Disposition of midazolam in asphyxiated neonates receiving therapeutic hypothermia--a pilot study.

Moderate hypothermia has become an established therapy for asphyxiated neonates. Midazolam is a frequently used sedative for this indication, although it has never been investigated how therapeutic hypothermia and asphyxia influence midazolam metabolism in neonates.9 asphyxiated newborns were treated with whole body hypothermia of 32-34°C for 72 h and all of them received continuous midazolam infusion for sedation. Serum concentrations of midazolam and its metabolites 1-hydroxy-midazolam and 4-hydroxy-midazolam were measured during hypothermia and the rewarming period. Renal and hepatic parameters were assessed to take into account the influence of asphyxia related renal or hepatic impairment.We found a high interindividual variability of serum midazolam concentrations in asphyxiated neonates with therapeutic hypothermia; median midazolam concentration was 369.3 ng/ml (minimum 36.6; maximum 3 218.6 ng/ml). The population pharmacokinetic model revealed a midazolam clearance of 2.57 ml/kg/min, comparable to midazolam clearances observed in normothermic critically ill neonates. However, midazolam clearance was significantly decreased in patients with asphyxia related renal and hepatic impairment.It seems that isolated hypothermia does not significantly influence midazolam metabolism. However, neonates with asphyxia related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations. In addition pronounced interindividual variability of midazolam metabolism may contribute to dangerously high midazolam concentrations.

The flexion withdrawal reflex reveals an increasing threshold during the first year of life and is influenced by the infant's state of consciousness.

BACKGROUND: The idea that preterm and term infants are capable of experiencing pain is now widely accepted. However, there is still insufficient knowledge how pain perception develops throughout infancy. A promising approach to quantify the level of spinal excitability in infants is to measure cutaneous sensitivity by the flexion withdrawal reflex (WR). In our study we wanted to test how the threshold of the WR develops in healthy infants during the first year of life. Furthermore, we aimed to analyse the impact of the state of consciousness on the reflex threshold. PATIENTS AND METHOD: In 44 healthy infants we tested the threshold of the WR with calibrated von-Frey-Filaments at the age of 3 days as well as with 4, 12, 26 and 52 weeks. To analyse the influence of the state of consciousness on the reflex threshold, we documented at 12, 26 and 52 weeks whether the infants were quietly awake or lightly asleep during testing. RESULTS: The median threshold of the WR increased during the first year of life from 1.2 g up to 4.6 g at the age of 1 year. At 12, 26 and 52 weeks we found significantly lower thresholds in sleeping infants compared to infants being awake (p=0.004, p<0.001 and p=0.086, respectively). CONCLUSION: The threshold of the flexion withdrawal reflex increases during infancy, probably reflecting neuronal maturation processes in the first year of life. Besides postnatal age, the threshold of the WR also depends on the state of consciousness. Therefore, future studies about the WR should consider postnatal age as well as the state of consciousness.

Angiotensin II receptor blocker induced fetopathy: 7 cases.

BACKGROUND: During a period of 12 months 7 newborns with a partially severe fetopathy caused most probably by maternal sartan-intake in pregnancy were treated in 5 German teaching hospitals. Sartans antagonize the effect of angiotensin II at the AT1-receptor and are used to treat arterial hypertension. METHOD: We presented 2 cases at the yearly GNPI meeting 2010 and we were informed about similar cases in other German teaching hospitals which we brought together in this publication. RESULTS: In the presented cases, maternal sartan intake was noticed at different times in pregnancy and was in part discontinued some weeks before delivery. In all pregnancies oligohydramnios was present and fetal kidneys displayed a hyperechogenic structure on ultrasound. The newborns' postnatal course varied: oligohydramnios sequence with lung hypoplasia, arterial hypotension and renal insufficiency were the predominant problems of the first days of life. The majority (4/7) of infants did not survive this period, in other cases there was a complete (1/7) recovery of renal function whereas others survived with renal impairment (2/7), in part requiring chronic dialysis. Further distinctive features seen frequently were disturbances of cranial ossification and flaccid paralysis of hands and feet with deviations as well as sensorineural hearing loss. CONCLUSION: These case reports again underline the hazardousness of maternal sartan intake with potential fatal outcome for the newborn. Though the use of sartans in pregnancy is contraindicated and several case reports of sartan induced fetopathies exist, the risk of sartan treatment generally seems to be underestimated.

