Pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome: current practice in pediatrics.

Pulmonary arterial hypertension (PAH) is an uncommon but serious disease characterized by severe pulmonary vascular disease and significant morbidity and mortality. PAH associated with congenital heart disease (APAH-CHD) is one etiology of PAH that has innate characteristics delineating it from other forms of PAH. The patient with APAH-CHD presents with unique challenges consisting of not only pulmonary vascular disease but also the complexity of the cardiac lesion. Eisenmenger syndrome (ES) represents the severe end of the spectrum for disease in APAH-CHD. Over time, systemic-to-pulmonary shunting through cardiac defects increases pulmonary vascular resistance to levels significant enough to reverse shunting across the defect. Historically, ES patients have been reported to have better outcomes than IPAH despite similarities in pulmonary vascular disease. However, recent studies are challenging this notion. Nonetheless, APAH-CHD survival has improved with the advent of modern PAH targeted therapies. New therapeutic options have allowed us to reconsider the dogma of inoperability in APAH-CHD patients with unrepaired defects. Certainly advances have been made, however, investigators must continue to advance the field through controlled clinical trials in both adult and pediatric APAH-CHD patients.

Pulmonary complications of congenital heart disease.

Cardiac and pulmonary pathophysiologies are closely interdependent, which makes the management of patients with congenital heart disease (CHD) all the more complex. Pulmonary complications of CHD can be structural due to compression causing airway malacia or atelectasis of the lung. Surgical repair of CHD can also result in structural trauma to the respiratory system, e.g., chylothorax, subglottic stenosis, or diaphragmatic paralysis. Disruption of the Starling forces in the pulmonary vascular system in certain types of CHD lead to alveolar-capillary membrane damage and pulmonary oedema. This in turn results in poorly compliant lungs with a restrictive lung function pattern that can deteriorate to cause hypoxemia. The circulation post single ventricle palliative surgery (the so called "Fontan circulation") poses a unique spectrum of pulmonary pathophysiology with restrictive lung function and a low pulmonary blood flow state that predisposes to thromboembolic complications and plastic bronchitis. As the population of patients surviving post CHD repair increases, the incidence of pulmonary complications has also increased and presents a unique cohort in both the paediatric and adult clinics.

Cardiac rhythm disturbances among children with idiopathic congenital central hypoventilation syndrome.

The objective of this study was to determine whether subjects with congenital central hypoventilation syndrome (CCHS) had an increased frequency of cardiac arrhythmias and decreased heart rate variability when compared to subjects without a known deficit in control of breathing, and that these abnormalities would be exaggerated by anesthesia. Continuous ambulatory Holter recordings were obtained in patients with CCHS and compared to two otherwise healthy control groups without a deficit in control of breathing: one with an intact airway (n = 11) and a second group with a tracheostomy (n = 6). Holter recordings were obtained before, during (under general anesthesia), and after bronchoscopy. Fourteen children with CCHS (age: 9.3 +/- 4.4 years mean +/- S.D.) were studied, and 7 underwent bronchoscopy. Seventeen control children were studied (age 6.6 +/- 3.6 years): 11 without a tracheostomy, and 6 with a tracheostomy who also underwent bronchoscopy. Maximum heart rate during baseline recording was significantly lower in the CCHS subjects as compared to controls (P = 0.0001). At baseline the difference in the number of arrhythmias/24 hr/subject in all CCHS vs. all control subjects was significant (P = 0.0002); for the subjects who had bronchoscopy, CCHS vs. control, the difference was also significant (P = 0.03). In addition, there was a significant decrease in the number of events/24 hr/subject among the CCHS subjects between baseline and post-bronchoscopy (P = 0.0288). The predominant arrhythmias were sinus bradycardia and transient asystole. The longest asystole in a CCHS subject was 6.50 sec, and in a control subject, 1.42 sec (at baseline the means of the longest asystole were 2.69 +/- 1.4 vs. 1.24 +/- 0.13; P = 0.003 in the CCHS vs. control groups). Other indices of heart rate variability were significantly reduced in the CCHS subjects (P < 0.05). These results substantiate our hypothesis that subjects with CCHS have more arrhythmias than controls, an increased frequency of bradyarrhythmias, and decreased cyclical sinus arrhythmia.

Heart rate variability in preterm brain-injured and very-low-birth-weight infants.

