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Biomedical subjects

Daniel J Penny

Publications and source records attributed to Daniel J Penny.

At least 19 recordsLinked to original sources
PubMed2006

Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children.

RATIONALE: Rebound pulmonary hypertension (PHT) can complicate the weaning of nitric oxide (NO), and is in part related to transient depletion of intrinsic cyclic guanosine monophosphate. Rebound is characterized by increased pulmonary arterial (PA) pressure, cardiopulmonary instability, and in some cases, the need to continue NO beyond the intended period of use. There is anecdotal evidence that sildenafil, a phosphodiesterase-5 inhibitor, may prevent recurrence of rebound. OBJECTIVES: We investigated the role of sildenafil in preventing rebound (an increase in PA pressure of 20% or greater, or failure to discontinue NO) in patients in whom previous attempts had not been made to wean from NO. METHODS: Thirty ventilated infants and children, receiving 10 ppm or greater inhaled NO, were randomized to receive 0.4 mg/kg of sildenafil, or placebo, 1 h before discontinuing NO. Twenty-nine patients completed the study. MEASUREMENTS: PA pressures and blood gases were measured before the study drug, and 1 and 4 h after stopping NO. MAIN RESULTS: Rebound occurred in 10 of 14 placebo patients, and 0 of 15 sildenafil patients (p < 0.001). PA pressure increased by 25% (14-67) in placebo patients, and by 1%(-9-5) in sildenafil patients (p < 0.001). Four placebo patients could not be weaned from NO due to severe cardiovascular instability, whereas all sildenafil patients were weaned (p = 0.042). Duration of ventilation after study was 98.0 (47.0-223.5) h for placebo patients and 28.2 (15.7-54.6) h for sildenafil patients (p = 0.024). CONCLUSION: A single dose of sildenafil prevented rebound after withdrawal of NO, and reduced the duration of mechanical ventilation. Prophylaxis with sildenafil should be considered when weaning patients from inhaled NO.

Administration, Inhalation↗
PubMed2006

Effect of intravenous sildenafil on pulmonary hemodynamics and gas exchange in the presence and absence of acute lung injury in piglets.

Sildenafil is becoming increasingly popular for the treatment of pulmonary hypertension. However, there are potential concerns regarding its effects on oxygenation and systemic hemodynamics that could theoretically reduce its utility in the neonatal population. We performed a prospective cumulative dose-response study of increasing doses of i.v. sildenafil (0.4, 1, and 3 mg/kg) on hemodynamics and oxygenation in 32 anesthetized piglets, of which 17 had meconium-induced pulmonary hypertension and lung injury, and 15 did not. Sildenafil caused a reduction in mean pulmonary artery pressure and pulmonary vascular resistance (PVR) at all doses, in non-lung-injured animals. There was no difference in pulmonary hemodynamics between doses. Oxygenation index [OI = mean airway pressure (cm H2O) * FiO2 * 100/PaO2 (mm Hg)] did not reach critical levels at any dose. In lung-injured animals, sildenafil also reduced mean pulmonary artery pressure and PVR by 30%. Again, this effect was achieved at the lowest dose, without subsequent changes at higher doses. However, in lung-injured animals, sildenafil produced a dose-related increase in oxygenation index. Sildenafil reduced the systemic vascular resistance (SVR) at the lowest dose in lung-injured animals, but this occurred only at higher doses in non-lung-injured animals. In conclusion, sildenafil is a potent pulmonary vasodilator. However, it should be administered with caution in the presence of lung injury because of a dose-related increase in oxygenation index and concomitant systemic vasodilatation.

Animals↗
PubMed2006

Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hypertension.

Since September 2001, 7 consecutive patients with childhood idiopathic pulmonary arterial hypertension (IPAH), a rapidly progressive and fatal condition, have been treated with combinations of bosentan, and other therapies (sildenafil/warfarin/epoprostenol), at our institution. Survival and clinical status in these patients were compared with a group of 12 historic control patients who were diagnosed prior to 1997 and received only conventional medical therapy. Survival in the bosentan-treated subjects was better than among historic controls with comparable disease severity (log rank, p = 0.04). Our findings indicate treatment with bosentan permits a delay in IPAH disease progression and, in combination with other therapies, improves survival compared with historic control patients.

