Transplacental lidocaine intoxication.

Neonatal seizures are frequent in neonatal intensive care and the most common cause is perinatal asphyxia. Among other causes, toxin exposure is rare.We present a boy with an uneventful vaginal birth, who presented one hour after birth with apnea, hypotonia, mydriasis, tongue fasciculation, and tonic seizures. There was no hypoxic ischemic encephalopathy and brain imaging was normal. Toxicology screening revealed a toxic concentration of lidocaine in his blood. The intoxication was transplacental, as a cord blood sample confirmed the toxic level. This was probably due to maternal perineal nerve block with lidocaine.Perineal local infiltration of lidocaine is not without risk for the newborn. Toxicology screen remains an important tool in the work-up of neonatal seizures and sudden unexpected postnatal collapse.

Might asphyxia cause respiratory inhibition after crying in mature infants?

BACKGROUND: To clarify the timing of injury in utero causing respiratory inhibition after crying (RIAC), the relationship between asphyxia and RIAC was investigated in infants whose gestational age was ≥ 36 weeks. METHODS: RIAC and cranial ultrasound abnormalities were examined for retrospectively in infants treated in the neonatal intensive care unit from April 2004 through March 2009. All included infants were gestational age ≥ 36 weeks and had an Apgar score <4 points at 1 min. The relationship between RIAC and perinatal factors was also examined. RESULTS: Twenty-six infants were included. Three infants had RIAC, seven infants had poor prognosis, and nine infants had ultrasound abnormalities in the ganglionic eminence (GE). There was a significant relationship between RIAC and ultrasound abnormalities in the GE (P= 0.032). Poor prognosis was significantly associated with low Apgar score at 5 min (P ≤ 0.001), disseminated intravascular coagulation (P= 0.047), hypoxic ischemic encephalopathy (P= 0.028), and brain hypothermia therapy (P= 0.028). There was no significant relationship between RIAC and poor prognosis. All infants had ultrasound abnormalities in the GE on the day of birth. CONCLUSION: Damage occurring in utero prior to 36 weeks gestation might cause increased echogenicity or cyst formation in the GE, potentially disturbing maturation of the respiratory center with the development of RIAC.

Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels in neonatal brain.

Ablation of the murine Slc5a3 gene results in severe myo-inositol (Ins) deficiency and congenital central apnea due to abnormal respiratory rhythmogenesis. The lethal knockout phenotype may be rescued by supplementing the maternal drinking water with 1% Ins. In order to test the hypothesis that Ins deficiency leads to inositide deficiencies, which are corrected by prenatal treatment, we measured the effects of Ins rescue on Ins, phosphatidylinositol (PtdIns) and myo-inositol polyphosphate levels in brains of E18.5 knockout fetuses. As the Slc5a3 gene structure is unique in the sodium/solute cotransporter (SLC5) family, and exon 1 is shared with the mitochondrial ribosomal protein subunit 6 (Mrps6) gene, we also sought to determine whether expression of its cognate Mrps6 gene is abnormal in knockout fetuses. The mean level of Ins was increased by 92% in brains of rescued Slc5a3 knockout fetuses (0.48 versus 0.25 nmol/mg), but was still greatly reduced in comparison to wildtype (6.97 nmol/mg). The PtdIns, InsP(5) and InsP(6) levels were normal without treatment. Mrps6 gene expression was unaffected in the E18.5 knockout fetuses. This enigmatic model is not associated with neonatal PtdIns deficiency and rescue of the phenotype may be accomplished without restoration of Ins. The biochemical mechanism that both uniformly leads to death and allows for Ins rescue remains unknown. In conclusion, in neonatal brain tissue, Mrps6 gene expression may not be contingent on function of its embedded Slc5a3 gene, while inositide deficiency may not be the mechanism of lethal apnea in null Slc5a3 mice.

Maturation of cough and other reflexes that protect the fetal and neonatal airway.

Although aspiration of contaminated amniotic fluid and gastric contents is common at birth, anecdotal evidence indicates that coughing occurs rarely if at all. Studies in which cough and other airway protective responses have been stimulated by introducing a small bolus of water or saline into the pharynx of sleeping infants have found that the predominant responses are swallowing, apnea and laryngeal closure. Coughing is rare. Collectively, these responses are known as the laryngeal chemoreflexes (LCR). These are mediated by receptors in the inter-arytenoid space. The LCR has been studied extensively in animal models. Upper airway infection increases the responses and in this case coughing becomes a common component. Studies in animal models indicate that with maturation, apnea and swallowing components of the LCR decrease while cough becomes increasingly prominent.

Malfunction of respiratory-related neuronal activity in Na+, K+-ATPase alpha2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons.

Na+, K+-ATPase 2 subunit gene (Atp1a2) knock-out homozygous mice (Atp1a2-/-) died immediately after birth resulting from lack of breathing. The respiratory-related neuron activity in Atp1a2-/- was investigated using a brainstem-spinal cord en bloc preparation. The respiratory motoneuron activity recorded from the fourth cervical ventral root (C4) was defective in Atp1a2-/- fetuses of embryonic day 18.5. The C4 response to electrical stimulation of the ventrolateral medulla (VLM) recovered more slowly in Atp1a2-/- than in wild type during superfusion with Krebs' solution, consistent with the high extracellular GABA in brain of Atp1a2-/-. Lack of inhibitory neural activities in VLM of Atp1a2-/- was observed by optical recordings. High intracellular Cl- concentrations in neurons of the VLM of Atp1a2-/- were detected in gramicidin-perforated patch-clamp recordings. The alpha2 subunit and a neuron-specific K-Cl cotransporter KCC2 were coimmunoprecipitated in a purified synaptic membrane fraction of wild-type fetuses. Based on these results, we propose a model for functional coupling between the Na+, K+-ATPase alpha2 subunit and KCC2, which excludes Cl- from the cytosol in respiratory center neurons.

