Open-lung biopsy guides therapy in children.

BACKGROUND: Open-lung biopsy is uncommon in children. Modern indications and outcomes are unknown. METHODS: This is a retrospective review of 64 open-lung biopsies (58 patients) from 1976 to 1996. Open-lung biopsies were used to grade vasculopathy in 8 patients (12% of 64) with pulmonary hypertension and in 10 patients (16% of 64) with combined pulmonary hypertension and lung parenchymal disease. Forty-six biopsies (72%) were obtained to diagnose parenchymal disease. Comparisons were made between biopsies performed from 1976 to 1989 and from 1990 to 1996. RESULTS: In the period 1990 to 1996, there were significantly more infants (p = 0.03), comorbid disease (p = 0.009), extracorporeal membrane oxygenation support (p < 10(-4)), and ventilator dependence (p = 0.05) and significantly less immunocompromise (p = 0.04). A definitive diagnosis was made in 43 of 64 cases (67%) and altered workup in 63 of 64 cases (98%). No correlation existed between Heath-Edwards grade of microangiopathy and catheterization data. Definitive diagnosis was most strongly associated with a nonimmunocompromised patient (p < 10(-4)). Although only one death (1.5%) was related to open-lung biopsy, the procedure was associated with a 30% inhospital mortality rate and an 11% morbidity rate. Of the 19 deaths, 1 patient died from the procedure, 13 died from their diseases, and 5 had support withdrawn. Death was associated with preoperative ventilator dependence (p < 10(-4)) and extracorporeal membrane oxygenation (p = 0.007). CONCLUSIONS: Pediatric open-lung biopsy commonly alters the diagnostic workup (98%). It is recommended for children who have been supported for 2 weeks by extracorporeal membrane oxygenation and for those with combined pulmonary hypertension and parenchymal lung disease. It is less useful in immunocompromised children.

Ion-exchange column chromatographic method for assaying purine metabolic pathway enzymes.

High energy phosphate levels fall rapidly during cardiac ischemia and recover slowly (more than one week) during reperfusion. The slow recovery of ATP may reflect a lack of purine metabolic precursors and/or increased activity of purine catabolic enzymes such as 5'-nucleotidase (5'-NT, EC 3.1.3.5) and adenosine deaminase (ADA, EC 3.5.4.4). The activity of enzymes involved in both the catabolism of ATP precursors (5-NT and ADA) and the restoration of ATP from slow synthetic pathways [adenosine kinase (AK, EC 2.7.1.20), adenine phosphoribosyl transferase (APRT, EC 2.4.2.7) and hypoxanthine phosphoribosyl transferase (HPRT, EC 2.4.2.8)] may directly affect the rate of ATP recovery. Strategies to enhance recovery will depend on the relative activity of these enzymes following ischemia. Their activity in different species and their response to ischemia are not well characterized. Hence, rapid assay methods for these enzymes would facilitate detailed time course studies of their activities in postischemic myocardium. We modified a single ion-exchange column chromatographic method using DEAE-Sephadex to determine the products of incubation of 5'-NT, AK, APRT and HPRT with their respective substrates. The uniformity of the final product measurement procedure for all assays permits the activities of the four enzymes to be rapidly determined in a single tissue sample and facilitates the study of a large number of samples. This technique should also be useful for enzymes of the pyrimidine metabolic pathway.

Aortic arch anomalies associated with long gap esophageal atresia and tracheoesophageal fistula.

