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A J Gunn

Publications and source records attributed to A J Gunn.

At least 19 recordsLinked to original sources
PubMed2006

The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep.

Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischaemia; however, it has not been tested in the preterm brain. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.3 to 29.5 +/- 2.6 degrees C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion led to severe acidosis and profound hypotension, which recovered rapidly after release of occlusion. After 3 days recovery the EEG spectral frequency, but not total intensity, was increased in the hypothermia-occlusion group compared with normothermia-occlusion. Hypothermia was associated with a significant overall reduction in loss of immature oligodendrocytes in the periventricular white matter (P < 0.001), and neuronal loss in the hippocampus and basal ganglia (P < 0.001), with suppression of activated caspase-3 and microglia (isolectin-B4 positive). Proliferation was significantly reduced in periventricular white matter after occlusion (P < 0.05), but not improved after hypothermia. In conclusion, delayed, prolonged head cooling after a profound hypoxic insult in the preterm fetus was associated with a significant reduction in loss of neurons and immature oligodendroglia, with evidence of EEG and haemodynamic improvement after 3 days recovery, but also with a persisting reduction in proliferation of cells in the periventricular region. Further studies are required to evaluate the long-term impact of cooling on brain growth and maturation.

Animals↗
PubMed2006

Differential effects of hypothermia on early and late epileptiform events after severe hypoxia in preterm fetal sheep.

Moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischemia; however, its mechanisms remain poorly defined. Using a model of complete umbilical cord occlusion for 25 min in 0.7 gestation fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.5 +/- 0.2 degrees C to <34 degrees C; mean +/- SD), from 90 min to 70 h after the end of the insult, on postocclusion epileptiform activity. In the first 6 h after the end of occlusion, fetal electroencephalographic (EEG) activity was abnormal with a mixture of fast and slow epileptiform transients superimposed on a suppressed background; seizures started a mean of 8 h after occlusion. There was a close correlation between numbers of these EEG transients and subsequent neuronal loss in the striatum after 3 days recovery (r(2) = 0.65, P = 0.008). Hypothermia was associated with a marked reduction in numbers of epileptiform transients in the first 6 h, reduced amplitude of seizures, and reduced striatal neuronal loss. In conclusion, neuroprotection with delayed, prolonged head cooling after a severe asphyxial insult in the preterm fetus was associated with potent, specific suppression of epileptiform transients in the early recovery phase but not of numbers of delayed seizures.

Animals↗
PubMed2006

Induced cerebral hypothermia reduces post-hypoxic loss of phenotypic striatal neurons in preterm fetal sheep.

Perinatal hypoxic-ischemic injury of the basal ganglia is a significant cause of disability in premature infants. Prolonged, moderate cerebral hypothermia has been shown to be neuroprotective after experimental hypoxia-ischemia; however, it has not been tested in the preterm brain. We therefore examined the effects of severe hypoxia and the potential neuroprotective effects of delayed hypothermia on phenotypic striatal neurons. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4+/-0.3 degrees C to 29.5+/-2.6 degrees C) from 90 min to 70 h after the end of occlusion. Hypothermia was associated with a significant overall reduction in striatal neuronal loss compared with normothermia-occlusion fetuses (mean+/-SEM, 5.5+/-1.2% vs. 38.1+/-6.5%, P<0.01). Immunohistochemical studies showed that occlusion resulted in a significant loss of calbindin-28 kd, glutamic acid decarboxylase isoform 67 and neuronal nitric oxide synthase-immunopositive neurons (n=7, P<0.05), but not choline acetyltransferase-positive neurons, compared with sham controls (n=7). Hypothermia (n=7) significantly reduced the loss of calbindin-28 kd and neuronal nitric oxide synthase, but not glutamic acid decarboxylase-immunopositive neurons. In conclusion, delayed, prolonged moderate head cooling was associated with selective protection of particular phenotypic striatal projection neurons after severe hypoxia in the preterm fetus. These findings suggest that head cooling may help reduce basal ganglia injury in some premature babies.

Animals↗
PubMed2006

Endogenous alpha2-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep.

