Prenatal cocaine exposure alters postnatal ornithine decarboxylase activity in rabbit brain.

Ornithine decarboxylase, a modulator of tissue growth during fetal and neonatal mammalian development, serves as a sensitive marker enzyme for perturbations in neural development. To test the hypothesis that cocaine is a central nervous system neurodevelopmental teratogen through mechanisms involving direct cellular injury, we measured ornithine decarboxylase activity in brain sections of 4- to 6-day-old rabbit pups which were prenatally cocaine exposed and in pair-fed and free-fed controls. Rabbit does were implanted with the osmotic minipump prior to Gestational Day 10 and cocaine and/or sterile water was delivered between Gestational Days 10 and 32. The flow rate in the cocaine group was calculated to provide a daily cocaine dose of 30 mg/kg/day. Pups were sacrificed, brains were dissected into the cortex, pons, and medulla, and ornithine decarboxylase activity was measured. When compared to the pair-fed group, prenatal cocaine exposure significantly decreased ornithine decarboxylase activity in the cortex (0.531 +/- 0.070 nmol/g/h SEM vs 0.913 +/- 0.201 nmol/g/h SEM; cocaine vs pair fed, respectively; P < or = 0.05) and in the pons (0.533 +/- 0.036 nmol/g/h SEM vs 0.728 +/- 0.075 nmol/g/h SEM, cocaine vs pair fed, respectively; P < or = 0.05) but not in the medulla (0.374 +/- 0.040 nmol/g/h SEM vs. 0.392 +/- 0.045 nmol/g/h SEM, cocaine vs pair fed, respectively; P > 0.05). Although there were no statistically significant differences in ornithine decarboxylase activity between the cocaine-exposed group and the free-fed group in any brain region, all regions showed a relative decrease in ornithine decarboxylase activity with prenatal cocaine exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prenatal cocaine on the ventilatory response to hypoxia in newborn rabbits.

Recently, investigators have reported an alteration of postnatal respiratory pattern, deficient hypoxic arousal from sleep, and an increased incidence of sudden infant death syndrome (SIDS) among human infants exposed to cocaine prenatally, thus suggesting that prenatal cocaine exposure may perturb the maturation of respiratory control thereby increasing the risk for SIDS. To investigate the effects of prenatal cocaine on postnatal respiration, we evaluated the ventilatory response to 0.21 FIO2 (baseline) and at 0.15, 0.10, and 0.08 FIO2 by the barometric method on days 4-5 of life in 23 New Zealand White rabbit pups born to cocaine-exposed (30 mg/kg/day of cocaine HCl by continuous subcutaneous infusion), pair-fed and free-fed does. The chamber pressure deflection (proportional to VT after appropriate calculation) was computer-sampled at 200 Hz when the unanesthetized pups were resting quietly with no gross body movements. Recording was made after 10 min acclimatization to a specific FIO2. We found that baseline ventilation did not differ significantly among study groups. However, minute ventilation (VI), inspiratory flow (VT/TI), tidal volume (VT), increased significantly with hypoxia to peak values at 0.08 FIO2 in pair-fed and free-fed pups but these measurements did not increase significantly in cocaine-exposed pups. Our finding of a deficient second phase of the hypoxic ventilatory response among cocaine-exposed pups supports the hypothesis that prenatal cocaine perturbs the maturation of respiratory control.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prenatal cocaine exposure on perinatal morbidity and postnatal growth in the rabbit.

Prenatal cocaine (CC) exposure may result in increased fetal loss, growth retardation, altered neurodevelopment, and sudden infant death syndrome (SIDS). We sought to establish an animal model for prenatal cocaine exposure which (1) would allow us to distinguish the direct effects from the indirect and nutritional effects of the drug, and (2) might be used to address questions of cocaine's toxicity, specifically to the developing respiratory control system. The study design included 38 New Zealand White rabbit does among CC, pair-fed (PF), and free-fed (FF) groups. Miniosmotic pumps were implanted in each doe on day 10 of timed gestation providing continuous subcutaneous administration of either 30 mg/kg/day of cocaine HCl in H2O (CC) or sterile H2O alone (PF and FF). Mean (SEM) plasma cocaine concentration was 1.71 +/- 0.21 mumol/l (519.4 +/- 64.4 ng/ml). Pregnancy outcome compared for incidence of stillbirth, maternal death, spontaneous abortion, and gross malformation among 211 pups was significant only for increased stillbirths among CC pups (18%, p less than 0.04) as compared to PF (6%) and FF pups (7%). External and renal malformation and postnatal weight, crown-rump length, and snout-occiput head circumference for pups aged 4 and 5 days of age did not differ among groups. The direct effects of prenatal cocaine evaluated in our model do not reproduce the altered perinatal outcome observed among humans. However, our results do not determine if physiologic function has been altered. Investigation of the physiologic and pathologic abnormalities that are relevant to this human condition, specifically to the developing respiratory control system, should add clarity to the mechanism of action of cocaine during pregnancy.

Effects of continuous low-frequency pacing on immature canine diaphragm.

Although diaphragm pacing has been shown to be a practical method of supporting ventilation in children, its usefulness has been limited because of concern that continuous (24 h/day) diaphragm pacing would fatigue and damage the diaphragm. We examined the functional and structural effects of continuous low-frequency diaphragm pacing on the left hemidiaphragm of five immature dogs aged 65 +/- 2 (SD) days at onset of pacing. Stimulus parameters approximated those required to pace infants: frequency 11.1 Hz, inspiratory time 810 ms, and respiratory rate 20 breaths/min. Animals were paced 24 h/day for 24-28 days. Paced tidal volumes and airway occlusion pressures were unchanged at low (less than 15 Hz) stimulus frequencies but were reduced at high (greater than 20 Hz) stimulus frequencies. Although histologically the paced hemidiaphragms appeared normal, histochemical studies showed a conversion from a mixture of type I (54%) and type II (46%) fibers to a uniform population of type I fibers with high oxidative enzyme activity. Transformation of muscle type was also demonstrated by pyrophosphate gel electrophoresis; fast and slow isomyosin bands were noted in control specimens, whereas only slow isomyosin was identified in paced specimens. Thus, in immature dogs, continuous low-frequency pacing affects both function and structure of the diaphragm.

Assessing validity of infant monitor alarms with event recording.

We evaluated the performance of an event recorder system in a large, consecutive series of referred monitored patients to determine the relative incidence of true apnea and true bradycardia, false alarms, and alarms for movement or a loose lead. In addition, we developed an event classification system based on the reason for the event being recorded. The recorder stored transthoracic impedance and electrocardiogram signals on a floppy disk before, during, and after each monitor alarm. These events on 302 disks from 83 patients were analyzed and classified as true, false, or movement-loose lead. Of 14,131 events, only 8% were caused by apnea or bradycardia (true events). Of true events, 70% were triggered by apnea and 30% by bradycardia. These true events occurred in 48% of the patients. False alarms constituted 23%, and movement-loose lead 69%, of all events. Even when movement-loose lead events were excluded, nearly three of four events were found to be false. Event recording proved helpful clinically, allowing discontinuation of the monitor in 49% of patients, modification of monitor alarm settings, or reassurance and counseling for parents.