against severe hypoxic-ischemic encephalopathy, but it is unknown whether delayed HT beyond 6 hours is effective or even injurious. Methods— One-hundred seven 7-day-old rat pups underwent unilateral hypoxia-ischemia of moderate severity. Pups were randomized to receive 5 hours of normothermia (NT) or HT starting immediately, 3 hours, 6 hours, or 12 hours after the 90-minute hypoxic period. One-hundred five 7-day-old rat pups underwent severe hypoxia-ischemia lasting 150 minutes, followed by the same group design as mentioned. Relative area loss of the left/right hemisphere was measured after 1 week of survival. Results— In the moderate NT group, the mean area loss of the left hemisphere was 40.5%. The area loss was significantly decreased to 24.8% with immediate HT (P<0.05) and increased linearly with the delay of HT by 1.788% per hour until at least 6 hours of delay (linear regression, P=0.026). After 12-hour delayed HT, the area loss was similar to the moderate NT group (41.1%). After severe NT, the mean area loss of the left hemisphere was 59.3%. Immediate HT, 3-hour delayed HT, and 6-hour delayed HT all resulted in similar area loss, whereas the 12-hour delayed-HT resulted in significantly increased area loss (69.5%; P=0.032). Conclusions— Immediate and delayed (⩽6 hours) HT provides neuroprotection after moderate hypoxia-ischemia in neonatal rats. This neuroprotection decreases linearly with increasing delay. After severe insults, however, immediate or delayed HT ⩽6 hours provides no neuroprotection. Twelve-hour delayed hypothermia increased brain injury after severe hypoxia-ischemia, which is of clinical concern.

Serum Gentamicin Concentrations in Encephalopathic Infants are Not Affected by Therapeutic Hypothermia

OBJECTIVE. Mild hypothermia for 72 hours is neuroprotective in newborns with moderate or severe hypoxic-ischemic encephalopathy. A core temperature of 33.5°C might reduce drug clearance leading to potential toxicity. Gentamicin is nephrotoxic and ototoxic at high serum concentrations. No study has investigated the influence of 72 hours of hypothermia on serum gentamicin concentrations (SGCs) in children of any age. We aimed to compare the SGCs in encephalopathic infants who underwent intensive care with therapeutic hypothermia or normothermia. METHODS. Data were collected retrospectively from 2 NICUs in Bristol, United Kingdom, that offered cooling therapy within clinical trials since 1998. Eligible infants (n = 55) developed grade 2/3 encephalopathy after birth and fulfilled the entry criteria defined in the CoolCap trial. Encephalopathic infants with similar demographic values were either nursed under normothermia or 72 h-hypothermia. Once-daily gentamicin dosage (4–5 mg/kg) was administered, and trough SGC was recorded with corresponding creatinine concentrations. The time and number of omitted drug doses were noted. RESULTS. Mean trough SGC (pre–second dose) and mean plasma creatinine concentrations for both treatment groups were similar (gentamicin: 2.19 ± 1.7 [hypothermia] and 2.30 ± 2.0 [normothermia] mg/L; creatinine: 115.6 ± 42.8 [hypothermia] and 121.0 ± 45.1 [normothermia] μmol/L). Forty percent of the trough SGCs in both groups were above the recommended trough concentration of 2.0 mg/L. A significant correlation (r2 = 0.36) was found between high SGCs and impaired renal function assessed by raised plasma creatinine levels regardless of treatment options. CONCLUSIONS. Our data confirm that impaired renal function is strongly associated with high SGCs. Reduced body temperatures do not affect the clearance of gentamicin.

A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs.

BACKGROUND: Asphyxia accounts for 23% of the 4 million annual global neonatal deaths. In developed countries, the incidence of death or severe disability after hypoxic-ischemic (HI) encephalopathy is 1–2/1000 infants born at term. Hypothermia (HT) benefits newborns post-HI and is rapidly entering clinical use. Xenon (Xe), a scarce and expensive anesthetic, combined with HT markedly increases neuroprotection in small animal HI models. The low-Xe uptake of the patient favors the use of closed-circuit breathing system for efficiency and economy. We developed a system for delivering Xe to mechanically ventilated neonates, then investigated its technical and practical feasibility in a previously described neonatal pig model approximating the clinical scenario of global HI injury, prolonged Xe delivery with and without HT as a potential therapy, subsequent neonatal intensive care unit management, and tracheal extubation. METHODS: Sixteen newborn pigs underwent a global 45 min HI insult (4%–6% inspired oxygen reducing the electroencephalogram amplitude to <7 &mgr;V), then received 16 h 50% inspired Xe during normothermia (39.0°C) or HT (33.5°C). A conventional neonatal ventilator provided breaths of oxygen to a lower chamber compressing a hanging bag within. This bag communicated with the upper closed part of the breathing system containing soda lime, unidirectional valves, Xe/oxygen analyzers, and a tracheal tube connection. At each end-inspiration, this bag emptied fully and a bolus of oxygen, the driving gas, crossed from the lower to upper chamber via an additional valve. This mechanically substituted the gas uptake from the circle during the previous breath cycle (oxygen + small volume of Xe) with an equivalent volume of oxygen creating a slow-rising inspired oxygen concentration. This was offset by manual injection of Xe boluses, infrequently at steady state, due to the low-Xe uptake of the patient. RESULTS: Total mean Xe usage was 0.18 (0.16–0.21) L/h with no differences between Xe-HT and Xe-NT groups, which had weights of 1767 (1657–1877) g and 1818 (1662–1974) g, respectively (95% CI). HT reduced heart rate in the cooled animals; 180 (165–195) vs 148 (142–155) bpm (P < 0.0001) with no differences in arterial blood pressure, oxygen saturation, arterial carbon dioxide tension, or weaning times between these groups. CONCLUSION: We describe a closed-circuit Xe delivery system with automatic mechanical oxygen replenishment, which could be developed as a single use device. Gas exchange was maintained while Xe consumption was minimal (<