Central alpha-adrenergic receptor activity is important for fetal adaptation to hypoxia before birth. It is unclear whether it is also important during recovery. We therefore tested the hypothesis that an infusion of the specific alpha(2)-adrenergic receptor antagonist idazoxan (1 mg/kg/h i.v.) from 15 min to 4 h after profound hypoxia induced by 25 min umbilical cord occlusion in fetal sheep at 70% of gestation (equivalent to the 28-32 weeks in humans) would increase neural injury. After 3 days' recovery, idazoxan infusion was associated with a significant increase in neuronal loss in the hippocampus (P<0.05), expression of cleaved caspase-3 (P<0.05), and numbers of activated microglia (P<0.05). There was no significant effect on other neuronal regions or on loss of O4-positive premyelinating oligodendrocytes in the subcortical white matter. Idazoxan was associated with an increase in evolving epileptiform electroencephalographic (EEG) transient activity after occlusion (difference at peak 2.5+/-1.0 vs. 11.7+/-4.7 counts/min, P<0.05) and significantly reduced average spectral edge frequency, but not EEG intensity, from 54 until 72 h after occlusion (P<0.05). Hippocampal neuronal loss was correlated with total numbers of epileptiform transients during idazoxan infusion (P<0.01; r(2)=0.7). In conclusion, endogenous inhibitory alpha(2)-adrenergic receptor activation after severe hypoxia appears to significantly limit evolving hippocampal damage in the immature brain.

Adrenergic alpha-Antagonists↗
PubMed2006

Post-hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near-term fetal sheep.

Secondary cerebral hypoperfusion is common following perinatal hypoxia-ischaemia. However, it remains unclear whether this represents a true failure to provide sufficient oxygen and nutrients to tissues, or whether it is simply a consequence of reduced cerebral metabolic demand. We therefore examined the hypothesis that cerebral oxygenation would be reduced during hypoperfusion after severe asphyxia, and further, that the greater neural injury associated with blockade of the adenosine A(1) receptor during the insult would be associated with greater hypoperfusion and deoxygenation. Sixteen near-term fetal sheep received either vehicle or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) for 1 h, followed by 10 min of severe asphyxia induced by complete occlusion of the umbilical cord. Infusions were discontinued at the end of the occlusion and data were analysed for the following 8 h. A transient, secondary fall in carotid artery blood flow and laser Doppler flow was seen from approximately 1-4 h after occlusion (P < 0.001), with no significant differences between vehicle and DPCPX. Changes in laser Doppler blood flow were highly correlated with carotid blood flow (r(2)= 0.81, P < 0.001). Cortical metabolism was suppressed, reaching a nadir 1 h after occlusion and then resolving. Cortical tissue P(O(2)) was significantly increased at 1, 2 and 3 h after occlusion compared to baseline, and inversely correlated with carotid blood flow (r(2)= 0.69, P < 0.001). In conclusion, contrary to our initial hypothesis, delayed posthypoxic hypoperfusion was associated with suppression of cerebral metabolism and increased tissue P(O(2)), and was not significantly affected by preceding adenosine A1 blockade. These data suggest that posthypoxic hypoperfusion is actively mediated and reflects suppressed cerebral metabolism.

Animals↗
PubMed2006

Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep.

Early onset cerebral hypoperfusion after birth is highly correlated with neurological injury in premature infants, but the relationship with the evolution of injury remains unclear. We studied changes in cerebral oxygenation, and cytochrome oxidase (CytOx) using near-infrared spectroscopy in preterm fetal sheep (103-104 days of gestation, term is 147 days) during recovery from a profound asphyxial insult (n= 7) that we have shown produces severe subcortical injury, or sham asphyxia (n= 7). From 1 h after asphyxia there was a significant secondary fall in carotid blood flow (P < 0.001), and total cerebral blood volume, as reflected by total haemoglobin (P < 0.005), which only partially recovered after 72 h. Intracerebral oxygenation (difference between oxygenated and deoxygenated haemoglobin concentrations) fell transiently at 3 and 4 h after asphyxia (P < 0.01), followed by a substantial increase to well over sham control levels (P < 0.001). CytOx levels were normal in the first hour after occlusion, was greater than sham control values at 2-3 h (P < 0.05), but then progressively fell, and became significantly suppressed from 10 h onward (P < 0.01). In the early hours after reperfusion the fetal EEG was highly suppressed, with a superimposed mixture of fast and slow epileptiform transients; overt seizures developed from 8 +/- 0.5 h. These data strongly indicate that severe asphyxia leads to delayed, evolving loss of mitochondrial oxidative metabolism, accompanied by late seizures and relative luxury perfusion. In contrast, the combination of relative cerebral deoxygenation with evolving epileptiform transients in the early recovery phase raises the possibility that these early events accelerate or worsen the subsequent mitochondrial failure.

