Isolated mental developmental delay in very low birth weight infants: association with prolonged doxapram therapy for apnea.

OBJECTIVE: We investigated factors associated with isolated mental delay in infants weighing < 1250 g at birth. STUDY DESIGN: With a case-control design, matching variables for 40 cases included gestation, birth weight, sex, grade of intraventricular hemorrhage, and socioeconomic status. Case subjects had a mental developmental index < 70, and controls had a mental developmental index > or = 85, according to the Bayley Scales of Infant Development II at 18 months' corrected age. RESULTS: There were no differences between the case and control subjects for neonatal complications and antenatal or postnatal steroid use. There was a marked difference in the cumulative dosage and duration of doxapram therapy used for apnea of prematurity (total dose 2233 +/- 1927 mg vs 615 +/- 767 mg, P < .001; duration 45.2 +/- 32.5 days vs 19.4 +/- 23.4 days, P < .001 for case subjects and control subjects, respectively). Multivariate analysis did not identify additive predictive variables. CONCLUSION: Isolated mental delay in infants weighing < 1250 g at birth was associated with the total dosage and duration of doxapram therapy for severe apnea. Although this may be a marker for cerebral dysfunction manifesting as apnea of prematurity, possible adverse effects of doxapram or its preservative, benzyl alcohol, on the developing brain deserve further study.

High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure.

Apnea of prematurity (AOP) is frequently managed with nasal continuous positive airway pressure (NCPAP). Nasal cannula (NC) are used at low flows (<0.5 L/min) to deliver supplemental oxygen to neonates. A number of centers use high-flow nasal cannula (HFNC) in the management of AOP without measuring the positive distending pressure (PDP) generated. Objective. To determine the NC flow required to generate PDP equal to that provided by NCPAP at 6 cm H(2)O and to assess the effectiveness of HFNC as compared NCPAP in the management of AOP. Method. Forty premature infants, gestation 28.7 +/- 0.4 weeks (mean +/- standard error of mean), postconceptual age at study 30.3 +/- 0.6 weeks, birth weight 1256 +/- 66 g, study weight 1260 +/- 63 g who were being managed with conventional NCPAP for at least 24 hours for clinically significant apnea of prematurity, were enrolled in a trial of ventilator-generated conventional NCPAP versus infant NC at flows of up to 2.5 L/min. End expiratory esophageal pressure was measured on NCPAP and on NC, and the gas flow on NC was adjusted to generate an end expiratory esophageal pressure equal to that measured on NCPAP. Two 6-hour periods were continuously recorded and the data were stored on computer. Results. The flow required to generate a comparable PDP with NC varied with the infant's weight and was represented by the equation: flow (L/min) = 0.92 + 0.68x, x = weight in kg, R = 0.72. There was no difference in the frequency and duration of apnea, bradycardia or desaturation per recording between the 2 systems. Conclusion. NC at flows of 1 to 2.5 L/min can deliver PDP in premature neonates. HFNC is as effective as NCPAP in the management of AOP.

The western Canadian experience with congenital diaphragmatic hernia: perinatal factors predictive of extracorporeal membrane oxygenation and death.

This study documents how congenital diaphragmatic hernia (CDH) is managed in level III neonatal intensive care units (NICUs) in western Canada and examines perinatal factors predictive of the need for extracorporeal membrane oxygenation (ECMO). Information was obtained retrospectively from all level III NICUs in western Canada about the management of infants with CDH between 1992 and 1996; 91 infants with isolated CDH were identified. A prenatal diagnosis was made in 42 cases (46%). Surfactant was used in 53%, high-frequency oscillation (HFO) in 29%, and nitric oxide (NO) in 27%. Of the 69 infants born in referral centers, 29 (42%) were referred for possible ECMO; 17 (59%) of those required ECMO, with 65% survival. The overall requirement for ECMO was 30%. Death or ECMO occurred in 40% of cases overall. Overall survival was 82%. Survival in those needing ECMO was 74%, and in those not needing ECMO 86%. Significant predictors of death or ECMO were: prenatal diagnosis (P < 0.05), maximum postductal arterial partial pressure of oxygen (PaO2) < 100 mmHg (P < 0.001), and an oxygenation index (OI) at 6 h > 15 (P < 0.001). In cases where there is a prenatal diagnosis of CDH the mother should deliver at an ECMO center. Alternatively, an OI of > 15 at 6 h and PaO2 < 100 mmHg should prompt referral to an ECMO center.