Heart rate variability (HRV) reflects the complex interplay of the sympathetic and parasympathetic innervation of the heart. Developmental maturation of the fetus and newborn results in predictable alterations in the neural cardiac control of heart rate. Furthermore, patterns of HRV are closely correlated to clinical outcome in several pathologic situations. The first aim of this study was to characterize the maturational patterns of HRV in a group of developmentally at-risk newborns (those with severe hemorrhagic or ischemic brain injury and extremely immature, low-birth-weight infants). Secondly, we sought to determine whether a correlation exists between HRV and length of hospital stay, diagnosis of cerebral palsy, and neurodevelopmental test scores at 1-year corrected age. Time domain indices of HRV were computed longitudinally from 32 to 37 weeks of corrected gestational age in 19 very low birth weight, preterm infants. Among the 19 infants studied, 7 infants had no evidence of brain injury, 7 infants had periventricular leukomalacia (PVL), 3 infants had grade III/IV intraventricular hemorrhage (IVH), and 2 infants had both IVH and PVL. Neurologic injuries were documented using ultrasound and neurodevelopmental progress was followed through 1 year of corrected gestational age. A multivariate repeated measures analysis was performed to determine the relationship between the type of perinatal brain injury and neurodevelopmental status at 1 year of corrected gestational age. The type of perinatal brain injury was highly correlated to specific patterns of HRV with multivariate regression models producing adjusted r(2) values ranging from 0.63 to 0.99. The type of perinatal brain injury was highly correlated to the developmental outcome measures (p < 0.0000) with PVL patients having the lowest neurodevelopmental scores, IVH patients having the highest scores, and noninjured infants having midrange, grossly normal values. Using ANOVA, HRV was correlated to outcome, but individual comparisons revealed statistical significance only for the noninjured group (p < 0.04). However, multivariate models, which characterized outcome within each brain injury group, were highly significant (adjusted r (2) ranged from 0.23 to 0.89). In summary, the type of perinatal brain injury determined the pattern of HRV and HRV was highly correlated to length of hospital stay and neurodevelopmental function assessed at 1 year of corrected gestational age.

Will a critical level of hyperventilation-induced hypocapnia always induce an absence seizure?

We wished to determine if the degree of hypocapnia correlates with increased frequency of absence seizures and if there is a critical pCO2 at which absence seizures are reliably provoked. Twelve untreated children with newly diagnosed absence epilepsy were continuously monitored by EEG and end-expiratory CO2 recording during quiet respiration and hyperventilation (to absence seizure or exhaustion) while breathing four gas mixtures: (a) room air, (b) 100% O2, (c) 4% CO2 in room air, or (d) 4% CO2 + 96% O2). In quiet respiration, a reduction in number of spike and wave bursts and total seconds of spike and wave was noted in children breathing supplemental CO2 (gases c and d vs. gases a and b), p < 0.05. Supplemental O2 had no effect. Eight subjects had absence seizures elicited with each trial of hyperventilation. All subjects had their own critical pCO2, ranging from 19 to 28 mmHg. Three children had no seizures, two despite hypocapnia to pCO2 of 19 and 21 and 1 who achieved a pCO2 of only 25. In 1, absence seizures were provoked in only six of nine hyperventilation trials to pCO2 of 17-23. In 67% of subjects, absence seizures were reliably provoked by hypocapnia. Critical pCO2 varied among children with absence. Determination of whether variation in sensitivity to hypocapnia may be helpful in determining response to antiepileptic drugs (AEDs) or remission of seizures will require further study.

Transvenous closure of patent ductus arteriosus in a sick 2780g infant.

A three-and-a-half-month-old 2780 g critically ill infant had successful transvenous coil occlusion of a ductus arteriosus. At six-and-a-half months of age the infant died, and autopsy showed coverage of the coil on the aortic aspect and no lumenal narrowing. It was concluded that transvenous coil occlusion of the patent ductus arteriosus in small infants is possible and that th venous route is preferred to be arterial route.

Technology assessment of nonsurgical closure of patent ductus arteriosus: an evaluation of the clinical effectiveness and costs of a new medical device.

OBJECTIVE: To assess the clinical efficacy and cost impact of a new medical device for the nonsurgical closure of patent ductus arteriosus (PDA). METHODS: This was a before-after study comparing the most recent 20 surgical procedures with the first 20 nonsurgical procedures for PDA using a new medical device. Clinical outcome, hospital stay, device cost, and physician fees were compared. RESULTS: Surgical closure was effective in all 20 patients, with an average cost of $4667. In a similar patient group, nonsurgical closure was achieved in 18 of 20 patients (90%), with an estimated average cost per successful procedure of $4690. A clinically insignificant PDA leak persisted beyond 12 months in four nonsurgically managed patients. CONCLUSION: Nonsurgical closure of PDA can be recommended as an effective new medical technique that is not associated with a measurable increase in direct costs and that provides significant indirect and intangible cost advantages.