Animals↗
PubMed2006

Hypothermic neuroprotection.

The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment.

Animals↗
PubMed2006

Acute systemic complications in the preterm fetus after asphyxia: role of cardiovascular and blood flow responses.

1. Poor perfusion of the kidneys and gut, and associated functional impairment, are major problems in the first days of life in very preterm infants. These complications can be associated with a substantial mortality and further problems such as reduced kidney growth and chronic renal problems in later childhood. 2. There is very little information, and consequently considerable debate, about how or even whether to improve perfusion of the vital organs of this most vulnerable group of babies. Current treatments simply do not consistently improve babies' perfusion generally or kidney and gut perfusion and function in particular. 3. In this review we critically examine clinical and experimental evidence that suggests that exposure to low oxygen levels before and during birth may be a significant contributor to impaired systemic perfusion, and highlight areas requiring further research. 4. This knowledge is essential to develop and refine ways of improving perfusion of the kidneys and other vital organs in premature babies.

Acute Disease↗
PubMed2005

Treatment in animal models.

It is now well established that neurons and other cell types may die many hours or even days after hypoxic-ischemic injury due to activation of programmed cell death (apoptotic) pathways. The potent anti-apoptotic factor IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury suggesting a possible a role for IGF-1 in endogenous brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury has now been shown to be protective in both grey and white matter, and leads to improved long-term neurological function. The limited window of opportunity for treatment with IGF-1 can be extended by spontaneous mild post-hypoxic hypothermia, probably due to delayed evolution of apoptotic processes. The efficacy of IGF-1 is specific to particular cellular phenotypes and brain regions, and its neuroprotective effects are mediated by IGF-1 receptors and binding proteins. Intriguingly its naturally cleaved N-terminal tripeptide (glycine-proline-glutamate, GPE) has been demonstrated to be neuroprotective after both central and peripheral administration. Peripheral administration of GPE also prevents the loss of dopamine neurons and improves long-term functional recovery following 6-OHDA lesion. However, GPE is unlikely to contribute significantly to the direct effects of IGF-1.

Animals↗
PubMed2003

Polyuria and impaired renal blood flow after asphyxia in preterm fetal sheep.

Renal impairment is common in preterm infants, often after exposure to hypoxia/asphyxia or other circulatory disturbances. We examined the hypothesis that this association is mediated by reduced renal blood flow (RBF), using a model of asphyxia induced by complete umbilical cord occlusion for 25 min (n = 13) or sham occlusion (n = 6) in chronically instrumented preterm fetal sheep (104 days, term is 147 days). During asphyxia there was a significant fall in RBF and urine output (UO). After asphyxia, RBF transiently recovered, followed within 30 min by a secondary period of hypoperfusion (P < 0.05). This was mediated by increased renal vascular resistance (RVR, P < 0.05); arterial blood pressure was mildly increased in the first 24 h (P < 0.05). RBF relatively normalized between 3 and 24 h, but hypoperfusion developed again from 24 to 60 h (P < 0.05, analysis of covariance). UO significantly increased to a peak of 249% of baseline between 3 and 12 h (P < 0.05), with increased fractional excretion of sodium, peak 10.5 +/- 1.4 vs. 2.6 +/- 0.6% (P < 0.001). Creatinine clearance returned to normal after 2 h; there was a transient reduction at 48 h to 0.32 +/- 0.02 ml.min(-1).g(-1) (vs. 0.45 +/- 0.04, P < 0.05) corresponding with the time of maximal depression of RBF. No renal injury was seen on histological examination at 72 h. In conclusion, severe asphyxia in the preterm fetus was associated with evolving renal tubular dysfunction, as shown by transient polyuria and natriuresis. Despite a prolonged increase in RVR, there was only a modest effect on glomerular function.

Algorithms↗
PubMed2003

Insulin-like growth factor-1 and post-ischemic brain injury.

