Alistair J. Gunn

Cerebral hypothermia for prevention of brain injury following perinatal asphyxia.

The possibility that hypothermia has a therapeutic role during or after resuscitation from severe perinatal asphyxia has been a longstanding focus of research. Early studies using short periods of cooling had limited and contradictory results. We now know that resuscitation can be followed by a “latent” phase, characterized by transient recovery of cerebral energy metabolism, before secondary deterioration occurs with seizures, cytotoxic edema, and cerebral energy failure 6 to 15 hours after birth. Recent experimental studies have shown that moderate cerebral hypothermia initiated as soon as possible in the latent phase, before the onset of secondary injury, and continued for 48 hours or more is associated with potent, long-lasting neuroprotection. These encouraging results must be balanced against the well-known adverse systemic effects of hypothermia. Randomized clinical trials are in progress to test the safety and efficacy of cerebral hypothermia.

Insulin-Like Growth Factor (IGF)-1 Suppresses Oligodendrocyte Caspase-3 Activation and Increases Glial Proliferation after Ischemia in Near-Term Fetal Sheep

Insulin-like growth factor (IGF-1) markedly increases myelination and glial numbers in white matter after ischemia in near-term fetal sheep; however, it is unclear whether this is due to reduced cell loss or increased secondary proliferation. Brain injury was induced in near-term fetal sheep by 30 minutes of bilateral carotid artery occlusion. Ninety minutes after the occlusion, fetuses were given, intracerebroventricularly, either a single dose of IGF-1 (either 3 or 30 μg), or 3 μg followed by 3 μg over 24 hours (3 + 3 μg). White matter was assessed 4 days after reperfusion. Three micrograms, but not 30 μg of IGF-1 prevented loss of oligodendrocytes and myelin basic protein density (P < 0.001) compared to the vehicle-treated ischemia controls. No additional effect was observed in the 3 + 3 μg group. IGF-1 treatment was associated with reduced caspase-3 activation and increased glial proliferation in a similar dose-dependent manner. Caspase-3 was only expressed in oligodendrocytes that showed apoptotic morphology. Proliferating cell nuclear antigen co-localized with both oligodendrocytes and astrocytes and microglia. Thus, increased oligodendrocyte numbers after IGF-1 treatment is partly due to suppression of apoptosis, and partly to increased proliferation. In contrast, the increase in reactive glia was related only to proliferation. Speculatively, reactive glia may partly mediate IGF-1 white matter protection.

Key Neuroprotective Role for Endogenous Adenosine A1 Receptor Activation During Asphyxia in the Fetal Sheep

BACKGROUND AND PURPOSE The fetus is well known to be able to survive prolonged exposure to asphyxia with minimal injury compared with older animals. We and others have observed a rapid suppression of EEG intensity with the onset of asphyxia, suggesting active inhibition that may be a major neuroprotective adaptation to asphyxia. Adenosine is a key regulator of cerebral metabolism in the fetus. METHODS We therefore tested the hypothesis that infusion of the specific adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), given before 10 minutes of profound asphyxia in near-term fetal sheep, would prevent neural inhibition and lead to increased brain damage. RESULTS DPCPX treatment was associated with a transient rise and delayed fall in EEG activity in response to cord occlusion (n=8) in contrast with a rapid and sustained suppression of EEG activity in controls (n=8). DPCPX was also associated with an earlier and greater increase in cortical impedance, reflecting earlier onset of primary cytotoxic edema, and a significantly smaller reduction in calculated cortical heat production after the start of cord occlusion. After reperfusion, DPCPX-treated fetuses but not controls developed delayed onset of seizures, which continued for 24 hours, and sustained greater selective hippocampal, striatal, and parasagittal neuronal loss after 72-hour recovery. CONCLUSIONS These data support the hypothesis that endogenous activation of the adenosine A1 receptor during severe asphyxia mediates the initial suppression of neural activity and is an important mechanism that protects the fetal brain.

The emerging role of induced hypothermia in the management of acute stroke

Current treatment of acute stroke remains unsatisfactory. This review presents experimental and clinical data which suggest that mild induced hypothermia could be a potent and practicable neuroprotective treatment of acute ischaemic stroke and intracerebral haemorrhage. Hypothermia, if proven to be safe, effective and widely practicable in patients with acute stroke, could have an enormous positive impact on reducing the burden of stroke worldwide. Critical issues that will need to be considered in a well designed randomised controlled trial of induced hypothermia in acute stroke patients are discussed.

Does early hospital discharge with home support of families with preterm infants affect breastfeeding success? A randomized trial.

The aim of the present study was to determine if earlier discharge of preterm infants (<37 wk) from hospital is safe and if it affects breastfeeding rates. In a pilot observational study, premature infants received full oral (sucking) feeds for a mean (SD) 7.7 ± 7.9 d before discharge. In the main study, 308 preterm infants were randomly assigned to either Early Discharge (148 infants) when fully orally fed but not yet gaining weight or Routine Discharge (160 infants) when fully orally fed and also gaining weight before discharge. A further 122 mothers declined randomization. The Early Discharge group was followed by Visiting Nurse Specialists who were available 24 h a day, while the Routine group was followed by the Home Care Nurses available on week days. There were no significant differences between the groups in birthweight or gestational age. The Early Discharge group were discharged 2.5 ± 2 d after full oral feeding compared to 4.4 ± 2.7 d for the Routine group (p < 0.001) and 6.1 ± 5 d for those who declined. However, there was no significant difference between the Early and Routine groups for breastfeeding either at discharge (80 vs 83%), or 6 wk (55 vs 60%) or 6 mo after discharge (36 vs 36%), or for weight gain, or rates of re‐hospitalization (8.8% vs 11.9% at 6 wk, p = 0.37).