PURPOSE: The purpose of this study was to determine whether aortic arch anomalies are associated with long gap esophageal atresia and tracheoesophageal fistula (EA-TEF). METHODS: The authors performed a retrospective review of all infants who had EA-TEF from 1980 to 1996 at two pediatric surgery centers. Two hundred three infants who had EA-TEF were identified. RESULTS: Twelve infants were noted to have both long gap EA-TEF defined as a gap length greater than 3 cm and aortic arch anomalies. Of these 12, 7 had aberrant right subclavian arteries originating from the descending aorta. Four of the seven infants who had aberrant right subclavian artery (SCA) had gap lengths greater than 4 cm. All four had their fistulae divided initially through a right thoracotomy with primary repair performed at a later date. The remaining five infants who had long gap EA-TEF had right-sided aortic arch with aberrant left subclavian arteries. All five initially underwent exploration through the right chest. On discovery of the long gap EA and concurrent vascular anomaly, the thoracotomies were closed, and the infants underwent definitive repair of both their EA-TEF and their vascular anomaly through a left thoracotomy. CONCLUSIONS: The authors find that aortic arch anomalies are associated with long gap EA-TEF. Patients who have these two anomalies tend to have a long gap. Preoperative diagnosis of these anomalies may alter the timing and technique of surgical intervention. The embryogenesis of these vascular lesions may account for this more severe form of esophageal atresia.

Development of a true primary repair for the full spectrum of esophageal atresia.

OBJECTIVE: To determine whether or not a true primary repair, without myotomies and with the gastroesophageal junction below the diaphragm, can be accomplished across the esophageal atresia (EA) spectrum. Our hypothesis is that the esophageal anastomosis can withstand significant tension. The consequences, particularly for those patients with a very long gap atresia, were assessed. SUMMARY OF BACKGROUND DATA: Difficulties arise roughly in proportion to the size of the gap between esophageal segments. Reported surgical complications remain frequent, and particularly at the far end of the EA spectrum, not all children are left with a satisfactorily functioning esophagus or esophageal substitute. METHODS: The outcomes of all infants who had a true primary repair of EA from 1976-1997 were determined. Surgically, the methods used to achieve a reliable true primary repair were expanded to accomplish this, even for a very long gap EA. RESULTS: From 1976-97, 70 infants with or without associated tracheoesophageal fistula (TEF) had primary repairs performed with no surgery-related deaths and 11% later deaths. No interpositions were performed since 1983. There were no discernible anastomotic leaks and one late recurrent TEF related to the early use of balloon dilation. Ten infants had gaps of 5.0-6.8 cm and, among these, four had gaps of 5.5-6.8 cm that could not be pulled together initially. Traction sutures in the esophageal ends, however, produced sufficient lengthening within 6-10 days for a true primary repair. Very long gap repairs produced more reflux (10 of 10 required a fundoplication versus 24 of 70 overall) and more dilations to relieve strictures. Two infants underwent stricture resection with no recurrence. On follow-up, all patients over 2 years of age were eating well or satisfactorily, and none had a gastrostomy tube. CONCLUSIONS: (1) The esophageal anastomosis can withstand considerable tension and allows a reliable true primary repair for the full EA spectrum. (2) Growth is rapid and traction sutures will produce significant esophageal lengthening within days. (3) With increasing tension, gastroesophageal reflux (GER) and strictures are more common; however, both are treatable. Follow-up reveals the benefits of true primary repair over other solutions.

Primary repair of ultra-long-gap esophageal atresia: results without a lengthening procedure.

Ultra-long-gap esophageal atresia, defined as a gap length of 3.5 cm or greater, has proved difficult to repair. When primary repair has been attempted, even with bougienage, circular myotomy, or intraabdominal esophageal mobilization to lessen anastomotic tension, leaks, anastomotic disruptions, and recurrent tracheoesophageal fistulas are frequent. Consequently, interposition grafts are commonly used. For long-term function the intact native esophagus should be preferable to an interposition graft or the consequences of circular myotomy. Therefore, even when an ultra-long gap is present, we have carried out a primary repair using our single-layer technique without myotomies. Since 1979, 8 of 58 infants (14%) with esophageal atresia had gaps ranging from 3.5 to 6 cm. All had a primary repair with follow-up from 1 to 11 years. Despite severe anastomotic tension in all cases, there were no anastomotic leaks, disruptions, recurrent tracheoesophageal fistulas, or deaths. The tension, however, may have led to major gastroesophageal reflux in 5 of 8 patients (62.5%), all treated by a Nissen fundoplication, and a stricture in 4 of 8 infants (50%). Three strictures responded to dilation and one was resected. Now, all children are eating a normal diet for age. In conclusion, this technique has allowed primary repair of ultra-long-gap esophageal atresia. Although the severe tension may contribute to strictures needing dilation and gastroesophageal reflux requiring fundoplication, primary repair resulted in a clinically functional native esophagus.