Comparison of sufentanil versus fentanyl in ventilated term neonates.

BACKGROUND: Increasingly frequent applications of opioid analgesics in neonatal intensive care require the evaluation of efficacy and side effects. PATIENTS: Mechanically ventilated term neonates were consecutively enrolled. METHODS: In a double-blind randomized trial 20 newborns received a continuous intravenous infusion of fentanyl (n=10) or sufentanil (n=10) in an assumed equipotent dose of 7:1. The analgesic dose was individually adjusted according to sedation scores. The period between cessation of analgesic medication and successful extubation (weaning time), adverse drug effects and urinary cortisol concentrations were evaluated. RESULTS: No significant difference of weaning time was seen between fentanyl and sufentanil group (mean weaning time (+/-SD) of fentanyl group 520+/-381 min, median 380 min; sufentanil group 585+/-531 min, median 405 min, p=0.78, 2-tailed U-Test, Mann and Whitney). The mean opioid dose resulted in a 10:1 ratio (fentanyl 4.11 microg/(kg x h) vs sufentanil 0.41 microg/(kg x h)). We found no marked differences in sedation levels, blood pressure, heart rate, oxygenation index, co-medication or urinary cortisol levels. In both groups similar adverse effects were assessed including respiratory depression, mild withdrawal symptoms or decrease of gastrointestinal motility. CONCLUSION: In our study sufentanil did not reduce the weaning period in ventilated term neonates when compared to fentanyl. The equipotent dose ratio for fentanyl/sufentanil was 10:1. According to sedation scores both substances provided effective pain and stress protection.

Remifentanil for INSURE in preterm infants: a pilot study for evaluation of efficacy and safety aspects.

AIM: To evaluate intubating conditions, extubation times and outcome in preterm infants receiving remifentanil as induction agent for the INSURE procedure. METHODS: In twenty-one preterm infants of 29 to 32 weeks gestation and signs of respiratory distress, we utilized remifentanil as induction agent for the INSURE procedure. Following intubation and surfactant application, the infants were mechanically ventilated until respiratory drive was judged to be satisfactory for continuing CPAP therapy. Intubating conditions were classified by our own scoring system by rating limb movements, coughing and breathing. Heart rate, blood pressure and oxygen saturation were recorded during the entire INSURE procedure. RESULTS: Remifentanil provided excellent or good intubating conditions in all patients. We observed no serious side effects after remifentanil infusion, in particular, no thorax rigidity, clinically significant bradycardia or arterial hypotension. Average extubation time after surfactant administration was 16.9 min (1-45 min); none of the infants had to be reintubated. Following extubation, the infants required only 3.3 days (1-8 days) of CPAP therapy. None exhibited serious complications of prematurity like periventricular leucomalacia, intraventricular haemorrhage >I degree, necrotizing enterocolitis or retinopathy. CONCLUSION: In this pilot study, INSURE with remifentanil was associated with good intubating conditions and early extubation resulting in an excellent neonatal outcome.

Rapid development of life-threatening complete atrioventricular block in Kearns-Sayre syndrome.

Kearns-Sayre syndrome is a rare mitochondrial disorder with defined diagnostic criteria. Knowledge of these diagnostic criteria and early diagnosis are important to ensure periodic electrocardiograms for identification of cardiac conduction disorders, which are the most important prognostic factor of the disease. We report on a 9-year-old girl with rapid development of a life-threatening complete atrioventricular block within 10 months and discuss the importance and time interval of regular electrocardiograms. Our patient survived by placing a temporary transvenous pacemaker lead followed by permanent pacemaker implantation a few days later.