White Matter Injury and General Movements in High-Risk Preterm Infants.

BACKGROUND AND PURPOSE: Very preterm infants (birth weight, <1500 g) are at increased risk of cognitive and motor impairment, including cerebral palsy. These adverse neurodevelopmental outcomes are associated with white matter abnormalities on MR imaging at term-equivalent age. Cerebral palsy has been predicted by analysis of spontaneous movements in the infant termed "General Movement Assessment." The goal of this study was to determine the utility of General Movement Assessment in predicting adverse cognitive, language, and motor outcomes in very preterm infants and to identify brain imaging markers associated with both adverse outcomes and aberrant general movements. MATERIALS AND METHODS: In this prospective study of 47 preterm infants of 24-30 weeks' gestation, brain MR imaging was performed at term-equivalent age. Infants underwent T1- and T2-weighted imaging for volumetric analysis and DTI. General movements were assessed at 10-15 weeks' postterm age, and neurodevelopmental outcomes were evaluated at 2 years by using the Bayley Scales of Infant and Toddler Development III. RESULTS: Nine infants had aberrant general movements and were more likely to have adverse neurodevelopmental outcomes, compared with infants with normal movements. In infants with aberrant movements, Tract-Based Spatial Statistics analysis identified significantly lower fractional anisotropy in widespread white matter tracts, including the corpus callosum, inferior longitudinal and fronto-occipital fasciculi, internal capsule, and optic radiation. The subset of infants having both aberrant movements and abnormal neurodevelopmental outcomes in cognitive, language, and motor skills had significantly lower fractional anisotropy in specific brain regions. CONCLUSIONS: Aberrant general movements at 10-15 weeks' postterm are associated with adverse neurodevelopmental outcomes and specific white matter microstructure abnormalities for cognitive, language, and motor delays.

Physician counseling, informed consent and parental decision making for infants with hypoplastic left-heart syndrome.

Until the development in 1980 by William Norwood of a staged palliative surgical procedure for hypoplastic left heart syndrome (HPLHS), there was no treatment for that condition. With medical developments in the 1980s, parents had the option of the Norwood procedure, transplantation or comfort care for a child born with HPLHS. With an improvement in the survival rate for the Norwood procedure from an initial 30% to now better than 80%, some physicians believe that comfort care should no longer be an option. If, however, medically sophisticated parents, who know the neurological and motor skills impairments that accompany HPLHS, object to the surgery, they are allowed to opt for comfort care. This two-pronged approach to medical treatment seems to violate the norms on equity and fairness in the care of the patient. Parents need to be informed about long-term neurological and motor skill development as well as survival rates to give informed consent.

Role of iNO in the modulation of pulmonary vascular resistance.

Inhaled nitric oxide (iNO) has quickly become a standard therapy for term and near-term infants with hypoxic respiratory failure and persistent pulmonary hypertension. Its effect on the lung is believed to be through the stimulation of soluble guanylyl cyclase and the increased production of cyclic guanosine 3',5'-monophosphate (cGMP). However, in addition to pulmonary vasodilation and a decrease in pulmonary vascular resistance, nitric oxide (NO) shows several additional potential beneficial effects on the lung. This article reviews NO mechanisms of action, early clinical trial of iNO and clinical aspects for the use of iNO in acute respiratory failure of the term and near-tem neonates.

Approaches to end-of-life decision-making in the NICU: insights from Dostoevsky's The Grand Inquisitor.

For many parents stopping life-sustaining medical treatment on their dying infant is psychologically impossible. Dostoevsky's insights into human behavior, particularly the fact that individuals do not want the anxiety and guilt associated with responsibility for making difficult decisions, might change the way physicians approach parents for permission to withdraw life-prolonging medical interventions on dying infants.

Resuscitation of the preterm infant against parental wishes.

Over the past 40 years, the norms on who is to make treatment decisions for newborns, and on what standards, have been significantly altered and revised. Today the standard for treatment of newborns is the "best interest" of the child. A recent ruling of the Texas Supreme Court authorizing a doctor to resuscitate a potentially viable very premature newborn over the parents' objection is a challenge to that standard.

Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group.

BACKGROUND: Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. METHODS: In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. RESULTS: Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. CONCLUSIONS: Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Physicians' refusal to provide life-prolonging medical interventions.

The intense and ongoing debate on physicians' right to refuse requested life-prolonging medical interventions highlights one of the emerging problems in modern medicine: the limits, if any, to a patient (or proxy's) claim to requested treatment. How is the physician to respond to requests for treatment believed by the physician to be futile, ineffective, or inappropriate? Three cases, Baby L, the extracorporeal membrane oxygenation (ECMO) baby, and Baby K, help focus the ethical and legal issues in this debate.