Glucagon effect on postischemic recovery of intestinal energy metabolism.

Glucagon is a potent mesenteric vasodilator, inotrope, and stimulant of intestinal metabolism that enhances survival when given during reperfusion after intestinal ischemia. However, the mechanism of improved survival is unclear and may be due to systemic hemodynamic effects rather than intestinal metabolic changes. We examined the effects of glucagon on intestinal energy metabolism during reperfusion after intestinal ischemia. Sprague-Dawley rats were subjected to 50 min intestinal ischemia by clamping the superior mesenteric artery. All received 10 ml/kg.hr 5% glucose in normal saline for 3 hr. One group (n = 17) received 1.6 micrograms/kg.min glucagon for 2 hr beginning at reperfusion. Control rats (n = 10) received only vehicle. Jejunal biopsies preischemia, end ischemia, 10, 20, 45, 80 min, and 24 hr after reperfusion were analyzed for ATP, ADP, and AMP. ATP decreased more than 60% with ischemia and recovered substantially in all animals by 10 min postischemia. ATP recovered steadily in control rats and by 24 hr was not distinguishable from baseline. In contrast, in glucagon-treated rats, ATP decreased at 20 and 45 min during reperfusion, but recovered incompletely by 24 hr after ischemia. Energy charge (EC = ([ATP] + 1/2[ADP]) divided by ([ATP] + [ADP] + [AMP])) decreased during ischemia but recovered immediately after reperfusion in both groups, implying that energy was available, energy metabolic enzyme systems were at least partially intact, and immediate recovery was not limited by available substrate and blood flow. However, energy charge decreased slightly during glucagon infusion, suggesting increased utilization of energy or some derangement of energy metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Internal mammary artery for arterial pressure monitoring after pediatric cardiac operations.

Establishing and maintaining arterial access in pediatric cardiac operations is a frequent and sometimes frustrating problem. We have modified a procedure commonly used in our research laboratory for arterial pressure monitoring and applied it successfully to the pediatric cardiac surgical patient. The internal mammary artery can provide reliable arterial access in the postoperative period.

Repair of multiple mycotic aortic aneurysms in a newborn.

Thoracoabdominal aortic and common and internal iliac artery mycotic aneurysms resulted from an umbilical arterial catheter in a 3 1/2-week-old boy. He underwent staged repair including an 8-mm Gore-tax tube graft, primary repair of the common iliac artery aneurysm, and resection of the internal iliac aneurysm. His operative and postoperative course was uneventful. He was asymptomatic at 17 months' follow-up, with equal blood pressure in the upper and lower extremities. Magnetic resonance imaging showed no stenoses or recurrent aneurysms at the anastomotic sites of the Gore-tex tube graft. Blood supply to his left leg came from collaterals, principally a large crossing vessel from the right iliac artery. This case represents the first successful aortic replacement in a 5 week old with extensive involvement of the thoracoabdominal aorta and its branch vessels.

The ivory tower from outside and in: a survey of Minnesota surgeons.

BACKGROUND: Increasing competition has eroded the patient base of many university hospitals and may jeopardize their teaching programs. METHODS: We questioned all private surgeons (PS), university surgeons (US), and resident surgeons (RS) in our state. Chi-squared analysis was used. RESULTS: Most PS, US, and RS, respectively, answered "yes" when asked to respond to the following items: whether teaching hospitals were the best way to educate new surgeons (77% versus 96% versus 87%), whether surgery residencies should be based at a university hospital (72% versus 96% versus 91%), and whether PS should refer complicated clinical cases for teaching purposes (75% versus 87% versus 68%). Differences appeared when the groups were asked whether the university should take the lead in guaranteeing the quality of surgical care in the state (67% versus 100% versus 77%, p = 0.002) and whether PS are better teachers of surgery than US (40% versus 4% versus 59%, p = 0.0001). An unexpected and disturbing trend was observed in RS when groups were asked whether practicing surgeons had any obligation to the state's university (57% versus 74% versus 22%, p = 0.0001) and whether surgeons had an obligation to repay society for their education (77% versus 83% versus 56%, p = 0.005). CONCLUSIONS: Despite recent changes in medical economics, most PS still feel residency programs should be university based. A significantly smaller percentage of RS feel an obligation to their university and to society than do either PS or US.