A Comparison of Cooling Methods Used in Therapeutic Hypothermia for Perinatal Asphyxia

2/h at

Neither Xenon nor Fentanyl Induces Neuroapoptosis in the Newborn Pig Brain

10/L*). We have shown it is both feasible and cost-efficient to use this Xe delivery method in newborn pigs for up to 16 h with or without concurrent cooling after a severe HI insult.

Immediate Hypothermia Reduces Cardiac Troponin I After Hypoxic-Ischemic Encephalopathy in Newborn Pigs

OBJECTIVE: The objective of this study was to compare cooling methods during therapeutic hypothermia (TH) for moderate or severe perinatal asphyxia with regard to temperature and hemodynamic stability. METHODS: A total of 73 newborns received TH in our center between 1999 and 2009 by 4 methods: (1) selective head cooling with mild systemic hypothermia by using cap (SHC; n = 20); (2) whole-body cooling with mattress manually controlled (WBCmc; n = 23); (3) whole-body cooling with body wrap servo-controlled (WBCsc; n = 28); and (4) whole-body cooling with water-filled gloves (n = 2). Target rectal temperatures (Trec) were 34.5 ± 0.5°C (SHC) and 33.5 ± 0.5°C (WBC). Trec, mean arterial blood pressure, and heart rate were collected from retrospective chart review. RESULTS: Groups had similar baseline characteristics and condition at birth. Trec was within target temperature ±0.5°C for 97% of the time in infants with WBCsc, 81% in infants with WBCmc, 76% in infants with SHC, and 74% in infants who were cooled with gloves. Mean overshoot was 0.3°C for WBCsc, 1.3°C for WBCmc, and 0.8°C for SHC groups. There was no difference in mean arterial blood pressure or mean heart between groups during the maintenance of cooling. In infants who were rewarmed at similar speed, there was greater variation in Trec in the SHC compared with the WBCsc group. CONCLUSIONS: Manually controlled cooling systems are associated with greater variability in Trec compared with servo-controlled systems. A manual mattress often causes initial overcooling. It is unknown whether large variation in temperature adversely affects the neuroprotection of TH.

Cooling neonates who do not fulfil the standard cooling criteria – short‐ and long‐term outcomes

Background:Some inhalation anesthetics increase apoptotic cell death in the developing brain. Xenon, an inhalation anesthetic, increases neuroprotection when combined with therapeutic hypothermia after hypoxic-ischemic brain injury in newborn animals. The authors, therefore, examined whether there was any neuroapoptotic effect of breathing 50% xenon with continuous fentanyl sedation for 24 h at normothermia or hypothermia on newborn pigs. Methods:Twenty-six healthy pigs (<24-h old) were randomized into four groups: (1) 24 h of 50% inhaled xenon with fentanyl at hypothermia (Trec = 33.5°C), (2) 24 h of 50% inhaled xenon with fentanyl at normothermia (Trec = 38.5°C), (3) 24 h of fentanyl at normothermia, or (4) nonventilated juvenile controls at normothermia. Five additional nonrandomized pigs inhaled 2% isoflurane at normothermia for 24 h to verify any proapoptotic effect of inhalation anesthetics in our model. Pathological cells were morphologically assessed in cortex, putamen, hippocampus, thalamus, and white matter. To quantify the findings, immunostained cells (caspase-3 and terminal deoxynucleotidyl transferase–mediated deoxyuridine-triphosphate nick-end labeling) were counted in the same brain regions. Results:For groups (1) to (4), the total number of apoptotic cells was less than 5 per brain region, representing normal developmental neuroapoptosis. After immunostaining and cell counting, regression analysis showed that neither 50% xenon with fentanyl nor fentanyl alone increased neuroapoptosis. Isoflurane caused on average a 5- to 10-fold increase of immunostained cells. Conclusion:At normothermia or hypothermia, neither 24 h of inhaled 50% xenon with fentanyl sedation nor fentanyl alone induces neuroapoptosis in the neonatal pig brain. Breathing 2% isoflurane increases neuroapoptosis in neonatal pigs.