Christopher A. Lear

Magnesium Is Not Consistently Neuroprotective for Perinatal Hypoxia-Ischemia in Term-Equivalent Models in Preclinical Studies: A Systematic Review

There is an important unmet need to further improve the outcome of neonatal encephalopathy in term infants. Meta-analyses of large controlled trials now suggest that maternal magnesium sulfate (MgSO4) therapy is associated with a reduced risk of cerebral palsy and gross motor dysfunction after premature birth, but that it has no effect on death or disability. Because of this inconsistency, it remains controversial whether MgSO4 is clinically neuroprotective and, thus, it is unclear whether it would be appropriate to test MgSO4 for treatment of encephalopathy in term infants. We therefore systematically reviewed the preclinical evidence for neuroprotection with MgSO4 before or after hypoxic-ischemic encephalopathy (HIE) in term-equivalent perinatal and adult animals. The outcomes were highly inconsistent between studies. Although there were differences in dose and timing of administration, there was evidence that beneficial effects of MgSO4 were associated with confounding mild hypothermia and, strikingly, the studies that included rigorous maintenance of environmental temperature or body temperature consistently suggested a lack of effect. On balance, these preclinical studies suggest that peripherally administered MgSO4 is unlikely to be neuroprotective. Rigorous testing in translational animal models of perinatal HIE is needed before MgSO4 should be considered in clinical trials for encephalopathy in term infants.

The myths and physiology surrounding intrapartum decelerations: the critical role of the peripheral chemoreflex.

A distinctive pattern of recurrent rapid falls in fetal heart rate, called decelerations, are commonly associated with uterine contractions during labour. These brief decelerations are mediated by vagal activation. The reflex triggering this vagal response has been variably attributed to a mechanoreceptor response to fetal head compression, to baroreflex activation following increased blood pressure during umbilical cord compression, and/or a Bezold–Jarisch reflex response to reduced venous return from the placenta. Although these complex explanations are still widespread today, there is no consistent evidence that they are common during labour. Instead, the only mechanism that has been systematically investigated, proven to be reliably active during labour and, crucially, capable of producing rapid decelerations is the peripheral chemoreflex. The peripheral chemoreflex is triggered by transient periods of asphyxia that are a normal phenomenon associated with all uterine contractions. This should not cause concern as the healthy fetus has a remarkable ability to adapt to these repeated but short periods of asphyxia. This means that the healthy fetus is typically not at risk of hypotension and injury during uncomplicated labour even during repeated brief decelerations. The physiologically incorrect theories surrounding decelerations that ignore the natural occurrence of repeated asphyxia probably gained widespread support to help explain why many babies are born healthy despite repeated decelerations during labour. We propose that a unified and physiological understanding of intrapartum decelerations that accepts the true nature of labour is critical to improve interpretation of intrapartum fetal heart rate patterns.

Magnesium sulphate and cardiovascular and cerebrovascular adaptations to asphyxia in preterm fetal sheep

Magnesium sulphate is the recommended treatment for pre‐eclampsia and is now widely recommended for perinatal neuroprotection. MgSO4 has vasodilatory and negative inotropic effects; however, it is unknown whether it impairs the cardiovascular and cerebrovascular adaptations to acute asphyxia in preterm fetuses. Intravenous infusion of a clinically comparable dose of MgSO4 to the preterm fetus was associated with no change in blood pressure, reduced fetal heart rate and increased femoral arterial conductance and blood flow; femoral arterial waveform height and width were increased, consistent with increased stroke volume during MgSO4 infusion. During asphyxia MgSO4 was associated with increased carotid and femoral arterial conductance and blood flows; after asphyxia, fetal heart rate was lower and carotid and femoral blood flows and vascular conductance were greater in MgSO4‐treated fetuses. These data demonstrate that MgSO4 may increase perfusion of peripheral vascular beds during adverse perinatal events such as asphyxia.

Sympathetic neural activation does not mediate heart rate variability during repeated brief umbilical cord occlusions in near‐term fetal sheep

Fetal heart rate variability and changes in the ST segment of the electrocardiogram are used clinically during labour to identify fetuses at risk of severe metabolic acidosis or death. Sympathetic nervous system activity contributes to heart rate variability in healthy normoxic fetuses, and is critical for the rapid haemodynamic adaptations to repeated episodes of asphyxia induced by brief complete umbilical cord occlusions at rates consistent with active labour. We now show that chemical sympathectomy did not alter fetal heart rate variability between episodes of brief repeated asphyxia or elevation of the ST segment during asphyxia. The lack of influence of the sympathetic system on fetal heart rate variability between episodes of brief asphyxia suggests that measures of fetal heart rate variability are unlikely to help monitor changes in sympathetic nervous system activity during active labour.

Effect of maternal position on fetal behavioural state and heart rate variability in healthy late gestation pregnancy

Fetal behavioural state in healthy late gestation pregnancy is affected by maternal position. Fetal state 1F is more likely to occur in maternal supine or right lateral positions. Fetal state 4F is less likely to occur when the woman lies supine or semi‐recumbent. Fetal state change is more likely when the woman is supine or semi‐recumbent. Fetal heart rate variability is affected by maternal position with variability reduced in supine and semi‐recumbent positions.