Neonatal pertussis requiring extracorporeal membrane oxygenation.

Despite widespread immunization against Bordetella pertussis, whooping cough remains potentially fatal in susceptible populations such as neonates. A case of neonatal pertussis with severe pulmonary hypertension (PH) requiring extracorporal membrane oxygenation (ECMO) is described. PH associated with pertussis severe enough to require ECMO is frequently irreversible and associated with a poor prognosis.

Quantification of recirculation by thermodilution during venovenous extracorporeal membrane oxygenation.

PURPOSE: The aim of this study was to determine whether recirculation could be quantified by a thermodilution technique during venovenous (VV) extracorporeal membrane oxygenation (ECMO) in a rabbit model. METHODS: Five New Zealand white rabbits, mean weight, 4.5 (range, 3.7 to 5.7) kg, were anesthetized, instrumented, cannulated with a double-lumen catheter, and placed on VV ECMO. Serial injections of ice-cold saline were performed at the arterial arm of the circuit, and the resultant temperature change at various pump flows was measured at the venous arm of the circuit using a thermistor-tipped catheter and a cardiac output computer. Results were compared with the respective 100% recirculation measured with all the circuit flow passing through the bridge. RESULTS: Using linear regression, recirculation percentage could be calculated as: 19 + 0.1 x pump flow (R2 = 0.81, P < .005). Recirculation correlated positively with pump flow. Variability between results at each flow was less than 10%. CONCLUSIONS: Recirculation can be quantified during VV ECMO by measuring the change in temperature in the venous arm using a cardiac output computer after injection of a known quantity of ice-cold saline in the arterial side of the circuit. The effect of interventions to reduce recirculation can be assessed conveniently and reliably.

Cerebral infarction in the term newborn: clinical presentation and long-term outcome.

OBJECTIVE: We evaluated the long-term neurodevelopmental outcome of cranial computed tomography (CT)-documented cerebral infarction in term neonates to ascertain factors that would help to predict the risk of subsequent neurodevelopmental sequelae in early childhood. STUDY DESIGN: From 1983 to 1997, all surviving neonates from two level III neonatal intensive care units were prospectively identified and subsequently assessed in childhood. Clinical presentation was characterized by retrospective chart review and blinded re-reading of computed tomography (CT) scans. Perinatal events were compared with neurodevelopmental outcome. RESULTS: Forty-six children were followed up for a mean of 42.1 months (range, 18-164 months). Neurodevelopmental outcome was normal in 15 and abnormal in 31. A single disability was present in 8, and multiple disabilities were present in 23. Cerebral palsy was present in 22 and cognitive impairment in 19. Abnormal findings on neurologic examination at discharge and seizures in the neonatal period were associated with the presence of one or more childhood disabilities. The site or laterality of the vascular distribution of the lesion on neonatal CT did not correlate with long-term outcome. CONCLUSION: After cerebral infarction in the neonatal period, one third of term infants have normal long-term development. Neonatal seizure history and the findings on neurologic examination at discharge help in counseling parents about the possible long-term outcome of neonatal stroke.

Pacing after shocks stronger than the upper limit of vulnerability: impact on fibrillation induction.

BACKGROUND: After upper-limit-of-vulnerability (ULV) shocks of the same strength and coupling interval (CI) during the T wave, (1) the epicardial activation pattern (EAP) for the first postshock cycle is indistinguishable between shocks that do (VF) and do not (NoVF) induce ventricular fibrillation (VF) and (2) >/=3 cycles in rapid succession always occur during VF but not during NoVF episodes. To study the role of these rapid cycles, rapid pacing was performed after a shock stronger than the ULV that by itself did not induce rapid cycles and VF. METHODS AND RESULTS: A 504-electrode sock was sutured to the heart in 6 pigs to map EAPs. The S2 shock strength and S1-S2 CI at the ULV were determined by T-wave scanning with an up/down protocol. Ten shocks 50 to 100 V above the ULV (aULV) were delivered at the same S1-S2 CI to confirm that VF was not induced. Then, the postshock interval after aULV shocks was scanned with an S3 pacing stimulus from the LV apex until the shortest S2-S3 CI that captured was reached. This was repeated for S4, S5, etc, until VF was induced. To induce VF, 3 pacing stimuli (S3-S5) with progressively shorter CIs were required; S3 or S3, S4 never induced VF. After cycle S5, which induced VF, 2 EAP types occurred: focal (74%) and reentrant (26%). CONCLUSIONS: At least 3 cycles with short CIs are necessary for VF induction after aULV shocks. Cycles S3-S4 may create the substrate for cycle S5 to initiate VF.