Parental discretion in refusal of treatment for newborns. A real but limited right.

Manslaughter charges were brought in Lansing, Michigan against Gregory Messenger, a local dermatologist, for removing his extremely premature infant son from a ventilator in a neonatal intensive care unit. The issue in the case was the degree of intervention required for the newborn for whom the parents had been counseled that there was a 50% to 70% mortality and that if the child did survive, there was a 20% to 40% chance of severe intraventricular hemorrhage and a likelihood of substantial respiratory problems. In light of those grim data, the parents requested that no aggressive measures be undertaken. The neonatologist instructed her physician's assistant to ventilate if the child was "vigorous." The homicide charge was based on Gregory Messenger's failure to provide proper medical treatment for his infant son.

Prediction of cerebral blood flow in fetal lambs by carotid artery ultrasonic flow transducer.

To determine whether common carotid artery blood flow measured with an ultrasonic flow transducer would predict brain blood flow in fetal sheep, we measured unilateral common carotid artery blood flow and compared this to simultaneous measurements of total brain blood flows made by radioisotope-labelled microsphere techniques. We studied anaesthetized, exteriorized fetal sheep with intact umbilical circulation after ligation of extracranial, extracerebral arteries and placement of a common carotid artery flow transducer; five fetuses at 120 d gestation had 19 total comparison measurements. As measured by microsphere technique, mean basal blood flow during undisturbed conditions to regional brain areas were similar to normal values reported for the exteriorized ovine fetus; these flows were highly correlated to fetal PaCO2 and successfully varied over a wide range (total brain 9.1-200.4 ml/min/100g and total cortex 6.1-153.1 ml/min/100g) in subsequent experimental conditions of hypercapnia or occluded blood flow. Blood flow as measured by flow transducer significantly correlated (P < or = 0.01) with microsphere measurements of blood flow to total brain (r = 0.56) and total cortex (r = 0.62); regional flow to cerebellum (r = 0.70) and thalamus (r = 0.60) also correlated to transducer measurements. Stronger correlations were observed at low-flow conditions to total brain (r = 0.83) and to total cortex (r = 0.90). As measured by microsphere technique, right and left cortical blood flows were highly correlated (P = 0.0001, r = 0.97), indicating that the flow transducer or surgical manipulation did not disturb the distribution of cerebral blood flow. The mean values for zero flow reference of the transducer were < 1.5% of mean basal flow values. It is concluded that the common carotid artery flow transducer technique developed in this study provides an accurate prediction of blood flow to total brain and total cortex over a wide range of values in fetal sheep. This technique provides a methodologic advantage to sequential experimental interventions and may prove advantageous to studies of fetal sheep cerebral circulation.

Which birthweight groups contributed most to the overall reduction in the neonatal mortality rate in the United States from 1960 to 1986?

We determined the relative contributions of individual birthweight groups to the reduction in neonatal mortality rate (NMR) of US singleton livebirths from 1960 to 1986, the period during which neonatal intensive care was introduced and became established. Changes in the NMR for each race (non-white/white) and birthweight group were assessed in terms of three components of NMR (1) birthweight-specific neonatal mortality rate (BWS-NMR), (2) birthweight distribution, and (3) the interaction resulting from simultaneous changes in BWS-NMR and birthweight distribution. Overall, NMR decreased from 16.7 per 1000 livebirths in 1960 to 5.5 per 1000 livebirths in 1986. This reduction was achieved mainly by improvements in the BWS-NMRs of all birthweight groups. Neonates who weighted > 1.5 kg at birth were the major contributors to the overall reduction in the NMR; approximately two-thirds of total reduction in NMR between 1960 and 1980 and 52.6% of the total reduction between 1980 and 1986 occurred in the > 1.5 kg birthweight groups. Our study demonstrates that with the introduction of neonatal intensive care, survival of infants with birthweights > 1.5 kg improved markedly and that this improvement accounted for most of the decline in the neonatal mortality rate in the United States from 1960 to 1986. Therefore, in measuring the effectiveness of neonatal intensive care, the assessment should include not only very low birthweight (< 1.5 kg) but all birthweight groups.

Concentration-dependent effects of cocaine on monoamine-induced constriction of cannulated, pressurized cerebral arteries from fetal sheep.