Age Factors↗
PubMed2005

Non-invasive measurement of intrapulmonary shunt during inert gas rebreathing.

We tested the agreement between non-invasive measurement of intrapulmonary shunt, using oxygen uptake and pulmonary capillary blood flow measurement obtained by nitrous oxide rebreathing, with that measured using mixed venous blood sampling. Nine patients were recruited pre- and post-cardiac surgery resulting in 20 sets of measurements overall. Mean shunt fraction was 12.5%, and bias between methods (+/-95% confidence limits) was -0.7% (+/-0.8%). The standard deviation of the difference was 1.7% with limits of agreement between the two methods of +2.6% and -3.9%. Correlation coefficient r was 0.90. Agreement with the invasive standard was less accurate and precise where cardiac output was measured by bolus thermodilution (mean bias +1.6%, standard deviation of the difference 2.2%, limits of agreement between the two methods of +5.8% and -2.8%, r = 0.86). Good agreement was demonstrated between the non-invasive method and the invasive reference standard.

Adult↗
PubMed2005

Preterm infants with congenital heart disease and bronchopulmonary dysplasia: postoperative course and outcome after cardiac surgery.

OBJECTIVE: Success in treatment of premature infants has resulted in increased numbers of neonates who have bronchopulmonary dysplasia (BPD) and require surgical palliation or repair of congenital heart disease (CHD). We sought to investigate the impact of BPD on children with CHD after heart surgery. METHODS: This was a retrospective, multicenter study of patients who had BPD, defined as being oxygen dependent at 28 days of age with radiographic changes, and CHD and had cardiac surgery (excluding arterial duct ligation) between January 1991 and January 2002. Forty-three infants underwent a total of 52 cardiac operations. The median gestational age at birth was 28 weeks (range: 23-35 weeks), birth weight was 1460 g (range: 431-2500 g), and age at surgery was 2.7 months (range: 1.0-11.6 months). Diagnoses included left-to-right shunts (n = 15), conotruncal abnormalities (n = 13), arch obstruction (n = 6), univentricular hearts (n = 4), semilunar valve obstruction (n = 3), Shone syndrome (n = 1), and cor triatriatum (n = 1). RESULTS: Thirty-day survival was 84% with 6 early and 6 late postoperative deaths. Survival to hospital discharge was 68%. There was 50% mortality for patients with univentricular hearts and severe BPD. The median duration of preoperative ventilation was 76 days (range: 2-244 days) and of postoperative ventilation was 15 days (range: 1-141 days). The median duration of cardiac ICU stay was 7.5 days (range: 1-30 days) and of hospital stay was 115 days (range: 35-475 days). Current pulmonary status includes on room air (n = 14), O2 at home (n = 4), and ventilated at home (n = 4) or in hospital (n = 4), and 5 patients were lost to follow-up. CONCLUSIONS: BPD has significant implications for children who have CHD and undergo cardiac surgery, leading to prolonged ICU and hospital stays, although most survivors are not O2 dependent. Postoperative mortality was highest among patients with univentricular hearts and severe BPD. Optimal timing of surgery and strategies to improve outcome remains to be delineated.

Bronchopulmonary Dysplasia↗
PubMed2004

Endothelin-A receptor blockade and inhaled nitric oxide in a porcine model of meconium aspiration syndrome.

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension.

Administration, Inhalation↗
PubMed2004

Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome.