Prevention of high incidence of neurally mediated ventricular arrhythmias by afferent nerve stimulation in dogs.

BACKGROUND: This study tested the hypothesis that the high incidence of ventricular arrhythmias caused by hypothalamic stimulation during acute myocardial ischemia could be attenuated by afferent nerve stimulation and investigated the cardiac mechanisms for those effects. METHODS AND RESULTS: In 18 anesthetized dogs, stimulating electrodes were implanted in the hypothalamus and in the isolated left peroneal nerve. The chest was opened and approximately 100 plunge needles were inserted into the ventricles for 3-D activation mapping. Each animal underwent 4 episodes of 2.5 minutes of acute myocardial ischemia. The first and fourth episodes served as controls. During the second and third episodes, animals received either hypothalamic stimulation, peroneal nerve stimulation, or both. Hypothalamic stimulation significantly increased the incidence of ventricular arrhythmias. This high incidence was reduced 34% by simultaneous stimulation of the hypothalamus and peroneal nerve. 3-D mapping showed a focal origin for all ventricular arrhythmias. Hypothalamic stimulation increased the number of arrhythmic beats and decreased the coupling interval between each arrhythmic beat and the preceding beat. These effects were reduced by peroneal nerve stimulation. CONCLUSIONS: Alteration in autonomic tone by hypothalamic stimulation causes a high incidence of ventricular arrhythmias during acute myocardial ischemia that can be decreased by afferent nerve stimulation.

Effect of altering the left ventricular pressure on epicardial activation time in dogs with and without pacing-induced heart failure.

BACKGROUND: The influence of an increased left ventricular end-diastolic pressure (LVEDP) on the development of lethal arrhythmias in chronic heart failure is unclear. We investigated the effect of chronic and acute LVEDP increase on the epicardial activation time of sinus (SB) and paced (PB) beats. METHODS: Six dogs underwent rapid ventricular pacing at 220-280[emsp4 ]beats/min for 6-14 weeks for induction of heart failure. On the study day, baseline (ba) LVEDP was determined for the surviving heart failure animals (HF-ba), and for seven control animals (C-ba). The epicardial activation time (EAT, time between the earliest and latest epicardial activation) for five consecutive SB and five ventricular PB during the baseline hemodynamic state were recorded using a 504 electrode mapping-sock. In the control animals a 2-litre volume (vl) was infused over 10[emsp4 ]min to acutely increase the LVEDP (C-vl) to a level comparable to the chronic increased LVEDP of the HF-ba. The same volume challenge was performed in two HF animals (HF-vl) and the EAT for SB and PB was redetermined. RESULTS: Three of six HF animals died during induction of heart failure. In the three remaining HF animals, chronic LVEDP increased from 6+/-1 to 17+/-10.8[emsp4 ]mmHg (P=0.07), EAT for SB increased by 68 % compared to control animals (HF-ba vs. C-ba, P<0.05). In contrast, in the control animals the acute rise in LVEDP from 6.8+/-4.5 to 14.7+/-6.2 mmHg P<0.05), shortened the EAT for SB (C-ba vs. C-vl, P<0.05). A similar decrease in EAT for SB caused by acute volume load was seen in the HF animals, but did not reach significance due to the small sample size (one of the three remaining HF animals died of spontaneous ventricular fibrillation before the volume load). Chronic LVEDP elevation significantly prolonged the EAT for PB from 72+/-11 to 120+/-31[emsp4 ]ms (C-ba vs. HF-ba) while acute LVEDP increase had no significant effect on EAT for PB. CONCLUSION: Chronic HF increases LVEDP and prolongs EAT, while an acute increase in LVEDP shortens the EAT for sinus beats. A prolongation of EAT in heart failure may make the heart more susceptible to ventricular arrhythmias and electromechanical dissociation.