Myocardial carnitine metabolism in congestive heart failure induced by incessant tachycardia.

Persistent tachycardia induces congestive heart failure (CHF), but the mechanism(s) of progressive ventricular dysfunction is (are) unclear. This study was designed to define possible metabolic causes of myocardial dysfunction in rapid ventricular pacing induced CHF. Twelve adult mongrel dogs were paced to 250 beats/min for 19 days. Plasma carnitine, norepinephrine and renin were measured at 0, 1, 2, and 3 weeks. Myocardial high energy phosphates, carnitine, glycogen, glucose, non-collagenous protein and collagen were measured at 19 days. Cardiac output, arterial pressure and pulmonary wedge pressure, measured at baseline and with CHF, showed a decrease in cardiac output and increase in pulmonary wedge pressure. Neurohumoral activation was evident by progressively increasing plasma norepinephrine and renin activity and depletion of myocardial norepinephrine. Plasma free carnitine rose significantly from 12.6 +/- 2.0 control to 28.3 +/- 3.8 nmol/ml at 19 days (p < 0.001), whereas myocardial total carnitine was lower in paced than in control dogs (6.0 +/- 1.9 vs. 14.1 +/- 3.5 nmol/mg non-collagenous protein, p < 0.001). Myocardial ATP ATP and ADP were unchanged, while AMP decreased 22%, and creatine phosphate decreased 30% compared to control animals. Myocardial glucose was normal but glycogen was decreased 54% (p < 0.005). The low myocardial carnitine and elevated plasma carnitine in pacing induced CHF suggests altered carnitine transport or membrane integrity.

Use of a modified van der Pol's oscillator to construct ventricular pressure-volume relations.

Ventricular pressure-volume (PV) loops provide information about ventricular function. Methodologic constraints have limited derivation of PV loops to the laboratory. The present study addresses derivation of PV loops from a direct left ventricular pressure measurement and left ventricular volume derived from continuous cardiac output. The measurements were performed in vivo in intact, innervated, normal canine hearts. Data from a total of 5 dogs and 13 different cardiac work states were analyzed. A nonlinear oscillator, a van der Pol's oscillator, described the PV relationships. Comparison of left ventricular stroke work derived from the van der Pol's oscillator model with that obtained from ultrasound transducers sutured directly to the myocardium demonstrated a linear correlation, close to the identity line, with R2 = 0.90. Modelling of LV PV loops by this technique was similar to loops derived by experimental measurements. This technique could lead to increased clinical uses for PV relationships.

Results of a right ventricular outflow patch for pulmonary atresia with intact ventricular septum.

BACKGROUND: Although overall outcome has improved, pulmonary atresia with intact septum remains a difficult surgical and clinical problem. To determine whether an early right ventricular outflow patch will result in biventricular repair for this lesion, we reviewed the long-term follow-up (5.8 +/- 0.8 years) of 19 newborns who underwent repair between 1979 and 1990. METHODS AND RESULTS: An early right ventricular outflow patch was placed in 15 of 19 newborns; in the remaining four, this was preceded by an aortopulmonary shunt. Prostaglandin E1 infusion postoperatively eliminated the need for shunt in 14 of 15. Coronary sinusoids were ligated in three newborns. Based on right ventricular morphology, the newborns were divided into two groups: group 1 (tripartite, n = 9) and group 2 (bipartite and monopartite, n = 10). Before surgery, group 1 had significantly larger right ventricular volumes (23.6 +/- 3.7 versus 5.2 +/- 1.1 ml/m2, p < 0.002). Five-year survival was 79% for the entire series. Four infants, all group 2, died within 12 months of their initial surgery. Fourteen of 15 survivors (nine group 1 and five group 2) currently are acyanotic and New York Heart Association functional class I. A biventricular repair was achieved in 12 of 15, and three other children are awaiting evaluation. All 15 survivors had significant right ventricular and tricuspid annulus growth. CONCLUSIONS: Our data suggest that early placement of a right ventricular outflow patch in infants with pulmonary atresia and intact ventricular septum, regardless of right ventricular anatomy, results in an excellent chance for biventricular repair.