Capacity of intrinsic cardiac neurons to modify the acutely autotransplanted mammalian heart.

The capacity of the intrinsic cardiac nervous system to modify the acutely autotransplanted heart was investigated in eight anesthetized open-chest canine preparations in which the adrenal glands had been removed from the circulation. Cardiac effects elicited by isoproterenol and nicotine were also examined before and after heart-lung transplantation. Cardiac augmentation induced by isoproterenol was similar before and immediately after cardiopulmonary transplantation, indicating that the surgery did not obtund cardiac myocyte function significantly. The initial bradycardia induced by nicotine was greater before transplantation. The subsequent augmentation in left atrial systolic pressure, as well as right and left ventricular intramyocardial systolic pressures, induced by nicotine were similar before and after transplantation. When nicotine was administered to transplanted preparations after atropine administration, cardiac augmentation was induced. Cardiac augmentation was not induced by nicotine after subsequent beta-adrenergic blockade. These data indicate that nicotine-sensitive adrenergic neurons which accompany the transplanted heart are capable of inducing considerable cardiac augmentation. Power spectral analysis of heart rate and left ventricular chamber rate of pressure rise variability indicated an almost complete lack of power in these indexes after, as opposed to before, transplantation. Together with intrinsic cardiac cholinergic neurons, intrinsic cardiac adrenergic neurons may be responsible for physiologically and pharmacologically induced alterations in cardiac variables that occur in acutely transplanted hearts.

Ambulatory monitoring of the sudden death of an adolescent with hypertrophic cardiomyopathy.

Sudden death is an important cause of mortality in hypertrophic cardiomyopathy. Several mechanisms have been proposed, but ambulatory monitoring of the event has rarely occurred. The case of an adolescent girl with congenital hypertrophic cardiomyopathy and arthrogryposis multiplex congenita is presented. Despite appropriate therapy and severe activity limitation, the patient's condition progressively worsened. The patient died suddenly in her sleep, one month after a myocardial myomectomy for subaortic stenosis. The fortuitous ambulatory electrocardiographic (ECG) monitoring of the event recorded polymorphic ventricular tachycardia degrading into ventricular fibrillation. Retrospective review of previous ambulatory ECG revealed the presence of nonsustained ventricular tachycardia, a predictive determinant for sudden death, and atrioventricular node dysfunction. However, the patient had never reported symptoms during the dysrhythmias. The pathological specimen showed an unexpected old apical infarction scar, suggesting that her preoperative cardiac status was worse than suspected. In summary, the mechanism of sudden death in this patient was revealed by ambulatory ECG monitoring, and the involvement of neural and myocardial factors are proposed.

Functional capacity of nicotine-sensitive canine intrinsic cardiac neurons to modify the heart.

The capacity of intrinsic cardiac efferent parasympathetic and sympathetic neurons to modify the heart was investigated in nine anesthetized open-chest dogs with adrenal glands removed from the circulation. The effects elicited by intravenously administered isoproterenol, tyramine, and nicotine on cardiac variables were examined before and after acute decentralization of the heart. Major vessels, as well as other tissues at the base of the heart, were denuded by means of an ultrasonic aspirator that removed neural elements without damaging muscles or blood vessels. The efficacy of the acute decentralization was assured by testing cardiac responses elicited by right and left stellate ganglia and cervical vagosympathetic complex stimulations after surgery. Heart rate, atrial force, and both right and left ventricular intramyocardial systolic pressures were augmented similarly by isoproterenol and tyramine before and after acute decentralization, indicating that the surgery necessary to decentralize the heart did not obtund cardiac myocyte function. Power spectral analysis of heart rate and left ventricular chamber pressure rate of change indicated an almost complete lack of variability of these indexes after, but not before, acute decentralization. Despite these changes, similar cardiac augmentation was elicited by nicotine before and after acute decentralization. Cardiac augmentation was elicited by nicotine in acutely decentralized preparations after atropine administration but not after beta-adrenergic blockade. These data indicate that the canine intrinsic cardiac nervous system contains a significant population of nicotine-sensitive adrenergic neurons that modulate the heart. Furthermore, the intrinsic cardiac nervous system does not appear to be primarily responsible for the heart rate and ventricular pressure variability found in intact hearts.