The effect of asphyxia on superior mesenteric artery blood flow in the premature sheep fetus

BACKGROUND/PURPOSE The aim of this study was to determine superior mesenteric artery blood flow changes during and after an asphyxial insult in utero in chronically instrumented unanaesthetised premature fetal sheep. METHODS Fetal sheep at 0.7 gestation (103 to 104 days) underwent 25 minutes of complete umbilical cord occlusion (n = 6) or sham occlusion (n = 6). Fetal heart rate, blood pressure, superior mesenteric artery (SMA) blood flow and vascular resistance, electroencephalographic activity, and nuchal electromyographic activity were measured from 6 hours before occlusion until 3 days after occlusion. Fetal gastrointestinal tissue was taken for histological assessment. RESULTS During occlusion, cardiovascular response was characterised by 3 phases: initial redistribution of blood flow away from the gut to maintain vital organ function, subsequently partial failure of this redistribution, and finally near terminal cardiovascular collapse with profound hypotension and gastrointestinal hypoperfusion. Postasphyxia there was a secondary period of hypoperfusion that was mediated by increased vascular resistance, not hypotension. There was no evidence of injury on standard histological assessment after 3 days of recovery. CONCLUSIONS SMA blood flow is not only significantly reduced during asphyxia, but also for several hours after an asphyxial insult. The authors speculate that these perturbations of gastrointestinal blood flow could compromise gut wall integrity potentially leading to increased vulnerability to necrotising enterocolitis.

Fetal heart rate overshoot during repeated umbilical cord occlusion in sheep

Objective To assess the clinical utility of overshoot fetal heart rate (FHR) decelerations by examining their occurrence after umbilical cord occlusions of varying frequency and length in near-term fetal sheep. Methods Fetuses were allocated to the following three groups: 1-minute umbilical cord occlusion repeated every 5 minutes (1:5 group, n = 8) or every 2.5 minutes (1:2.5 group, n = 8) or 2-minute occlusions repeated every 5 minutes (2:5 group, n = 4). Occlusions were continued for 4 hours or until fetal mean arterial pressure decreased below 20 mmHg during two successive occlusions. Results In the 1:5 group, fetuses tolerated 4 hours of occlusion without hypotension or clinically significant acidosis and overshoot never occurred. In the 2:5 group, fetuses rapidly became hypotensive and acidotic, and occlusions were terminated at 116.3 ± 22.9 min (mean ± standard deviation). Overshoot was seen after every occlusion, starting with the first occlusion. In the 1:2.5 group, fetuses became progressively acidotic and hypotensive and occlusions were stopped at 183.1 ± 42.8 min. Overshoot occurred after 91.6 ± 42.5 minutes, at a pH of 7.17 ± 0.06, base deficit 9.3 ± 4.5 mmol/L. After the appearance of overshoot there was a more rapid decrease in fetal mean arterial pressure (0.25 [0.21, 0.35, 25–75th percentile] mmHg/minute versus 0.11 [0.03, 0.15] mmHg/minute before overshoot appeared, P < .01). Conclusion These data suggest that overshoot is related to longer (2-minute) occlusions or to developing fetal acidosis and hypotension during 1-minute occlusions. This pattern could have clinical utility, as 1-minute contractions are typical of active labor.

Meconium and fetal hypoxia: some experimental observations and clinical relevance

In an experimental study, chemically sympathectomised near term fetal sheep and a control group were subjected to repeated episodes of acute hypoxia. Despite severe hypotension and metabolic acidosis, no animal in the control group had meconium‐stained amniotic fluid, whereas every animal in the sympathectomised group had heavily meconium‐stained amniotic fluid at the end of the experiments. These data and the available literature do not support a direct association between acute hypoxia and meconium‐stained amniotic fluid but suggest that a reduction in sympathetic neural tone must be a component of meconium passage. Clinical and experimental data on the occurrence of meconium‐stained amniotic fluid are reviewed.

Failure of mouth-to-mouth resuscitation in cases of sudden infant death

We describe two cases of sudden infant death syndrome (SIDS) and one case of apparent life threatening apnoea where resuscitation was attempted by the mouth-to-mouth route. This was associated with evidence of gastric distension, including reflux of milk into the airway in the first two cases. In the second case the mother used mouth-to-mouth breathing after finding that she could not cover her babys nose-and-open-mouth with her mouth. In the last case, the mother went on to try the mouth-to-nose route, with a good outcome. Systematic documentation of the route of resuscitation and its outcome in all cases of SIDS and near-miss SIDS may provide valuable insights into the optimal route for infant resuscitation.

Hypothermic Centralization: New Use for Old Knowledge?

Potential neuroprotective effects with mild to moderate cerebral cooling have been clearly demonstrated after experimental hypoxic–ischemic injury.1 However, the difficulties of establishing an effective regime in clinical practice are formidable. In the absence of definitive evidence of clinical efficacy, it is essential that hypothermia be used safely. Pilot studies have suggested that, under tightly defined conditions, hypothermia is generally safe even in the severely asphyxiated infant,2–4 and multicenter, randomized, controlled trials are currently underway to further investigate different hypothermic strategies. Many of the clinical issues raised by Thoresen and Whitelaw5 can be readily understood in relation to the physiology of adaptation to hypothermia, including both the conservation and production of heat. Hypothermia leads to rapid peripheral vasoconstriction, ie, centralization of blood flow. This vasoconstriction occurs in a spatially and temporally controlled manner, dependent on tightly integrated input from central and skin thermoreceptors.6Although both core and skin temperatures are physiologically relevant, in man, … Address correspondence to Alistair Jan Gunn, MBChB, PhD, FRACP, Department of Paediatrics, Faculty of Medicine and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: aj.gunn{at}auckland.ac.nz