Staged repair of interrupted aortic arch and ventricular septal defect in infancy.

Staged repair of interrupted aortic arch and ventricular septal defect was carried out in 20 infants from 1979 through 1990. Among the important associated cardiac defects were transposition of the great arteries, truncus arteriosus, and anomalous origin of the right pulmonary artery. The first stage, usually consisting of the placement of an 8- or 10-mm polytetrafluoroethylene graft, pulmonary artery banding, and ligation of the patent ductus arteriosus, resulted in 20 survivors (100%) There were two interim deaths (10%) before the second stage of ventricular septal defect closure and pulmonary artery band removal, which had 15 survivors (83%, 15/18). Because the major morbidity and mortality early in this experience could be traced to leaving the pulmonary artery band on too long, early removal (within 2 to 3 months) was begun. Since 1985, 8 (100%) of 8 infants have survived both stages and are now doing well. Because of the relatively large polytetrafluoroethylene graft, only 1 child (aged 9 years) has experienced substantial late aortic arch obstruction and undergone placement of an 18-mm Dacron graft without difficulty. Of interest is the finding that in only 1 (5%) of the 20 patients has major (greater than or equal to 40-mm Hg gradient) left ventricular outflow tract obstruction developed. In summary, the staged repair of interrupted aortic arch with ventricular septal defect has become very reliable despite the condition of the infant or major associated cardiac anomalies and can be recommended for infants at high risk for primary repair. More long-term information will be needed to determine which approach will be the best choice for the majority of infants.

Ischemic contracture begins when anaerobic glycolysis stops: a 31P-NMR study of isolated rat hearts.

The relationships among myocardial ATP, intracellular pH, and ischemic contracture in Langendorff-perfused rat hearts were investigated by 31P nuclear magnetic resonance spectroscopy during total global normothermic ischemia while the left ventricular pressure was recorded continuously via an intraventricular balloon. Glucose-perfused hearts (n = 63) were divided into five groups based on the time of onset of contracture (TOC), and three other groups of hearts were treated to vary the ischemic glycogen availability. ATP levels, which showed no evidence of accelerated ATP depletion during contracture, were significant and variable at TOC. Intracellular pH initially declined and then leveled off at TOC, with lower final pH in hearts with later TOC. We conclude that contracture began when anaerobic glycolysis (and thus glycolytic ATP synthesis) stopped. These results, though consistent with the concept that ischemic contracture in normal hearts results from rigor bond formation due to low ATP levels at the myofibrils, suggest that TOC is more closely related to glycolytic ATP production than to total cellular ATP content, thus providing evidence of some degree of subcellular compartmentation or metabolite channeling. In glycolytically inhibited hearts, the quite early contracture may have a Ca2+ component.

31P NMR measurement of mitochondrial uncoupling in isolated rat hearts.

Mitochondrial uncoupling is often invoked as a mechanism underlying cellular dysfunction; however, it has not been possible to study this phenomenon directly in intact cells and tissues. In this paper, we report direct evaluation of mitochondrial uncoupling in the intact myocardium using 31P NMR magnetization transfer techniques. Langendorff perfused rat hearts were exposed to either a known uncoupler, 2,4-dinitrophenol (DNP), or a potential uncoupler, octanoate. Both DNP and octanoate decreased mechanical function as measured by the rate pressure product and caused an increase in the oxygen consumption rate (MVO2); with DNP this increase in MVO2 was dose-dependent. The ATP synthesis rate measured by 31P NMR, however, was not elevated commensurately with MVO2; instead, the P/O ratio declined. In contrast, the linear relationship between the ATP synthesis rate and rate pressure product was not altered by the uncoupling agents. These data demonstrate that 1) 31P NMR magnetization transfer can be utilized to measure uncoupling of oxidative phosphorylation in intact organs, 2) octanoate does not induce excess ATP utilization in the intact heart, and 3) high levels of octanoate induce mitochondrial uncoupling in the intact myocardium; and this may, in part, be the cause of the toxic effects associated with fatty acid exposure.