Postnatal maturation of baroreflex heart rate control in neonatal swine.

OBJECTIVE: Despite extensive knowledge about basic baroreceptor function, there continues to be controversy as to whether there is postnatal maturation of the cardiovascular baroreflex. DESIGN/ANIMALS: Acutely studied postnatal developmental changes in baroreflex sensitivity with a neonatal porcine model in 28 chloralose-anesthetized piglets from birth to six weeks of age. INTERVENTIONS: Steady-state heart rate versus blood pressure response curves were generated by altering blood pressure with increasing doses of phenylephrine or nitroprusside. Data were fitted to the Hill equation for sigmoidal curves, and the maximum heart rate, maximum slope (sensitivity) and blood pressure at 50% maximal heart rate (P50) were calculated. MAIN RESULTS: Baroreflex sensitivity was found to increase from birth to six weeks of age (P < 0.0001), with the most rapid changes occurring after two weeks of age. Increasing age was accompanied by shift of the baroresponse curve to an increased range of heart rate changes at higher blood pressures. Maximal heart rates did not differ with advancing postnatal age. CONCLUSIONS: Swine baroreflex sensitivity increases from birth to six weeks of age, with higher blood pressures causing greater bradycardia in older piglets. These findings are consistent with postnatal maturation of the cardiovascular autonomic nervous system.

Massive pericardial effusion as a cause for sudden deterioration of a very low birthweight infant.

We describe the successful resuscitation of a very low birthweight infant after sudden deterioration caused by a massive pericardial effusion. The neonatal course of this 740 gm, 26-week gestational age infant had been complicated by moderate respiratory distress syndrome, apnea, and bronchopulmonary dysplasia. A Silastic catheter was placed percutaneously in the right axillary vein on day 6 of life and documented to be in the superior vena cava prior to continuous parenteral nutrition. On day 38, her cardiorespiratory status abruptly deteriorated, blood return could not be obtained from the central line, and it was removed. Chest radiograph and subsequent echocardiogram confirmed a massive pericardial effusion. Under echocardiographic guidance, an emergency percutaneous pericardiocentesis allowed aspiration of 23 ml of straw-colored fluid. Her vital signs immediately returned to normal and reaccumulation of the effusion did not occur. Despite the high mortality of premature infants from pericardial effusion as a complication of central venous catheterization, early diagnosis and prompt therapy can assure a good outcome. As a cause of sudden deterioration of very low birthweight infants, tamponade must not be forgotten, since it is now a rapidly treatable complication of central venous cannulation.

Effects of transient coronary artery occlusion on canine intrinsic cardiac neuronal activity.

In order to further elucidate the regulatory function of canine epicardial neurons, the effects of transient coronary artery occlusion on their spontaneous activity was studied. Fifty-eight individual, spontaneously active units were identified by means of their action potential configurations in specific loci of atrial and ventricular epicardial fat of 10 anesthetized dogs. The activity of 49 of the units was modified by one minute of coronary artery occlusion. Twenty-four of the 49 responding units exhibited increased activity and 37 decreased activity during coronary artery occlusions. Activity changes were sometimes, but not always, associated with decreased left ventricular intramyocardial systolic pressure. During reperfusion, the activity of 6 units was increased compared to control levels, even though ventricular pressures remained the same. Following acute decentralization, 48% of previously active units generated spontaneous activity; the activity of 89% of these was altered during coronary artery occlusion despite the fact that overall cardiodynamics were unchanged. Following hexamethonium administration, the activity generated by 9 of 10 spontaneously active units was modified by coronary artery occlusion. It is concluded that transient coronary artery occlusion can modify the activity generated by intrinsic cardiac neurons, such modification involving central and peripheral neuronal interactions.

Tranexamic acid in the treatment of Kasabach-Merritt syndrome in infants.

Kasabach-Merritt syndrome (thrombocytopenia, consumption coagulopathy, and, occasionally, microangiopathic hemolysis) is an infrequent but often lethal complication of giant capillary hemangiomas in the infant. We report the clinical course of an infant who came to us with this syndrome shortly after birth. She was successfully treated with transfusions of blood products, high-dose oral prednisone, and a fibrinolytic inhibitor, tranexamic acid. No complications of the treatment occurred. The hematological abnormalities resolved completely by 2 years of age. Although prednisone may have been necessary for stabilization and involution of the hemangioma, the addition of tranexamic acid allowed earlier tapering of the steroid therapy and fewer transfusions. Tranexamic acid was extremely well tolerated in this newborn.