Successful chelation therapy in a case of neonatal iron overload following intravascular intrauterine transfusion.

OBJECTIVE: We report a newborn infant who was successfully treated with chelation therapy having developed severe liver disease secondary to iron overload following multiple intrauterine, intravascular transfusions (IVTs). STUDY DESIGN: Case report with review of the literature. RESULTS: An infant was born at 33 weeks' gestation having received multiple IVTs for severe rhesus hemolytic disease. At birth there was severe anemia with hydrops and ascites. Severe liver disease was present with portal hypertension, coagulopathy and abnormal liver enzymes. A liver biopsy showed histologic features consistent with iron overload. The serum ferritin was in excess of 4000 micrograms/l. A 7-week course of deferoxamine resulted in a marked reduction in ferritin levels and significant improvement in liver function. CONCLUSION: The possibility of neonatal iron overload following multiple IVTs should be borne in mind. Successful chelation therapy is possible in such cases.

Congenital orbital teratoma.

A case of congenital orbital teratoma is described in which there was no organized eye only microscopic evidence of ocular tissues within the disorganized teratoma. A baby boy presented at birth with a 10-x-8-cm mass extruding from the left orbit. Magnetic resonance imaging (MRI) showed a mixed cystic-solid orbital mass containing areas of calcification and deforming the bony orbit around its margins. There was no organized eye and no intracranial extension. The eye was removed with reconstruction of the eyelids. Histopathology showed representation from all three germ cell layers consistent with a teratoma. There was no organized eye, but some disorganized ocular structures within the teratoma. Follow-up has been uneventful. Neonatologists and pediatricians should be aware of the possible diagnoses in a newborn presenting with an orbital mass, so that early definitive surgery can be performed with preservation of the globe where possible.

Myeloid colony-stimulating factors: use in the newborn.

Bacterial and fungal sepsis are major causes of morbidity and mortality in the newborn. Multiple factors contribute to this increased susceptibility to infection, including quantitative and qualitative neutrophil defects, with a reduction in neutrophil number and function. Neutropenia in the newborn may occur in association with sepsis and has a poor prognosis. In addition to antibiotic therapy and supportive care, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce morbidity and mortality. Granulocyte CSF is the physiological regulator of neutrophil production and function. Administration of G-CSF results in increased neutrophil production and counts and improved neutrophil function. Several studies of animal and human newborns having neutropenia or suspected sepsis investigated the use of G-CSF and GM-CSF to elevate neutrophil counts and reduce morbidity and mortality in this population. Results of small clinical trials using G-CSF and GM-CSF in very low-birth-weight infants having neutropenia show increased neutrophil counts and a reduced incidence of sepsis during the neonatal period. Despite these promising early results, further studies of the safety and efficacy of G-CSF and GM-CSF administration in neonates are required before their routine use can be recommended as either prophylaxis or treatment for neonatal sepsis.

Can early timed internal atrial defibrillation shocks reduce the atrial defibrillation threshold?

The defibrillation threshold is markedly reduced very early following the initiation of ventricular fibrillation. The purpose of this study was to determine if the same finding holds true for atrial defibrillation. Sustained, reproducible AF was induced with programmed atrial pacing using acetyl-beta-methylcholine chloride (40-640 microL/min) in six adult sheep (heart weight 245-300 g). Seven timing intervals (125 ms, 200 ms, 1 s, 3 s, 10 s, 30 s, and 5 min after AF induction) and two lead configurations: (1) RA as cathode and CS as anode; and (2) RA as cathode and RV apex as anode were tested. Single capacitor biphasic waveforms (3/1 ms) were delivered and atrial defibrillation thresholds (ADFTs) were determined in random order. No significant differences in leading edge voltage and total energy were detected for the RA-CS configuration for the seven timing intervals. For the RA-RV configuration, a significant difference was detected comparing the voltage for 125 ms to the 5-minute timing interval. For all times except 125 ms, the RA-RV threshold was significantly higher than the RA-CS level. In contrast to ventricular defibrillation, the ADFT does not change significantly within the first 5 minutes after the initiation of AF for the RA-CS configuration. However, if the shock is given very early (125 ms after AF induction) with the RA-RV configuration, the ADFT is lowered almost to the RA-CS level.