There has been recent interest in the use of the phosphodiesterase-5 inhibitor sildenafil for treating pulmonary hypertension. We examined the interaction between inhaled nitric oxide (iNO) and i.v. sildenafil in 12 piglets with acute pulmonary hypertension and lung injury secondary to meconium aspiration. Six animals (controls) received no intervention after meconium instillation, and six received iNO (20 ppm) from 120 min, with the addition at 240 min of an i.v. sildenafil infusion (2 mg/kg over 2 h). Meconium instillation increased mean pulmonary artery (PA) pressure from 16.0 +/- 3.1 to 24.8 +/- 4.6 mm Hg (p < 0.01) and pulmonary vascular resistance (PVR) from 0.047 +/- 0.008 to 0.089 +/- 0.027 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.01). Oxygenation index increased from 3 +/- 0.8 to 8.3 +/- 3.0 (p < 0.01). There were no further changes beyond 120 min in controls. iNO reduced PA pressure and PVR to baseline values, without influencing oxygenation. The addition of sildenafil further reduced PA pressure, tended to increase the cardiac output, and reduced PVR from 0.049 +/- 0.02 to 0.028 +/- 0.01 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.05). Sildenafil lowered the systemic blood pressure and systemic vascular resistance and produced profound arterial hypoxemia, reducing arterial Po(2) from 69 +/- 23 mm Hg to 49 +/- 15 mm Hg, despite substantial increases first in inspired oxygen fraction and subsequently in mean airway pressures. Consequently, the oxygenation index increased by 13.9 +/- 4.8 (p = 0.01). When given in addition to iNO, sildenafil at a dose of >0.5 mg/kg produced profound pulmonary vasodilation, but this was coupled with an unacceptable deterioration in oxygenation and systemic vasodilation in this model of pulmonary hypertension with acute parenchymal lung disease.

Administration, Inhalation↗
PubMed2004

What's happening in paediatric cardiology?

Recent decades have witnessed dramatic advances in the care of adults with heart disease. However, equally significant advances have occurred in the care of children. In this review we describe some of the advances, which have been made in the care of children with heart disease, focusing not only on technological advances, but also on developments in team-based care, which together have resulted in significant improvements in outcomes.

Journal Article↗
PubMed2004

Insulin-like growth factor 1 improves the relationship between systemic oxygen consumption and delivery in piglets after cardiopulmonary bypass.

OBJECTIVE: We sought to assess the effects of insulin-like growth factor 1 on the balance between systemic oxygen consumption and oxygen delivery after cardiopulmonary bypass in piglets. METHODS: Twelve piglets weighing 4.5 to 8.3 kg undergoing hypothermic (28 degrees C) cardiopulmonary bypass for 70 to 120 minutes with 40 minutes of aortic crossclamping were studied before and during the first 6 hours after cardiopulmonary bypass. Oxygen consumption was continuously measured by an indirect calorimeter, Deltatrac II MBM-200 Metabolic Monitor (Datex Division Instrumentarium, Helsinki, Finland). Oxygen delivery and cardiac output were calculated from oxygen consumption and the arterial and mixed venous oxygen contents sampled before and every 30 minutes after cardiopulmonary bypass. Oxygen extraction ratio was derived by the ratio of oxygen consumption to oxygen delivery. Arterial blood lactate was measured before and every 30 minutes after cardiopulmonary bypass. Six animals were randomly assigned to receive an intravenous infusion of insulinlike growth factor 1 at 1.2 mg/h from 1 to 6 hours after cardiopulmonary bypass; the remaining 6 served as a control group. RESULTS: Relative to the control group, intravenous infusion of insulin-like growth factor 1 significantly reduced oxygen consumption (P =.02) and increased cardiac output (P =.016) and oxygen delivery (P =.049) during the first 6 hours after surgery with hypothermic cardiopulmonary bypass. As a result, oxygen extraction was significantly decreased (P =.012). CONCLUSIONS: Intravenous infusion of insulin-like growth factor 1 improved oxygen transport by reducing oxygen consumption as well as increasing cardiac output and oxygen delivery during the first 6 hours after cardiopulmonary bypass in piglets. This may have important clinical implications for the care of critically ill children after surgery with cardiopulmonary bypass.

Age Factors↗
PubMed2004

Stretch-induced regional mechanoelectric dispersion and arrhythmia in the right ventricle of anesthetized lambs.

