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10.1576/toag.13.3.169.27669 http://onlinetog.org
2011;13:169–174
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Review How long have we got to get the baby out? A review of the effects of acute and profound intrapartum hypoxia and ischaemia Authors Janet Rennie / Lewis Rosenbloom
Key content: • Intrapartum hypoxic ischaemia can damage the neonatal brain. • There are two main models: acute profound and prolonged partial. • Acute profound hypoxic ischaemia can damage the neonatal brain very quickly, with permanent brain injury occurring in some babies after >10 minutes of profound circulatory collapse. • Magnetic resonance imaging is a powerful tool in the recognition of the pattern of acute profound hypoxic ischaemia.
Learning objectives: • To learn about the role of magnetic resonance imaging in diagnosing acute profound hypoxic ischaemia. • To be aware of the literature on fetal hypoxic ischaemic brain damage in animal models and human babies.
Ethical issues: • How can we advance knowledge in this field now that primate experiments are no longer considered ethical? • Are there alternatives to animal experiments that would produce equally valid results? Keywords bradycardia / brain damage / cardiotocography / magnetic resonance imaging Please cite this article as: Rennie J, Rosenbloom L. How long have we got to get the baby out? A review of the effects of acute and profound intrapartum hypoxia and ischaemia. The Obstetrician & Gynaecologist 2011;13:169–174.
Author details Janet Rennie MA MD FRCP FRCPCH DCH Consultant and Senior Lecturer in Neonatal Medicine Elizabeth Garrett Anderson Obstetric Hospital, University College London Hospitals, 2 North 250 Euston Rd, London NW1 2PQ, UK Email:
[email protected] (corresponding author)
Lewis Rosenbloom FRCP FRCPCH Honorary Consultant in Paediatric Neurology Royal Liverpool Children’s NHS Foundation Trust, Alder Hey Hospital, Eaton Road, West Derby, Liverpool, L12 2AP, UK
© 2011 Royal College of Obstetricians and Gynaecologists
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Introduction There is no longer any doubt that some babies sustain permanent brain injury as a result of intrapartum hypoxia-ischaemia; the spectrum of end-stage disability that is recognised to be a consequence of this process has widened in recent years.1 Magnetic resonance imaging (MRI) of the brain has been proven to be a very powerful tool. Many babies with a perinatal history consistent with intrapartum hypoxia who have birth depression, early metabolic acidosis and encephalopathy, and whose MRI shows damage in the borderzone areas of the brain, are now considered to have acquired their damage as a result of hypoxic ischaemia even if their adverse outcome is limited to learning disability without any motor impairment.2 In this respect thinking has moved on considerably from the rigid criteria proposed by an international consensus group,3 whose essential criteria for intrapartum hypoxic insult specified that the adverse outcome was limited to spastic quadriplegic or athetoid cerebral palsy. The neonatal brain can be damaged very quickly indeed when the cause is acute near-total or acute
Box 1
The pattern of acute profound damage caused by intrapartum hypoxic ischaemia at term
• Damage occurs to the deep grey matter, the thalami and the perirolandic cortex; sometimes the hippocampi and cerebellar vermis are involved. • Basal ganglia and thalamic lesions are regarded as the imaging signature of hypoxic ischaemic sentinel events. • The clinical abnormality seen as a consequence is most commonly extrapyramidal motor dysfunction. • Depending upon the degree and extent of the brain damage the least severely affected children may exhibit subtle features of a dyskinetic (athetoid) cerebral palsy with preservation of social and cognitive functioning. • More severely affected individuals are likely to be profoundly disabled with immobility, a very high degree of dependence and commensurate care needs.
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profound hypoxic ischaemia. Rapid recognition and response times in such potentially damaging situations remain extremely challenging for the obstetrician. An equally difficult problem is presented by a cardiotocograph (CTG) that is consistent with, but not diagnostic of, fetal hypoxic stress that may eventually be sufficient to cause fetal brain damage as a result of prolonged partial hypoxic ischaemia. The CTG is, of course, known to be an overly sensitive tool and a very poor indicator of fetal neurological status.4 With the benefit of hindsight, however, once the outcome is known the CTG is often the only tool with which to attempt a temporal reconstruction of any fetal decline. In this paper we review the literature that reflects on the time to fetal hypoxic ischaemic brain damage in animal models and human babies. We have restricted our comments to the acute profound hypoxic ischaemic model.
Acute profound or acute neartotal brain injury Evidence of the way that the mature human baby reacts to hypoxia combined with ischaemia has now accrued from relatively large numbers of MRIs from babies in the neonatal period and beyond. There are two basic patterns of damage seen as a result of intrapartum hypoxic ischaemia at term. The first pattern is usually termed acute profound damage (Box 1 and Figure 1). The second pattern involves damage to the white matter in the borderzones between the vascular territories of the major cerebral arteries and is termed prolonged partial damage; we have not considered it further. Other patterns are rarely seen and are beyond the scope of our review.