Inhibition of cardiac myocyte division in c-myc transgenic mice.

Overexpression of the c-myc protooncogene in the heart of transgenic mice has been demonstrated to result in cardiac enlargement due to increased myocyte hyperplasia during the fetal period. To determine the age of completion of the proliferative phase of myocyte growth in neonatal mice with c-myc overexpression, we used a transgenic (TG) mouse model in which c-myc overexpression is limited to the heart. Bromodeoxyuridine (BrdU) was given to TG and wild type (WT) mice (n=3/group) at 1, 2, 3, 5, 7, 10, 14, 16, 18 and 20 days of age to identify cells in S-phase of the cell cycle. Increased cardiac mass was present in TG compared to WT mice at all time periods (P<0. 05). Using computer assisted image analysis, myocardial total nuclear density (NT) in TG mice was 7-31% greater in both the left ventricle (LV) and the interventricular septum (IVS) than in WT at all ages (P<0.05), indicative of a smaller myocyte size. In WT mice, the labeling index (LI) remained almost constant at approximately 11-12% until 7 days of age, and then rapidly dropped to approximately 2% by 14 days and to less than 1% by 20 days. In contrast, LI in TG dropped continuously from birth to approximately 4% at 7 days and approximately 2% at 10 days of age (P<0.001). Thus, overexpression of the c-myc protooncogene is associated with enhanced hyperplastic growth of the heart during fetal development, and accelerated neonatal conversion to hypertrophic myocyte growth.

Transgenic animals as a tool for studying the effect of the c-myc proto-oncogene on cardiac development.

Transgenic animals provide a model system to elucidate the role of specific proteins in development. This model is now being used increasingly in the cardiovascular system to study cardiac growth and differentiation. During cardiac myocyte development a transition occurs from hyperplastic to hypertrophic growth. In the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc functions to regulate myocyte proliferation and/or differentiation, we examined the in vivo effect of increasing c-myc expression during fetal development and of preventing the decrease in c-myc mRNA expression that normally occurs during myocyte development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. Increased c-myc mRNA expression is associated with both atrial and ventricular enlargement in the transgenic mice. This increase in cardiac mass is secondary to myocyte hyperplasia, with the transgenic hearts containing greater than twice as many myocytes as nontransgenic hearts. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth, and suggest a regulatory role for the c-myc protooncogene in cardiac myogenesis.

The c-myc proto-oncogene regulates cardiac development in transgenic mice.

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

Regional myocyte size in two-kidney, one clip renal hypertension.

Regional variations in the size and shape of isolated myocytes were studied using the two-kidney, one clip (2K1C) renal model of hypertension. Weanling male Sprague-Dawley rats (50 to 75 g) were anesthetized by ketamine (100 mg/kg) during renal artery clipping (0.2 mm internal diameter silver clip) and were then allowed to grow for 6 to 8 weeks, when the blood pressure had stabilized at 180 mmHg. Hearts were removed, weighed and then were perfused with a calcium-free Joklik medium containing collagenase. Isolated myocytes were collected from five regions and fixed in isoosmolar glutaraldehyde: right ventricular free wall (RVFW), right and left halves of the interventricular septum (RIVS, LIVS), and epicardial and endocardial halves of the left ventricular free wall (LEPI, LENDO). Myocyte volume was measured by Coulter Counter. Myocyte length was measured by sonic digitizer. Cross-sectional area was calculated from myocyte volume and length. Tailcuff systolic pressure and heart weight were significantly increased in 2K1C rats as compared to control. Body weights were not different. Cell volume was significantly increased in RIVS, LIVS, LEPI, and LENDO, but not in RVFW. Cell length was not significantly increased in any region. Thus, the 2K1C model showed a predominant left ventricular hypertrophy in which the right half of the septum acted in concert with the left ventricle. The shape of the hypertrophied myocytes, having an increase in volume due to an increase in cross-sectional area but not length, was most consistent with a pressure-induced form of cardiac hypertrophy.