Regional mechanical and electrophysiological changes accompany most ventricular arrhythmias and, it has been suggested, by mechanoelectric feedback. We hypothesized that an intervention producing regional mechanical dispersion was associated with regional, proarrhythmic electrical dispersion and studied the regional mechanoelectric feedback in the right ventricle (RV) of anesthetized lambs. Ten lambs were deeply anesthetized, and their hearts were exposed. Three tripodal devices, each incorporating three monophasic action potential electrodes and an integrated strain-gauge system, were placed on the RV apex outflow and inflow regions. Measurements were made before, during, and after 10-s pulmonary arterial occlusion. Pulmonary arterial occlusion increased RV pressure and overall regional segment length. Length excursion became out of phase with RV pressure beats immediately after occlusion, and the strain patterns were different in the three regions at the peak of occlusion. The occlusion resulted in different alterations in regional monophasic action potential morphology, including reduction in monophasic action potential amplitude and duration by different amounts and early afterdepolarizations that were unevenly distributed in the monophasic action potential recordings. This was associated with dispersion of repolarization and recovery time. The combination of electromechanical events precipitated a variety of arrhythmias. Acute RV distension is proarrhythmic, possibly through a causal relationship among mechanically induced afterdepolarizations, dispersion (heterogeneity) of mechanical strain, and dispersion of electrical recovery. The relationship among the different wall motions, the dispersion of repolarization, and arrhythmia underscored mechanoelectric feedback as an important part of arrhythmogenesis in pulmonary embolism and commotio cordis.

Action Potentials↗
PubMed2003

Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery.

OBJECTIVE: To investigate the acute effects of intravenous sildenafil on haemodynamics and oxygenation, and its interaction with inhaled nitric oxide (iNO) in infants at risk of pulmonary hypertension early after cardiac surgery. DESIGN: Prospective, randomised trial. SETTING: Paediatric intensive care unit of a children's hospital. PATIENTS AND PARTICIPANTS: Sixteen ventilated infants early after closure of ventricular or atrioventricular septal defects, were randomly assigned to one of two groups. The study was completed in 15 infants. INTERVENTIONS: Studies were commenced within 7 h of separation from bypass. Seven infants received iNO (20 ppm) first, with the addition of intravenous sildenafil (0.35 mg/kg over 20 min) after 20 min. Eight infants received sildenafil first, iNO was added after 20 min. Vascular pressures, cardiac output and a blood gas were recorded at 0, 20 and 40 min. MEASUREMENTS AND RESULTS: In infants receiving iNO first, iNO lowered the pulmonary vascular resistance index (PVRI) from 3.45 to 2.95 units (p=0.01); sildenafil further reduced PVRI to 2.45 units p<0.05). In those receiving sildenafil first, PVRI was reduced from 2.84 to 2.35 units (p<0.05) with sildenafil, and fell to 2.15 units (p=0.01) with the addition of iNO. In both groups, sildenafil reduced the systemic blood pressure and systemic vascular resistance (p<0.01) and worsened arterial oxygenation and the alveolar-arterial gradient (p<0.05). CONCLUSION: Intravenous sildenafil augmented the pulmonary vasodilator effects of iNO in infants early after cardiac surgery. However, sildenafil produced systemic hypotension and impaired oxygenation, which was not improved by iNO.

Administration, Inhalation↗
PubMed2003

Right ventricular myocardial responses to chronic pulmonary regurgitation in lambs: disturbances of activation and conduction.

Patients after repair of tetralogy of Fallot are at increased risk of arrhythmic death. Clinical data suggest that pulmonary regurgitation predisposes to these arrhythmias, although the cellular electrophysiologic effects of pulmonary regurgitation are unknown. We induced pulmonary regurgitation in lambs, and 3 mo later, having quantified the pulmonary regurgitant (PR) fraction, studied right ventricular mechanical and electrophysiologic properties in vivo and in vitro. The PR fraction was greater in PR (75 +/- 10%) than in sham-operated animals (8 +/- 4%; p < 0.01). In vivo, monophasic action potential duration and activation time, at rest and during acute right ventricular stretch, were similar in both groups. However, the dispersion of activation time was greater in PR animals at rest (13 +/- 1.1 versus 8 +/- 1.1 ms; p < 0.05). Furthermore, the dispersion of activation increased during right ventricular stretch in PR, but not in sham-operated animals. In vitro, myocardial force-frequency responses were similar in both groups, indicating preserved systolic performance, but mechanical restitution studies showed a prolonged refractory period (447 +/- 22 versus 370 +/- 26 ms; p < 0.05) and a decreased recovery time constant (184 +/- 19 versus 265 +/- 20 ms; p < 0.001) in PR animals, indicating altered calcium cycling. Furthermore, the myocardial conduction velocity was reduced in PR animals (31 +/- 3.58 versus 47.9 +/- 5.1 cm/s; p < 0.01), resulting from a 2-fold increase in intracellular resistance (437.25 +/- 125.93 versus 194 +/- 43.27 Omega. cm; p = 0.025). Chronic PR leads to inhomogeneity of right ventricular activation, alters myocardial calcium cycling, reduces conduction velocity, and increases intracellular resistivity. These may contribute to the development of arrhythmias associated with PR, including those in patients after tetralogy repair.