A comparison of different carbohydrates as substrates for the isolated working heart.

Ribose has been shown to greatly enhance ATP recovery in situations such as postischemia when total adenine nucleotides have been depleted by catabolism. In addition, metabolic studies have reported that both five carbon sugars and alcohols (ribose and xylitol) can support energy metabolism presumably after conversion to substrates for glycolysis. Because of the importance of these two aspects of energy metabolism to myocardial function, we compared the ability of ribose and xylitol with glucose and pyruvate as exclusive substrates for the isolated working rat heart. Our studies revealed, however, that the utilization of ribose or xylitol as substrates by the myocardium is not sufficiently rapid to rely on these as exclusive oxidizable substrates. In fact, ribose or xylitol are no more effective than substrate-free medium in this regard. Myocardial glycogen was depleted in these groups and after a lag period consumption of oxygen also decreased. In contrast to the postischemic situation the total adenine nucleotide levels were preserved during ribose, xylitol or substrate-free perfusion. Consequently, the energy charge in these hearts fell significantly. In hearts perfused with ribose, xylitol or no substrate, the rate pressure product and the stroke volume rapidly declined after an initial brief stable period corresponding to glycogen depletion. Glycogen levels were 6% of the average control value in ribose- and xylitol-perfused hearts and were undetectable in substrate-free perfused hearts. In contrast, either glucose or pyruvate supported steady levels of ATP and myocardial oxygen consumption; maintained the energy charge; and supported the stroke volume, rate pressure product, and cardiac work. In glucose-perfused hearts the glycogen was reduced to 21% of control values, while in pyruvate-perfused hearts the average glycogen levels were 76% of control. Thus, although the heart is able to metabolize ribose and xylitol through the hexose monophosphate pathway, the rate of utilization through glycolysis and presumably the TCA cycle is not sufficient for these compounds to serve as exclusive substrates for the isolated working heart.

Alterations in oxidative function and respiratory regulation in the post-ischemic myocardium.

In the normal and post-ischemic, isovolumic Langendorff perfused rat hearts, 31P NMR spectra and mechanical performance were evaluated over a wide range of myocardial oxygen consumption rates (MVO2). Hearts were perfused with either glucose and insulin, palmitate and glucose, or pyruvate and glucose as exogenous carbon sources. After ischemia at 38 degrees C until the onset of ischemic contracture and subsequent reperfusion, the "free" ADP levels were significantly reduced as compared to controls. In the control palmitate + glucose and glucose + insulin groups, the ADP levels were virtually independent of approximately 2.5-fold variation in MVO2; in contrast, they changed 4-fold with a approximately 30% variation in MVO2 in the post-ischemic myocardium following ischemia to contracture. In the pyruvate + glucose group, ADP levels varied with MVO2 in controls and post-ischemia; however, MVO2-ADP relationship was significantly altered following ischemia. Analysis of these observations within the concept of kinetic regulation of oxidative phosphorylation yielded the following significant conclusions: 1) the mode of respiratory regulation changed from a non-ADP to an "ADP:Pi limited" domain with non-pyruvate carbon sources; 2) respiratory regulation was in the ADP:Pi limited domain before and after ischemia in the pyruvate + glucose group; however, the Km for the relationship between MVO2 and ADP was reduced following the ischemia/reperfusion insult; 3) the post-ischemic oxidative capacity (Vmax for MVO2) was significantly reduced in all groups and this reduction would limit maximal post-ischemic mechanical performance.