Magnesium sulfate reduces EEG activity but is not neuroprotective after asphyxia in preterm fetal sheep

Magnesium sulfate is now widely recommended for neuroprotection for preterm birth; however, this has been controversial because there is little evidence that magnesium sulfate is neuroprotective. Preterm fetal sheep (104 days gestation; term is 147 days) were randomly assigned to receive sham occlusion (n = 7), i.v. magnesium sulfate (n = 10) or saline (n = 8) starting 24 h before asphyxia until 24 h after asphyxia. Sheep were killed 72 h after asphyxia. Magnesium sulfate infusion reduced electroencephalograph power and fetal movements before asphyxia. Magnesium sulfate infusion did not affect electroencephalograph power during recovery, but was associated with marked reduction of the post-asphyxial seizure burden (mean ± SD: 34 ± 18 min vs. 107 ± 74 min, P < 0.05). Magnesium sulfate infusion did not affect subcortical neuronal loss. In the intragyral and periventricular white matter, magnesium sulfate was associated with reduced numbers of all (Olig−2+ve) oligodendrocytes in the intragyral (125 ± 23 vs. 163 ± 38 cells/field) and periventricular white matter (162 ± 39 vs. 209 ± 44 cells/field) compared to saline-treated controls (P < 0.05), but no effect on microglial induction or astrogliosis. In conclusion, a clinically comparable dose of magnesium sulfate showed significant anticonvulsant effects after asphyxia in preterm fetal sheep, but did not reduce asphyxia-induced brain injury and exacerbated loss of oligodendrocytes.

Complex interactions between hypoxia-ischemia and inflammation in preterm brain injury

Children surviving preterm birth have a high risk of disability, particularly cognitive and learning problems. There is extensive clinical and experimental evidence that disability is now primarily related to dysmaturation of white and gray matter, defined by failure of oligodendrocyte maturation and neuronal dendritic arborization, rather than cell death alone. The etiology of this dysmaturation is multifactorial, with contributions from hypoxia‐ischemia, infection/inflammation and barotrauma. Intriguingly, these factors can interact to both increase and decrease damage. In this review we summarize preclinical and clinical evidence that all of these factors trigger secondary or chronic inflammation and gliosis. Thus, we hypothesize that these shared pathological features play a key role in a final common pathway that leads to the impaired neural maturation and connectivity and cognitive/motor impairments that are commonly observed in infants born preterm. This raises the possibility that secondary or chronic inflammation may be a viable therapeutic target for delayed interventions to improve neurodevelopmental outcomes after preterm birth.

Analgesics, sedatives, anticonvulsant drugs, and the cooled brain

Multiple randomized controlled trials have shown that prolonged, moderate cerebral hypothermia initiated within a few hours after severe hypoxia-ischemia and continued until resolution of the acute phase of delayed cell death reduces mortality and improves neurodevelopmental outcome in term infants. The challenge is now to find ways to further improve outcomes. In the present review, we critically examine the evidence that conventional analgesic, sedative, or anticonvulsant agents might improve outcomes, in relation to the known window of opportunity for effective protection with hypothermia. This review strongly indicates that there is insufficient evidence to recommend routine use of these agents during therapeutic hypothermia. Further systematic research into the effects of pain and stress on the injured brain, and their treatment during hypothermia, is essential to guide the rational development of clinical treatment protocols.

The effects of dexamethasone on post-asphyxial cerebral oxygenation in the preterm fetal sheep.

Mothers at risk of preterm delivery are routinely given synthetic glucocorticoids such as dexamethasone to help mature fetal lungs and improve survival after birth. We have previously shown that dexamethasone given after an acute episode of asphyxia in preterm fetal sheep is associated with greater brain injury. In this study we found that fetal exposure to dexamethasone after asphyxia in preterm fetal sheep was associated with reduced intracerebral oxygenation during the critical latent phase of recovery. In the secondary phase, maternal dexamethasone was associated with increased epileptiform transient activity and evidence of greater mitochondrial oxidation. These findings suggest that fetal exposure to the synthetic glucocorticoid dexamethasone is associated with a critical mismatch between the brains demand for oxygenation and the supply of oxygen that may contribute to greater brain injury.

In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature?

In the era of therapeutic hypothermia, reliable preclinical studies are integral to successfully identify neuroprotective strategies to further improve outcomes of encephalopathy at term. We reviewed preclinical neuroprotection studies reported between January 2014 and June 2016 to assess the use of effective temperature monitoring and control. As a secondary measure, we examined whether studies addressed other methodological issues such as stage of brain development, sex differences, the timing of the treatment relative to the insult, and the histological and functional endpoints used after hypoxia-ischemia. The extent and duration of temperature monitoring was highly inconsistent. Only a minority of papers monitored core (19/61; 31%) or brain temperature (3/61; 5%). Most (40/45) of the neuroprotectants either were likely to affect thermoregulation or their impact is unknown. In 85% of papers neonatal rodents were used (67% at P7); 51% of papers did not report the sex of the animals or tested the effect of potential neuroprotectants on just one sex. In 76% of studies, treatment was before or immediately after the insult (within the first 2 h), and few studies assessed long-term histological and behavioral outcomes. In conclusion, many recent preclinical neonatal studies cannot exclude the possibility that apparent neuroprotection might be related to drug-induced hypothermia or to other methodological choices. Close monitoring and control of brain temperature during, as well as for many days after, experimental hypoxia-ischemia are now critical to reliably develop new ways to improve neurodevelopmental outcomes after perinatal hypoxic-ischemic encephalopathy.