Drugs, such as cocaine, which may alter monoamine neurotransmitter responsiveness, could adversely affect the regulation of cerebral vasculature. Cocaine exhibits at least two mechanisms that may alter vascular responsiveness: synaptic uptake inhibition, which may augment response to stimulation, and Na+ channel inhibition, which may attenuate response. To help elicit the concentration-dependent effects of cocaine, the effects of cocaine on monoamine neurotransmitter responsiveness were studied in vitro on fetal sheep cerebral arteries (120 days gestation). The changes in diameter of segments of cannulated, pressurized fetal sheep cerebral artery were measured with a videomicroscaler system. Cumulative concentration-response curves (10(-10) to 10(-4)M) were generated for two monoamines, norepinephrine and serotonin, alone and in the presence of cocaine (10(-5) or 10(-4)M). Cocaine caused concentration-dependent alteration of response. At 10(-4)M, cocaine attenuated mean maximal norepinephrine-induced vasoconstriction 46.2% (P < 0.05). At 10(-5)M, cocaine increased sensitivity to norepinephrine (log EC50 decreased -6.63 +/- 0.09 to -7.11 +/- 0.03) and to serotonin (log EC50 decreased -7.24 +/- 0.04 to -7.81 +/- 0.09) (P < 0.05). The higher concentration of cocaine (10(-4)M) did not significantly decrease log EC50 norepinephrine. Cocaine (10(-4)M) also attenuated the response to single doses of norepinephrine (10(-6)M) and serotonin (10(-6)M) by 26.5% and 40.0%, respectively (P < or = 0.05). It is concluded that cocaine has concentration-dependent effects on vasoconstriction of the fetal sheep cerebral artery in vitro. This cocaine-induced alteration of cerebral vascular responsiveness to monoamines may be important in the regulation of fetal cerebral blood flow.

Effects of cocaine, benzoylecgonine, and cocaine metabolites in cannulated pressurized fetal sheep cerebral arteries.

Prenatal cocaine exposure has been reported to cause neurovascular complications in the developing fetus. To determine the effect of cocaine on the fetal neurovasculature, we studied the in vitro response of fetal sheep cerebral arteries to cocaine and cocaine metabolites. The change in diameter of cannulated pressurized cerebral artery segments from fetal sheep was measured using a video microscaler system. Cumulative dose-response curves (10(-12)-10(-4) M) were generated for cocaine and the major cocaine metabolites in fetal sheep cerebral artery segments. Benzoylecgonine (> 10(-10) M) also caused concentration-dependent constriction, and cerebral artery segments were significantly more sensitive to benzoylecgonine than to cocaine and the other cocaine metabolites. Benzoylecgonine-induced vasoconstriction appeared to be mediated through alpha-adrenergic stimulation, predominantly through stimulation of alpha 1-adrenergic receptor subtypes. We conclude that cocaine and benzoylecgonine cause significant fetal cerebral artery vasoconstriction in vitro. Cocaine and benzoylecgonine-induced cerebral vasoconstriction may contribute to the perinatal neurovascular complications associated with prenatal cocaine exposure.

Hemodynamic and cerebral blood flow effects of cocaine, cocaethylene and benzoylecgonine in conscious and anesthetized fetal lambs.

We studied hemodynamic responses to cocaine and two metabolites, cocaethylene (CE) and benzoylecgonine (BE), in five conscious ewes and fetuses, which were chronically instrumented to measure maternal and fetal aortic pressures, uterine artery blood flow (Qutr) and fetal common carotid artery blood flow (Qcar) to estimate cerebral blood flow. Conscious ewes of 121 to 128 days' (mean, 124 days) gestation received 1.0 mg/kg i.v. of cocaine (n = 12 doses), CE (n = 14) or BE (n = 12) and responses were compared to seven additional ewes and fetuses at 115 to 127 days' (mean, 122 days) gestation each given one 1.0 mg/kg i.v. of cocaine dose while anesthetized with halothane. In conscious ewes, cocaine, CE and BE all caused maternal and fetal hypertension. Qutr decreased 31% after cocaine, increased 37% after CE and was unaffected by BE. Cocaine induced fetal hypoxemia; fetal arterial blood gas tensions were unaffected by CE or BE. Fetal Qcar was reduced 51% at peak effect by cocaine (57 +/- 8 to 28 +/- 6 ml/min) and 46% by CE (65 +/- 7 to 33 +/- 6 ml/min), and was unaffected by BE because of variable subject response, although all three drugs increased calculated fetal cerebral vascular resistance. The cocaine-induced changes were attenuated or abolished in anesthetized sheep. Fetal/maternal peak serum concentrations were 100% for CE and only 2% for BE; amniotic fluid concentrations of CE were 10-fold higher than both fetal and maternal serum concentrations. Cocaine and cocaine metabolites have important effects on maternal and fetal hemodynamics and fetal cerebral blood flow which, for CE and BE, are not dependent on decreased uterine blood flow or fetal hypoxemia.