Thalamic locus mediates hypoxic inhibition of breathing in fetal sheep.

The effects of lesions rostral to the brain stem on breathing responses to hypoxia were determined in chronically catheterized fetal sheep (>0.8 term). These studies were designed to test the hypothesis that the diencephalon is involved in hypoxic inhibition of fetal breathing. As in normal fetuses, hypoxia inhibited breathing with transection rostral to the thalamus or transection resulting in virtual destruction of the thalamus but sparing most of the parafascicular nuclear complex. Neuronal lesions were produced in the fetal diencephalon by injecting ibotenic acid through cannulas implanted in the brain. Hypoxic inhibition of breathing was abolished when the lesions encompassed the parafascicular nuclear complex but was retained when the lesions spared the parafascicular nuclear region or when the vehicle alone was injected. A new locus has been identified immediately rostral to the midbrain, which is crucial to hypoxic inhibition of fetal breathing. This thalamic sector involves the parafascicular nuclear complex and may link central O2-sensing cells to motoneurons that inhibit breathing.

Fetal breathing movements are associated with changes in compliance of the left ventricle.

We have tested the hypothesis that the limited fetal ventricular distensibility is not only an intrinsic cardiac characteristic but is also contributed to by the pressure exerted by the intrathoracic organs. To this purpose we have studied the diastolic cardiac function by Doppler velocimetry in 11 fetuses during fetal breathing and in 22 fetuses during apnea, controlling for gestational age at examination and heart rate. Inspiration was associated a significant increase in left ventricular compliance, as measured by deceleration time (inspiration 182.6 +/- 15.5 s vs. expiration 137.1 +/- 13.1 s vs. apnea 151.7 +/- 51.8 s), and in ventricular filling, as measured by velocity time integral (inspiration 0.086 +/- 0.020 m vs. expiration 0.064 +/- 0.014 m vs. apnea 0.065 +/- 0.011 m), compared with both the expiration and apnea groups. These increases most likely reflect changes in venous return and ventricular end-diastolic volume secondary to a decrease in intrathoracic pressure during fetal breathing.

Maturation of spontaneous fetal diaphragmatic activity and fetal response to hypercapnia and hypoxemia.

The electromyogram (EMG) of the diaphragm, lateral rectus, and nuchal and hindlimb muscles were studied during spontaneous activity and during hypercapnia or hypoxemia in eight fetal sheep from 0.5 to 0.8 gestation (73-128 days). At the earliest gestational age, diaphragmatic EMG activity was mainly tonic and associated with tonic activity of somatic muscles. The stimulus for the diaphragmatic activity originated centrally. Brief periods of a rapid-eye-movement (REM) state characterized by phasic lateral rectus and diaphragmatic activity and absence of nuchal activity were recognized. Furthermore, from 0.5 to 0.7 gestation onward, activity of all muscles increased. Thereafter increased specificity of activity in relation to the apparent REM and non-rapid-eye-movement (NREM) state occurred. With maturation, phasic diaphragmatic activity increased at the expense of tonic activity. The most striking effect of maturation on apnea was a greater proportion of apnea lasting greater than 1 min, but the total duration of apnea as a percent of a total recording remained unchanged. The quantitative response to hypercapnia during maturation was independent of the pattern of spontaneous diaphragmatic activity. Hypercapnia at 0.5 gestation changed the pattern of diaphragmatic EMG activity from mainly tonic to phasic. Thus the central chemoreceptors and appropriate neuronal pathways are present and functional as early as 0.5 gestation. Hypercapnia at 0.5 gestation caused a shift in diaphragmatic EMG power to lower frequencies similar to that found during control conditions in the older fetus. This might suggest that during maturation there is increased recruitment of phrenic motoneurons. Hypoxemia abolished tonic somatic activity at 0.5 gestation and decreased phasic diaphragmatic activity at more advanced gestational ages. Therefore the central inhibitory mechanisms of hypoxemia are developed by 0.5 gestation.

Upper airway resistances in fetal sheep: the influence of breathing activity.

Fetal breathing movements (FBM) and lung liquid volume are known to affect lung development, but little is known about mechanisms controlling movement of liquid through the upper respiratory tract (URT). Therefore we measured resistances of the URT in 8 unanesthetized fetal sheep during late gestation while FBM were monitored from pressures in the lower trachea or from electromyogram of respiratory muscles. URT resistance to liquid flow toward the amniotic sac increased from 3.5 +/- 1.9 Torr X ml-1 X min during episodes of FBM to 21.1 +/- 5.7 Torr X ml-1 X min during apnea. Laryngeal resistance during apnea was greater (P less than 0.001) than supralaryngeal resistance in each of six fetuses in which URT resistance was partitioned. Fetal paralysis abolished the increase in laryngeal resistance to efflux that was previously related to the high-voltage electrocortical state and apnea. We were unable to quantify URT resistance to fluid movement toward the lungs because the larynx acted as a valve, permitting flow toward the lungs only in the presence of FBM. The supralaryngeal portion of the URT also apparently acts as a valve, normally preventing the entry of amniotic fluid into the pharynx. These findings help to explain our earlier observations that efflux of liquid from the fetal lungs is greater during episodes of FBM than during apnea.