Figure 1
(a) Axial section of T2-weighted MRI scan showing abnormalities (white areas) in the posterior putamina and the ventrolateral nuclei (b) Diagram corresponding to the plane of section in Figure 1a, showing the damaged areas in heavy black
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Animal models of acute profound damage Animal models used to mimic acute total damage tend to involve hypoxic ischaemia sufficient to produce an oxygen saturation level of 30%, a 50% drop in heart rate and a virtual cessation in blood pressure. In monkeys the classic experiments on acute profound damage are those of Myers,9,10 in which asphyxia was produced by tying the umbilical cord completely and placing a rubber bag over the head of the fetus to prevent breathing; this insult produced bradycardia, gasping and metabolic acidosis within minutes (the pH fell from 7.3 to 6.8 in about 12 minutes). Ranck and Windle11 detached the entire placenta in near-term fetal monkeys and delivered them 11–16 minutes later. In spite of complete cessation of the circulation the heart continued to exhibit an electrical discharge at 60–70 beats per minute (bpm) and the circulation could be restored by resuscitation; when the baby monkeys were resuscitated they took >17 minutes to establish spontaneous breathing. Monkeys subjected to >20–25 minutes of such an insult could be resuscitated but died later. Brain damage was seen after 10 minutes.10 Windle described his experiences with a similar experimental model,12 in which asphyxiation for >7 minutes ‘invariably produced at least transient neurologic signs and permanent brain damage’. The areas of the brain that were damaged after this catastrophic asphyxial insult included the basal ganglia and thalami together with the inferior colliculi: Myers10 reported a ‘monotonously repetitive rank order’, with the colliculi and posterior and lateral ventral thalamic nuclei damaged after 10–13 minutes and more widespread thalamic involvement after 16–18 minutes. Barbiturate anaesthesia extended the time to damage, as did hypothermia. Total asphyxial damage often also included the brain stem and on rare occasions the brain stem is also involved in human babies.13 These data are now almost 40 years old, many of the animals were anaesthetised and modern neonatal intensive care probably achieves survival of babies whose insult was equivalent to that which inevitably proved fatal in these early primate experiments. Nevertheless, these experiments have stood the test of time and the results remain extremely valuable. Windle’s careful descriptions11,12 of the evolving neurological syndrome he observed as the asphyxiated monkeys matured remain highly relevant today. Initially, the infant monkeys were helpless, excessively sleepy and had seizures, they took a long time to acquire the ability to drink milk from a bottle and they lacked curiosity; later they had an inability to grasp and reach, with athetoid movements. Eventually, 8–10 years later, the monkeys adjusted to their deficits and appeared superficially normal but they © 2011 Royal College of Obstetricians and Gynaecologists
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still had difficulties with tasks such as picking up raisins and could not retain simple information as well as their non-asphyxiated peers. More recently, results of umbilical cord clamping experiments using a primate model have been reported.14 Pregnant monkeys who were near term were anaesthetised with isoflurane and underwent surgery in which the umbilical cord was exteriorised and then clamped for 12–15 minutes. The monkey fetuses were then delivered by caesarean section and resuscitated with positive pressure ventilation, undergoing electroencephalography and MRI in the neonatal period. After 15 minutes of clamping, the umbilical cord pH was 6.86 with a base deficit of 23 mmol/l and the animals took between 13–30 minutes to take their first breath. The authors found that 12 minutes did not produce a reliably severe insult using this model, whereas 15 minutes did. These results confirm the very short time between no damage and damage: after 15 minutes of clamping 100% of the animals had significant brain injury. Modern primate experiments cannot be conducted without anaesthesia and isoflurane binds to gamma-amino butyric acid (GABA), glutamate and glycine receptors; some studies suggest neuroprotection. Primate experiments are probably the most relevant, but many other animal models of neonatal hypoxic ischaemia have been developed using piglets, lambs, gerbils, mice and rats. Some argue that the piglet brain is closest in maturation to the human newborn.15 Cord occlusion for 10 minutes in fetal sheep resulting in acidosis (pH 6.9, lactate 6 mmol/l) and hypotension was followed by brain damage, predominantly in the hippocampus but also in the basal ganglia and thalamus.16 The blood pressure was not completely abolished, but was reduced to about 50% of the pre-occlusion level, and the heart rate fell from about 175 bpm to about 75 bpm in these lambs. Occlusion of the carotid artery of fetal sheep (after ligation of the anastomoses between the carotid and vertebral circulation) for 30 minutes produced an electrically silent electroencephalograph which persisted for 7–9 hours after release of the occlusion and was followed by delayed seizures and damage in the parasagittal cortex.17 Mild selective neuronal loss in the thalami and striatum was seen after only 10 minutes of occlusion in this experimental model (Figure 2). Repeated short umbilical occlusions can also cause damage to the striatum (equivalent to the deep grey matter) in lambs and may be closer to the insult that often affects the human fetus.16 In these experiments, four periods of 5 minutes of total umbilical cord occlusion produced neuronal damage in the striatum, with selective loss of GABAergic neurons in the basal ganglia. Selective 171