Role of carotid and central chemoreceptors in the CO2 response of sympathetic preganglionic neurons.

In anesthetized, vagotomized, paralyzed, artificially ventilated cats with aortic nerves cut, we recorded the response of 28 sympathetic preganglionic neurons (SPNs) of the cervical sympathetic trunk of changes in arterial pCO2. We observed the effects on these responses of: (i) surgical denervation of carotid sinus chemoreceptors in normoxia (paO2 110 mm Hg); and (ii) hyperoxia (paO2 greater than 350 mm Hg) which is known to depress peripheral chemoreceptor sensitivity to CO2. Stimulus-response curves, obtained by rebreathing at constant paO2, were used to detect the effects of these manoeuvres. The present experiments have confirmed previous observations demonstrating the CO2-sensitivity of this neuron population. The population average firing rate, as a function of paCO2, describes a sigmoid curve, increasing continuously between 20 and 90 mm Hg and asymptotically approaching plateaus at the highest and lowest paCO2 values. Carotid sinus nerve section caused a decrease of the average response of the population at all paCO2 values, resulting in a displacement to the right of the response curve, in a decrease in slope and maximum values. On the assumption that the CO2 response curve after carotid sinus nerve section is due to central chemoreceptor input, and that there is a simple addition between the effects of central and carotid chemoreceptors, the difference between CO2 response curves ("difference curves") before and after denervation represents the contribution of the carotid chemoreceptors. A comparison of this "difference curve" with the curve obtained after denervation reveals that the contribution of the carotid chemoreceptors is of the same magnitude as that of the central chemoreceptors up to a paCO2 value of 60-70 mm Hg. Beyond this value, the carotid contribution declines and becomes a smaller component of the total response, whereas the contribution of the central chemoreceptors continues to increase. Similar results were obtained with rebreathing in hyperoxia, after correction for the central excitatory effect of hyperoxia. Hyperoxia never caused a depression of the CO2 response of units after section of the carotid sinus nerve. Observation of the effects of the two manoeuvres on individual SPNs leads to the conclusion that in approximately half of the CO2-sensitive units there is an overlap of central and peripheral chemoreceptor input. The remainder of the CO2-sensitive units receive input only from the central chemoreceptors.

Cardiovascular control by medullary surface chemoreceptors.

The cardiovascular and respiratory effects of superfusion of the ventral surface of the medulla with acid hypercapnic or alkaline hypocapnic solutions have been studied in anaesthetized, paralyzed, artificially ventilated cats. Peripheral chemoreceptor and baroreceptor denervation was achieved by section of carotid sinus, aortic and cervical vagus nerves. Systemic arterial and central venous pressure, hindquarters blood flow, heart rate and phrenic nerve activity were recorded. Acid hypercapnic (pH 6.8, pCO2 85 mm Hg) superfusion caused increases in systemic arterial pressure, phrenic nerve activity and heart rate, and a decrease in hindquarters blood flow. Alkaline hypocapnic (pH u.i, pCO2 less than 10 mmHg) superfusion caused opposite effects. These experiments indicate a significant role of the chemoreceptors of the ventral surface of the medulla in cardiovascular control.

Evaluation of a screen oxygenator suitable for small animal organ perfusion.

A small vertical screen oxygenator was built using a stainless steel screen enclosed in a Plexiglas box as the oxygenating surface. The unit was primed with 35 ml dextran-diluted blood (Hct 25.1 +/- 0.6%. mean +/- SE) and tested in cats with a partial cardiopulmonary bypass circuit. An oxygen saturation of more than 95% was always obtained, even when the incoming venous saturation was as low as 15%. The O2 exchange capacity was minimally affected by changes in blood flow (1.5 to 70 ml/min) through the unit. CO2 extraction was not flow limited over the range tested. Output PCO2 was 33.3 +/- 0.6 mmHg and pH was 7.29 +/- 0.02. These results were obtained when 3% CO2 in O2 was passed through the oxygenator chamber at 1.0 to 5.0 l/min. The performance of the unit was stable for periods up to 4 h. The small priming volume and reliable performance make this oxygenator suitable for organ perfusion in small experimental animals.