Animals↗
PubMed2003

Risk factors for long intensive care unit stay after cardiopulmonary bypass in children.

OBJECTIVES: To determine whether children who experience longer intensive care unit (ICU) stays after open heart surgery may be identified at admission by clinical criteria. To identify factors associated with longer ICU stays that are potential targets for quality improvement. SETTING: Tertiary pediatric cardiac surgical center. DESIGN: A retrospective review was performed of pre-, intra-, and postoperative factors for children undergoing open heart surgery. All factors were evaluated for strength of association with length of ICU stay (LOS) using a negative binomial model. After multiple analysis, factors were deemed significant if associated with a LOS with p < .02. PATIENTS: A total of 355 pediatric patients who had cardiac surgery with cardiopulmonary bypass in a 1-yr period from April 1999 until March 2000. MEASUREMENTS AND MAIN RESULTS: Children who fell above the 95th percentile for LOS in our institution occupied 30% of bed days and had a three-fold greater mortality. Of all clinical factors considered, those significantly associated with LOS were as follows: preoperative--mechanical ventilation, neonatal status, medical problems, and transfer from abroad; intraoperative--higher operative complexity, increased cardiopulmonary bypass time or ischemic time, and circulatory arrest; and postoperative--delayed sternal closure, sepsis, renal failure, pulmonary hypertension, chylothorax, diaphragm paresis, and arrhythmia. A model combining all factors identified preoperative mechanical ventilation, neonatal status, major medical problems, operative complexity, cardiopulmonary bypass time, and a postoperative complication score as independently associated with LOS (p < .01). CONCLUSIONS: At the time of ICU admission after open heart surgery, clinical criteria are evident that highlight a child's risk of longer ICU stay. These pre- and intraoperative factors relate to LOS independent of subsequent postoperative events. Those postoperative complications that are most strongly associated with increased LOS are identified and, therefore, made accessible to quality control.

Cardiopulmonary Bypass↗
PubMed2003

Measured versus estimated oxygen consumption in ventilated patients with congenital heart disease: the validity of predictive equations.

OBJECTIVE: To determine the validity of predictive equations in calculating oxygen consumption (Vo(2)) in ventilated patients with congenital heart disease. DESIGN: Prospective study. SETTING: Cardiac catheterization laboratories and intensive care units of two university teaching hospitals. PATIENTS: A total of 126 patients with congenital heart disease were studied. Of these, 75 patients received anesthesia in the pediatric cardiac catheterization laboratory, and 51 were deeply sedated in the intensive care unit after open heart surgery. MEASUREMENTS AND MAIN RESULTS: Vo(2) was measured directly in all patients using respiratory mass spectrometry. Estimated values for absolute Vo(2) (mL/min) and indexed Vo(2) (mL.min-1.m-2) were calculated from the four predictive equations published by LaFarge and Miettinen, Lundell et al., Wessel et al., and Lindahl. The agreement between measured and estimated Vo(2) was evaluated by calculating their bias and limits of agreement. A failure of agreement between measured and estimated Vo(2) was noted in both groups of patients, irrespective the equation used, and the agreement was poorer in patients in the intensive care unit. The equation by LaFarge and Miettinen produced the closest estimation in patients at cardiac catheterization with a bias of 4.5 mL/min for absolute Vo(2) and 6.9 mL.min-1.m-2 for indexed Vo(2). A systematic error of overestimating lower and underestimating higher indexed Vo(2) mL.min-1.m-2 was introduced in both groups. CONCLUSION: Predictive equations do not accurately estimate Vo(2) in ventilated patients with congenital heart disease.

Adolescent↗