Robert P. Lemke

Recent advances in understanding the pathogenesis of nitrofen‐induced congenital diaphragmatic hernia

In this review, we discuss recent advances in the study of the pathogenesis of congenital diaphragmatic hernia (CDH). Much of the research has involved the use of an animal model of CDH in which diaphragmatic defects are produced in fetal rats by administering the herbicide nitrofen to dams during mid‐gestation. The animal model is described and the relevance to the human condition is discussed. The data derived from the animal studies are critically assessed in the context of commonly cited hypotheses proposed for the pathogenesis of CDH. Finally, experimental strategies are proposed for systematically examining the normal and pathological formation of the pleuroperitoneal fold.

MMP-2 and MMP-9 and their tissue inhibitors in the plasma of preterm and term neonates.

Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in a variety of physiologic growth and development and pathophysiologic inflammatory conditions. We hypothesized that 1) MMP-2 and -9 plasma activities and TIMP-1 and -2 plasma concentrations in preterm and term neonates were dependent on the gestational and postnatal age; and 2) the respective MMP and their inhibitors were deranged in the development of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) in preterm neonates. From 1998 to 1999, blood samples were collected from preterm neonates (25–36 wk gestation) with or without BPD and/or IVH as well as from healthy term (37–40 wk gestation) neonates during the first 28 d of life. MMP-2 and MMP-9 plasma activities were measured by zymography; TIMP-1 and TIMP-2 plasma concentrations were determined by ELISA. In neonates without BPD or IVH (n = 50), MMP-2 and MMP-9 plasma activities both appeared to be gestational age dependent, with the highest levels observed in neonates of 33–36 wk gestation. TIMP-1 plasma concentration was highest in term neonates but no gestational difference was found in TIMP-2. Only MMP-9 showed a 50% decrease after d 1 in the first postnatal month. Twelve preterm infants with BPD and/or IVH had significantly lower MMP-2 but higher MMP-9 activity and higher TIMP-1 concentration than those of corresponding neonates without BPD or IVH. These findings show the gestational age–dependent expression of plasma MMP activities and their inhibitors. MMP and TIMP may be involved in the feto-neonatal development and may contribute to the pathogenesis of BPD and/or IVH in critically ill preterm neonates.

Airway closure during mixed apneas in preterm infants: is respiratory effort necessary?

Airway closure during mixed apneas in preterm infants may be due to lack of tone in the upper airway followed by collapse and obstruction or diaphragmatic action inducing obstruction. We examine whether respiratory efforts are necessary for airway closure using a new method of detecting airway obstruction, based on the disappearance of an amplified cardiac pulse observed on the respiratory flow tracing. We analyzed 198 episodes of mixed apnea of various lengths (> or = 3 seconds) observed in 33 preterm infants (birth weight, 1.4 +/- 0.1 kg [mean +/- SEM]; study weight, 1.7 +/- 0.1 kg; gestational age, 29 +/- 1 weeks; post-natal age, 33 +/- 4 days). The great majority of these episodes (88%) had a central, followed by an obstructive, component. Infants were studied by using a nosepiece and a flow-through system. Respiratory efforts (abdominal and chest movements) were recorded. Of the apneas, 20 were or = 20 seconds. Of the 198 mixed apneas, 151 (76%) occurred in the absence of any respiratory effort; 43 (22%) showed a simultaneous cessation of the cardiac oscillation and respiratory effort; and 4 (2%) showed diaphragmatic activity appearing after cessation of the cardiac oscillation (airway occlusion). Respiratory efforts never preceded the cessation of the cardiac oscillation. The findings suggest that diaphragmatic action is not needed to occlude the airway in mixed apneas. The simultaneous cessation of cardiac oscillations (airway occlusion) and onset of respiratory efforts may indicate that such effort contributes to closure or is induced by the same stimulus that closes the airway. We speculate that the mechanism for airway closure in mixed apneas is most likely a lack of upper airway tone, which normally occurs with the cessation of a central drive to breathe.

Subarachnoid fluid collections: A cause of macrocrania in preterm infants

We report the outcome of 12 very low birth weight infants with macrocrania caused by subarachnoid fluid collections. By the age of 15 to 18 months, head growth had stabilized along a curve above and parallel to the 95th percentile. No infant required neurosurgical intervention, nor was cerebral palsy or mental retardation diagnosed in any of the infants.

EXPRESSION AND ACTIVITY OF MATRIX METALLO PROTEINASES 2 AND 9 AND THEIR INHIBITORS IN RAT LUNGS DURING THE PERINATAL PERIOD AND IN DIAPHRAGMATIC HERNIA

During lung development, the extracellular matrix undergoes dynamic remodeling. Matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinases (TIMPs), are important enzymes that participate in regulating tissue remodeling. There is an abnormal balance of the synthesis and degradation of collagen and elastin in perinatal lung associated with congenital diaphragmatic hernia (CDH). This study was designed to (1) determine the expression and gelatinolytic activity patterns of MMPs 2 and 9 and TIMPs 1 and 2 in rat lungs during the perinatal period, and (2) to test the hypothesis that they are abnormal in nitrofen-induced CDH. Measurements were made using reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and zymography. The mRNA expression and activity of MMP 2 did not change significantly from embryonic day 16 to postnatal day 14. The most striking feature found was the rapid increase in the expression of MMP 9 soon after birth. Measurements were repeated on lung tissue isolated from embryonic rats with nitrofen-induced CDH. The expression and activity of MMPs and TIMPs were similar to control values and thus we conclude that these proteins appear not to be responsible for the altered extracellular matrix and morphological abnormalities noted in CDH lungs at birth.