Insulin-like growth factor-1 (IGF-1) is a naturally occurring neurotrophic factor that plays an important role in promoting cell proliferation and differentiation during normal brain development and maturation. The present review examines recent evidence that endogenous IGF-1 also plays a significant role in recovery from insults such as hypoxia-ischemia and that giving additional exogenous IGF-1 can actively ameliorate damage. It is now well established that neurons and other cell types die many hours or even days after initial injury due to activation of programmed cell death pathways. IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury, suggesting a possible a role for IGF-1 in brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury is now known to be protective in both gray and white matter and leads to improved somatic function. In contrast, pre-treatment is ineffective, likely reflecting limited intracerebral penetration of IGF-1 into the uninjured brain. The neuroprotective effects of IGF-1 are mediated by IGF-1 receptors and its binding proteins and are specific to particular cellular phenotypes and brain regions. The window of opportunity for treatment with IGF-1 is limited to a few hours after normothermic brain injury, reflecting its specific actions on early, intracellular events in the apoptotic cascade. However, injury-associated mild post-hypoxic hypothermia, which delays the development of cell death, can shift and dramatically extend the window of opportunity for delayed treatment with IGF-1. Such a combined approach is likely to be essential for any clinical treatment.

Animals↗
PubMed2002

A review of the anatomy of the upper airway in early infancy and its possible relevance to SIDS.

BACKGROUND: Since the danger of prone sleeping in the first 6 months of life has been publicised, there has been a dramatic and consistent reduction in the incidence of sudden infant death syndrome (SIDS). However, unexpected infant deaths and apparent life-threatening events (ALTEs) continue to occur that are clearly not associated with known epidemiological risk factors. AIMS: To review the unique features of the anatomy and function of the upper airway of the young infant which contribute to increased vulnerability to hypoxia in this age group. We discuss the clinical identification of those infants at risk of obstruction or restriction of the upper airway and the management of the 'at risk' infant. CONCLUSIONS: In the era after the "back to sleep" campaigns, it is likely that an increasing proportion of cases of ALTEs and SIDS will be related to obstruction or limitation of upper airway size leading to sleep hypoxia/asphyxia. This type of problem may be anticipated by evaluation and investigation of infants with signs or a clinical history consistent with possible upper respiratory tract compromise, including micrognathia.

Humans↗
PubMed2001

Differential changes in insulin-like growth factors and their binding proteins following asphyxia in the preterm fetal sheep.

1. The purpose of this study was to examine the changes in circulating concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1, IGFBP-2 and insulin following asphyxia in utero. 2. Fetal sheep at 90-93 days gestation underwent either sham occlusion (n = 7) or asphyxia (n = 6) induced by complete umbilical cord occlusion for 30 min. Fetal blood samples were taken before occlusion and 4, 6, 24, 48 and 72 h post-occlusion. 3. During the early phase of recovery there was a substantial fall (80 %) in circulating plasma IGF-I concentrations by 6 h post-asphyxia (P < 0.001). This was associated with a rapid rise in IGFBP-1 (P < 0.001), but no change in IGF-II or IGFBP-2. Insulin was significantly reduced at 4 h (P < 0.001) and glucose slightly elevated (P < 0.05), but insulin values returned to baseline by 6 h. Between 24 and 72 h of recovery, IGF-I gradually increased, IGFBP-1 returned to control values, and there was an increase in IGFBP-2 after 24 h (P < 0.05) and in IGF-II by 72 h (P < 0.05) after asphyxia. 4. These data demonstrate a differential effect of asphyxia on the IGF axis of the premature fetal sheep. A key finding was the large fall in circulating IGF-I, but not IGF-II, during the early phase of recovery. IGF-I bioavailability was, in part, regulated by IGFBP-1, but maximal changes in IGF-I and IGFBP-1 were independent of plasma insulin and glucose.5. The impact of this substantial change in circulating IGF-I on the fetus is unknown. It may facilitate metabolic requirements by promoting catabolism. Alternatively, as IGFs play a role in wound repair, the acute changes in IGF-I and IGFBP-1 may reflect transport of IGF-I from the circulatory pool to injured tissues to promote wound repair.

Animals↗
PubMed2001

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.

Acidosis↗
PubMed2001

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 baby's 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.

Apnea↗
PubMed2001

Hypoxic-ischemic brain injury in the newborn: pathophysiology and potential strategies for intervention.

There is increasing clinical and experimental data describing the evolution of hypoxic-ischemic encephalopathy in the perinatal period. Outcome to the fetus is determined not only by the impact of gross asphyxial insult, but also external factors that sensitize the brain to injury. Delayed neuronal and glial death occurring in the hours and days after the insult by apoptotic and related processes are observed following severe injury, and offer the most promise for pharmacological intervention. Furthermore, new technologies allow the identification of subtle insults with evolving encephalopathies that have implications for long-term neurological outcome. Application of this knowledge will allow us to identify strategies for early intervention and prevent the course of damage caused by hypoxic-ischemic injury.

Female↗