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Figure 2
Neuronal damage in nine brain regions following increasing durations of ischaemia, ranked in order of total damage scores on a linearised scale of 0–100. The insult involved inflation of carotid artery cuffs in fetal sheep for 0, 10, 20, 30 or 40 minutes.17 Reproduced with permission from the American Neurological Association
neuronal loss, predominantly in the hippocampus but also in the striatum and parasagittal cortex, was consistently seen after an isolated 10-minute episode of umbilical cord occlusion in near-term sheep fetuses (two of the nine did not recover from the insult).18 While all these animal data were obtained from experiments that are designed to provide a reproducible severe acute asphyxia, they may not always be directly referable to the nonanaesthetised human fetus subjected to a uterine rupture, cord prolapse, massive placental abruption, cord occlusion or shoulder dystocia. Nevertheless, the information obtained is valuable and there are many similarities to the human situation. The newborn animals developed a marked acute metabolic acidosis, required resuscitation, developed an early encephalopathy and acquired damage to the deep grey matter of the brain. Virtually all were permanently and seriously damaged after an insult lasting 12–15 minutes and many were damaged after 10 minutes (some after 7) or repeated episodes of 5 minutes of umbilical cord occlusion. Animal experiments are costly and difficult to perform and the aim of a researcher in this field is to produce a reliably severe lesion in virtually all animals, not to use an insult which leaves up to half the animals undamaged. In general, of course, in the human situation an intrapartum hypoxic ischaemic insult is rarely isolated in the way we have described and it is important to note that fetal monkeys who were 172
already acidotic because of a period of partial asphyxia acquired damage to the deep grey matter after a very short period of superimposed acute asphyxia, lasting 3–4 minutes,9 and some piglets cannot be resuscitated after short insults. The animal data we reviewed have been used to synthesise a 10-minute rule which reflects that, on the balance of probability, a human fetus will acquire damage of the acute profound type after a short severe asphyxial insult lasting >10 minutes and that >50% of fetuses probably sustain some damage after an insult of this duration. We consider this to be a reasonable conclusion. It follows from this that the obstetrician probably only has a 10-minute period in which to deliver a fetus that has developed a sustained bradycardia. While the 10-minute rule has proved to be a useful rule of thumb, there is a degree of biological variability and variation in the severity of the insult and the prior state of the fetus. Hence it is helpful to re-examine the evidence from time to time, as we have done here. We have also re-evaluated the published human cases below.
Human cases with known time to damage in the acute profound model Between us we, the authors, have studied hundreds of cases of children with damage to the deep grey matter acquired as a result of an acute profound hypoxic ischaemic insult which © 2011 Royal College of Obstetricians and Gynaecologists
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occurred either during or before labour at term, but it is not always possible to time the damaging event with precision. Nevertheless, we have seen children with severe damage that was sustained after only 10–15 minutes of bradycardia when the previous CTG was normal and others who appear to have survived, albeit often with very severe damage, after 40–50 minutes. Given the frequency with which this pattern of damage is now recognised in clinical practice there are surprisingly few published cases in which the duration of insult has been addressed and more work is needed in this area in order to inform obstetric practice. Okumura and colleagues19 reported two cases in which fetal monitoring showed a fetal bradycardia for 20 minutes and in which there was MRI evidence of damage to the basal ganglia, thalami and around the central sulci. The first was a boy whose CTG was entirely normal until he experienced a sudden fall in fetal heart rate to 60 bpm which lasted 30 minutes before recovering and who was delivered 36 minutes after the end of the bradycardia. Following his delivery by emergency caesarean section his Apgar scores were 2 and 4 at 1 and 5 minutes and he was hypotonic and jittery. He was tube fed, developed severe spastic quadriplegia and mental retardation and died at the age of 15 months. Naeye and Lin20 made a retrospective study of the notes of all children in their institution with cerebral palsy who were singletons born at >37 weeks of gestation and who had had a documented fetal bradycardia of 10 minutes after maternal collapse requiring resuscitation survive to be healthy individuals, although there were some normal survivors in the group delivered between 11–15 minutes afterwards. © 2011 Royal College of Obstetricians and Gynaecologists
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Uterine rupture can be a catastrophic event for the fetus, particularly if it results in extrusion from the uterus; the human fetus is probably exposed to a situation that is close to that of the primate experiments. In a retrospective study23 of 106 cases of uterine rupture between 1983 and 1992, five babies were diagnosed as having asphyxia (there was no long-term follow up or MRI). A prolonged deceleration was defined as a fetal heart rate