Noninvasive Quantification of Recirculation during Double Lumen Venovenous Extracorporeal Membrane Oxygenation (ECMO)

Noninvasive Quantification of Recirculation during Double Lumen Venovenous Extracorporeal Membrane Oxygenation (ECMO)

Effects of a Prolonged Infusion of a Placental Extract on Breathing and Electrocortical Activity in the Fetal Sheep. • 1783

We have previously found that brief infusion (2 minutes) of a placental extract into the carotid artery inhibited spontaneous fetal breathing in sheep; in 50% of the infusions, the electrocortical activity (ECoG) switched from low voltage (LV) to high voltage (HV). The action was primarily found in the 1-10 kD subfraction and was tissue specific. In the present study we determined the effects of a more prolonged infusion of the 1-10 kD subfraction(over 3 hr) to see if the inhibition of breathing was independent of changes in ECoG and whether it persisted throughout the infusion. Infusion of the 1-10 kD subfraction (40 cc/hr) into the carotid artery of the fetal sheep (139± 2 days of gestation), induced a decrease in the incidence of breathing from 58% (baseline) to 43%, 27%, and 7% during the first, second, and third hour of infusion respectively (p<0.001); during the first hr post-infusion, breathing increased to 51%. There was also a decrease in the time spent in LV-ECoG from 57% (baseline) to 50%, 38%, and 18% during the 3 hr of infusion (p<0.005); this increased to 58% during the first hr post-infusion. The decrease in breathing was independent of the changes in ECoG, since there was a simultaneous decrease in breathing during LV-ECoG from 92% (baseline) to 65%, 56%, and to 17% during the infusion (p<0.001); this breathing activity in LV-ECoG recovered to 78% during the first hr post infusion. Krebs solution (control) had no effect on breathing or ECoG. No significant changes were observed in blood gases and pH during the infusions. The findings suggest that a) the inhibitory action of the placental factor is independent of changes in electrocortical activity; and b) continuous infusion of a placental factor is capable of inhibiting fetal breathing for prolonged periods and may be responsible for the inhibition of breathing observed in fetal life. Supported by the Childrens Hospital of Winnipeg Research Foundation.

Airway Closure During Mixed Apneas in Preterm Infants: Is Respiratory Effort Necessary? |[bull]| 1800

Airway closure during mixed apneas in preterm infants may be due to lack of tone in the upper airway followed by collapse and obstruction or diaphragmatic action inducing obstruction. We examine whether respiratory efforts are necessary for airway closure using a new method of detecting airway obstruction, based on the disappearance of an amplified cardiac pulse observed on the respiratory flow tracing. We analyzed 198 episodes of mixed apnea of various lengths (> or = 3 seconds) observed in 33 preterm infants (birth weight, 1.4 +/- 0.1 kg [mean +/- SEM]; study weight, 1.7 +/- 0.1 kg; gestational age, 29 +/- 1 weeks; post-natal age, 33 +/- 4 days). The great majority of these episodes (88%) had a central, followed by an obstructive, component. Infants were studied by using a nosepiece and a flow-through system. Respiratory efforts (abdominal and chest movements) were recorded. Of the apneas, 20 were < 5 seconds; 78, 5 to < 10 seconds; 45, 10 to < 15 seconds; 27, 15 to < 20 seconds; and 28, > or = 20 seconds. Of the 198 mixed apneas, 151 (76%) occurred in the absence of any respiratory effort; 43 (22%) showed a simultaneous cessation of the cardiac oscillation and respiratory effort; and 4 (2%) showed diaphragmatic activity appearing after cessation of the cardiac oscillation (airway occlusion). Respiratory efforts never preceded the cessation of the cardiac oscillation. The findings suggest that diaphragmatic action is not needed to occlude the airway in mixed apneas. The simultaneous cessation of cardiac oscillations (airway occlusion) and onset of respiratory efforts may indicate that such effort contributes to closure or is induced by the same stimulus that closes the airway. We speculate that the mechanism for airway closure in mixed apneas is most likely a lack of upper airway tone, which normally occurs with the cessation of a central drive to breathe.

When are Follow-Up Sleep Studies Necessary in Preterm Infants Discharged Home on Theophylline?

When are Follow-Up Sleep Studies Necessary in Preterm Infants Discharged Home on Theophylline?

In Search of the Respiratory Center: Medullary Pacemaker Cells and Their Response to Neurotransmitters

In Search of the Respiratory Center: Medullary Pacemaker Cells and Their Response to Neurotransmitters