Steven M. Yabek

Noninvasive pulsed Doppler determination of cardiac output in neonates and children

Mean blood flow velocity (VAo) in the ascending aorta was measured noninvasively in 33 children, ages 3 days to 17 years, by pulsed Doppler technique at the time of cardiac catheterization. Measurements were made from a suprasternal approach with a portable, range-gated device. The ascending aortic diameter was determined echocardiographically and aortic cross sectional area calculated (A = pi d2/4 cm2). Aortic flow (QAo) was computed from Doppler recordings: QAo (ml/minute) = VAo (cm/second) X A (cm2) X 60 (second/minute). Values were compared with cardiac outputs determined according to the Fick principle, using measured oxygen consumption calculated oxygen capacity, and oxygen saturation. Subjects with aortic valve abnormalities or left ventricular outflow tract obstruction were excluded from study. Agreement between the two methods was excellent (linear regression r = 0.98, slope = 1.07, y-intercept = -4.5 ml, range 403 to 5.540 ml/minute). The Doppler technique is a quick, noninvasive, and accurate method of determining ascending aortic blood flow in neonates and children.

Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics

Dl-sotalol is a specific beta-adrenergic blocking agent that markedly lengthens cardiac action potential duration. To determine whether d-sotalol, with little or no beta-blocking effect, also lengthens repolarization, standard microelectrode studies were used to determine the electrophysiologic properties of dl-sotalol and its stereoisomers in isolated rabbit and canine myocardial fibers. D- and l-sotalol produced concentration-dependent increases in action potential duration to 50% (APD50) and 90% (APD90) repolarization, respectively, and in the effective refractory period without changes in the maximal rate of rise of action potential. In rabbit sinoatrial node, d- and l-sotalol produced concentration-dependent increases in spontaneous sinus cycle length (29 and 35%, respectively) by lengthening the action potential duration (by 58 and 55%) without effect on phase 4 depolarization. At the highest concentration (27.2 micrograms/ml), d- and l-sotalol prolonged APD90 (by 38 and 54%, respectively, in Purkinje fibers and by 32 and 34% in ventricular muscle) and effective refractory period (by 49 and 49% in Purkinje fibers and 29 and 40% in ventricular muscle). The effects of the two isomers were not significantly different. At the middle concentration (2.7 micrograms/ml), d-sotalol, unlike l-sotalol, had no beta-adrenergic blocking effect, but the electrophysiologic effects of dl-, d- and l-sotalol were indistinguishable. The data indicate that d-sotalol is equipotent with l-sotalol in lengthening the action potential duration and effective refractory period in cardiac muscle, an action unrelated to adrenergic antagonism or pharmacokinetic differences between the stereoisomers.

Effects of amiodarone and its metabolite, desethylamiodarone, on the electrophysiologic properties of isolated cardiac muscle.

Summary: The electrophysiologic (EP) effects of chronically administered amiodarone (AM) is known, but the nature of its acute effects are unclear. Whether the delayed onset of AM action is due to its metabolite, desethylamiodarone (DAM), is also uncertain. By standard microelectrode techniques in isolated canine ventricular muscle (VM) and Purkinje fibers (PF) and in rabbit sinoatrial (SA) node and atrium, we therefore studied the comparative effects of AM and DAM, 10−6 M (0.68 μg/ml), 10−5 M (6.8 μ/ml), and 5 × 10−5 M (34 μg/ml), dissolved in ethanol and homologous serum. In VM, PF, and atria stimulated at 1 Hz, AM and DAM had no effect on &OV0312;max, action potential amplitude (APA), or resting membrane potential. At 2–4 Hz, AM exerted a marked use-dependent effect in VM and PF. In atria, 5 × 10−5 M, AM and DAM increased (p < 0.01) action potential duration at 90% repolarization (APD90); the effective refractory period (ERP) increased by 10.5% (p < 0.05 for AM) and 21.6% (p < 0.01 for DAM). In VM, AM increased APD90 by 9.6% (p < 0.01) at 10−6 M, 13.7% (p < 0.01) at 10−5 M, and 16.9% (p < 0.01) at 5 × 10−5 M. The corresponding values for DAM were 5.6% (NS), and 7.3% (p < 0.01), respectively. The ERP in VM was increased significantly by AM but not by DAM at all 3 drug concentrations without a change in APD90/ERP ratio. In PF, AM and DAM decreased APD50 and APD90; the effects were greater than those produced by the superfusion medium, but the degree of shortening in ERP induced by AM and DAM was not. AM and DAM (10−5 and 5 × 10−5 M) increased spontaneous cycle length of rabbit SA node. AM significantly decreased slope of phase 4 depolarization (10.4% at 10−6 M, p < 0.05; 14.5% at 10−5 M, p < 0.01; 24.0% at 5 × 10−5 M, p < 0.01). At 5 × 10−5 M, AM significantly decreased APA, maximum diastolic potential and threshold potential with an insignificant effect on APD100. The data suggest that: (a) AM and DAM exert qualitatively and quantitatively similar EP effects in isolated cardiac muscle, (b) in the case of AM, the delay in repolarization and refractoriness is less striking than that previously reported following chronic drug administration, and (c) the modest increase in ERP occurs essentially by a voltage-dependent mechanism but the drugs use-dependent effects on &OV0312;max suggest a significant class I antiarrhythmic action at fast stimulation frequencies. We conclude that AM and DAM exert complex, acute EP effects in cardiac muscle reflecting changes in repolarization as well as in fast and slow depolarization currents.

