James Tooley

Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective

Hypothermia is potentially therapeutic in the management of neonatal hypoxic‐ischemic brain injury. However, not all studies have shown a neuroprotective effect. It is suggested that the stress of unsedated hypothermia may interfere with neuroprotection. We propose that selective head cooling (SHC) combined with mild total‐body hypothermia during anesthesia enhances local neuroprotection while minimizing the occurrence of systemic side effects and stress associated with unsedated whole‐body cooling. Our objective was to determine whether SHC combined with mild total‐body hypothermia while anesthetized for a period of 24 hours reduces cerebral damage in our piglet survival model of global hypoxia‐ischemia. Eighteen anesthetized piglets received a 45‐minute global hypoxic‐ischemic insult. The pigs were randomized either to remain normothermic or to receive SHC. We found that the severity of the hypoxic‐ischemic insult was similar in the SHC versus the normothermic group, and that the mean neurology scores at 30 and 48 hours and neuropathology scores were significantly better in the SHC group versus the normothermic group. We conclude that selective head cooling combined with mild systemic hypothermia and anesthesia is neuroprotective when started immediately after the insult in our piglet model of hypoxic‐ischemic encephalopathy. Ann Neurol 2003;53:000–000

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.

Effective selective head cooling during posthypoxic hypothermia in newborn piglets.

Selective head cooling has been proposed as a neuroprotective intervention after hypoxia-ischemia in which the brain is cooled without subjecting the rest of the body to significant hypothermia, thus minimizing adverse systemic effects. There are little data showing it is possible to cool the brain more than the body. We have therefore applied selective head cooling to our hypoxia-ischemia piglet model to establish whether it is possible. Nine piglets were anesthetized, and brain temperature was measured at the surface and in the superficial (0.2 cm) and deep (1.7–2.0 cm) gray matter. Rectal (6-cm depth), skin, and scalp temperatures (T) were recorded continuously. Lowering T-rectal from normothermia (39°C) to hypothermia (33.5–33.8°C) using a head cap perfused with cold (6–24°C) water was undertaken for up to 6 h. To assess the impact of the 45-min hypoxia-ischemia insult on the effectiveness of selective head cooling, four piglets were cooled both before and after the insult, and four, only afterward. During selective head cooling, it was possible to achieve a lower T-deep brain than T-rectal in all animals both before and after hypoxia. However, this was only possible when overhead body heating was used. The T-rectal to T-deep brain gradient was significantly smaller after the insult (median, 5.3°C; range, 4.2–8.5°C versus 3.0°C; 1.7-7.4°C;p = 0.008). During rewarming to normothermia, the gradient was maintained at 4.5°C. We report for the first time a study, which by direct measurement of deep intracerebral temperatures, validates the cooling cap as an effective method of selective brain cooling in a newborn animal hypoxia-ischemia model.

Delayed Hypothermia as Selective Head Cooling or Whole Body Cooling Does Not Protect Brain or Body in Newborn Pig Subjected to Hypoxia-Ischemia

The neuroprotective efficacy of hypothermia (HT) after hypoxia-ischemia (HI) falls dramatically the longer the delay in initiating HT. Knowledge is scarce regarding protective or adverse effects of HT in organs beyond the brain. In addition, the relative effectiveness of selective head cooling (SHC) and whole body cooling (WBC) has not been studied. We aimed to examine whether 24 h HT, initiated 3 h after global HI is brain- and/or organ-protective using pathology, neurology, and biochemical markers. Fifty, ≤1-d-old pigs were subjected to global HI causing permanent brain injury. Animals were randomized to normothermia (NT), (Trectal) 39.0°C, SHCTrectal 34.5°C, or WBCTrectal 34.5°C for 24 h, all followed by 48 h NT. There was no difference in injury to the brain or organs between groups. There was no gender difference in brain injury but females had significantly more organs injured [2.3 (± 1.3) [mean ± SD] vs. 1.4 ± (1.0)]. The postinsult decline in lactate was temperature independent. However, HT animals normalized their plasma-calcium, magnesium, and potassium significantly faster than NT. Delayed SHC or WBC, initiated 3 h after HI, does not reduce pathology in the brain nor in organs. Delayed HT improves postinsult recovery of plasma-calcium, magnesium, and potassium. There were no differences in adverse effects across groups.

Significant head cooling can be achieved while maintaining normothermia in the newborn piglet

Background: Hypothermia has been shown to be neuroprotective in animal models of hypoxia-ischaemia. It is currently being evaluated as a potentially therapeutic option in the management of neonatal hypoxic-ischaemic encephalopathy. However, significant hypothermia has adverse systemic effects. It has also recently been found that the stress of being cold can abolish the neuroprotective effects of hypothermia. It is hypothesised that selective head cooling (SHC) while maintaining normal core temperature would enable local hypothermic neuroprotection while limiting the stress and side effects of hypothermia. Objective: To determine whether it is possible to induce moderate cerebral hypothermia in the deep brain of the piglet while maintaining the body at normothermia (39°C). Methods: Six piglets (<48 hours old) were anaesthetised, and temperature probes inserted into the brain. Temperature was measured at different depths from the brain surface (21 mm (Tdeep brain) to 7 mm (Tsuperficial brain)). After a 45 minute global hypoxic-ischaemic insult, each piglet was head cooled for seven hours using a cap circulated with cold water (median 8.9°C (interquartile range 7.5–14)) wrapped around the head. Radiant overhead heating was used to warm the body during cooling. Results: During SHC it was possible to cool the brain while maintaining a normal core temperature. The mean (SD) Tdeep brain during the seven hour cooling period was 31.1 (4.9)°C while Trectal remained stable at 38.8 (0.4)°C. The mean Trectal−Tdeep brain difference throughout the cooling period was 9.8 (6.1)°C. The mean Tskin required was 40.8 (1.1)°C. There was no evidence of skin damage secondary to these skin temperatures. During cooling only one piglet shivered. Conclusions: It is possible to maintain systemic normothermia in piglets while significantly cooling the deeper structures of the brain. This method of cooling may further limit the side effects associated with systemic hypothermia and be feasible for premature infants.

Therapeutic hypothermia during neonatal transport

Aim:  To compare the effectiveness of different cooling methods used during neonatal transport in maintaining target temperature.

Falling rates of perinatal postmortem examination: are we to blame?

Information from a high-quality postmortem examination is the right of every parent after the death of their child.1 Postmortem examination rates worldwide, however, continue to fall. Much of this decline has been attributed to changing societal views on postmortem examination, recent issues of organ retention, and evidence to suggest that parents or carers are less likely to give consent.2 Having reviewed our own practice, we hypothesised that rather than a decline in parental consent, clinicians were less likely to offer a postmortem examination. In November 2004, we carried out a semistructured telephone interview of 60 consultants from 46 level 2 …

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

Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinically defined neurological condition after lack of oxygen and often associated with cardiac dysfunction in term infants. Therapeutic hypothermia (HT) after birth is neuroprotective in infants with HIE. However, it is not known whether HT is also cardioprotective. Four newborn pigs were used in the pilot study and a further 18 newborn pigs [randomly assigned to 72 h normothermia (NT) or 24 h HT followed by 48 h NT] were subjected to global HIE insults. Serum cTnI was measured before and post the HIE insult. Blood pressure, inotropic support, blood gases, and heart rate (HR) were recorded throughout. Cardiac pathology was assessed from histological sections. Cooling reduced serum cTnI levels significantly in HT pigs by 6 h (NT, 1.36 ± 0.67; HT, 0.34 ± 0.23 ng/mL; p = 0.0009). After rewarming, from 24 to 30 h postinsult, HR and cTnI increased in the HT group; from HR[24 h] = 117 ± 22 to HR[30 h] = 218 ± 32 beats/min (p = 0.0002) and from cTnI[24 h] = 0.23 ± 0.12 to cTnI[30 h] = 0.65 ± 0.53 ng/mL, (p = 0.05). There were fewer ischemic lesions on cardiac examination (37%) in the HT group compared with the NT group (70%). HT (24 h) pigs did not have the postinsult cTnI increase seen in NT-treated pigs. There was a trend that HT improved cardiac pathology in this 3-d survival model.

The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval.

BACKGROUND:Therapeutic hypothermia is the standard of care after perinatal asphyxia. Preclinical studies show 50% xenon improves outcome, if started early. METHODS:During a 32-patient study randomized between hypothermia only and hypothermia with xenon, 5 neonates were given xenon during retrieval using a closed-circuit incubator-mounted system. RESULTS:Without xenon availability during retrieval, 50% of eligible infants exceeded the 5-hour treatment window. With the transportable system, 100% were recruited. Xenon delivery lasted 55 to 120 minutes, using 174 mL/h (117.5–193.2) (median [interquartile range]), after circuit priming (1300 mL). CONCLUSIONS:Xenon delivery during ambulance retrieval was feasible, reduced starting delays, and used very little gas.

Hypocarbia Soon after Birth is not Associated with Poor Outcome in Infants Treated with Therapeutic Hypothermia after Perinatal Asphyxia

Background: Most infants affected by perinatal asphyxia are born in poor condition needing resuscitation and ventilatory support after birth. Therapeutic hypothermia reduces brain injury and has become standard of care for these infants. In term and preterm infants that were not cooled, hypocarbia soon after birth was previously associated with poor outcome. We assessed whether hypocarbia is associated with poor outcome in term neonates treated with therapeutic hypothermia.Methods: Blood gases were analysed in 46 term newborn infants before the onset of therapeutic hypothermia. The effect of hypocarbia (< 4 kPa) alone or in combination with hyperoxaemia (> 40% O2) was correlated with poor outcome (death/disability at 18-24months). Poor outcome in survivors were either a Bayley II-MDI or -PDI score < 70.Results: Of 46 infants, 14 had poor outcome (10 died). The mean (SD) 10 minute Apgar score was 5.2 (2.9) and worst pH was 6.9 (0.2). The mean (SD) HIE grade was 2.4 (0.6). The median (IQR) lowest pCO2 level was 4.1 kPa (2.2 - 12.8 kPa) and median (IQR) FiO2 level in the first hour of life was 57% (21 - 100%). 23 infants had a pCO2 < 4 kPa (mean 3.1, SD 0.7) and 31 infants had a FiO2 >40% (mean 72.6%, SD 26), 15 infants had the combination of hypocarbia+hyperoxaemia. Low CO2 was not associated with poor outcome neither in combination with low or high FiO2.Conclusion: Neither hypocarbia alone nor the combination of hypocarbia+hyperoxaemia were associated with poor outcome in newborns treated with therapeutic hypothermia.