Effects of Digoxin in Infants with a Congested Circulatory State Due to a Ventricular Septal Defect

Digoxin alone was used to treat a congested circulatory state in 21 infants (mean age, 2.7 months; mean weight, 3.8 kg) with a ventricular septal defect. The dose was adjusted on the basis of pharmacokinetics to achieve a mean steady-state concentration of 1.6 +/- 0.3 ng of digoxin per milliliter of serum. The mean red-cell level of sodium-potassium ATPase fell from 23.1 +/- 7.0 to 12.6 +/- 5.2 nmol per milligram per minute with treatment. Only 6 of the 21 patients had an inotropic response, as reflected by echocardiographic measurements, but the drug was of clinical benefit to 12 infants (including these 6). These results show that not all infants with a congested circulatory state due to a ventricular septal defect benefit from digoxin therapy. Furthermore, in some subjects clinical improvement occurs in the absence of a measurable inotropic response.

Effect of patent ductus arteriosus on left ventricular output in premature infants

A 5 MHz range-gated portable pulsed Doppler velocity meter was used to measure mean ascending aortic blood flow velocity noninvasively. Studies were performed from a suprasternal approach in 18 preterm infants with patent ductus arteriosus. Measurements were made in each patient before and after medical or surgical closure of the PDA. The internal ascending aortic diameter was determined echocardiographically and aortic cross-sectional area calculated according to the equation AAo = pi d2/4. Ascending aortic blood flow was computed as QAo (ml/min) = VAo (cm/sec) x AAo (cm2) x 60 (sec/min). Prior to PDA closure, QAo averaged 343 ml/min/kg, well above predicted normal values. After PDA closure, QAo fell to 252 ml/min/kg, significantly lower than the preclosure level (P less than 0.001), but slightly higher than the mean cardiac output of healthy newborn infants. The mean QAo after surgical ligation of the PDA was closer to the predicted normal value than after treatment with indomethacin alone. This study reflects the effect of left-to-right ductus shunting on left ventricular output and emphasizes the demands placed on the neonatal left ventricle by PDA.

Acute effects of amiodarone on the electrophysiologic properties of isolated neonatal and adult cardiac fibers

The acute cellular electrophysiologic actions of amiodarone on isolated neonatal and adult canine ventricular muscle and Purkinje fibers were evaluated using standard microelectrode techniques. Amiodarone, 10(-6) to 5 X 10(-5) M (0.68 to 34 micrograms/ml), significantly (p less than 0.05) prolonged adult ventricular muscle action potential duration and voltage-dependent refractoriness at all concentrations, thereby demonstrating typical class III antiarrhythmic effects. Similar concentrations had no significant effects on neonatal ventricular muscle. Amiodarone significantly shortened action potential duration and refractoriness of both neonatal and adult Purkinje fibers, with neonatal fibers having a greater sensitivity to the drug. At the standard stimulation rate of 1 Hz, amiodarone had no effects on action potential amplitude or maximal rate of rise of phase 0 of the action potential (Vmax) of any tissues. At faster stimulation frequencies (2 to 4 Hz), amiodarone produced frequency-dependent decreases in action potential amplitude and Vmax of all neonatal and adult preparations. The data indicate that amiodarone exhibits a complex aggregate of electrophysiologic actions that include significant frequency-related class I effects. Compared with adult myocardium, neonatal tissues demonstrated altered responsiveness to amiodarone, a feature common to many antiarrhythmic compounds.

Accuracy of echocardiography in assessing left ventricular dimensions and volume.

SUMMARYThe accuracy of determining left ventricular function from echocardiography was assessed in 26 children (group I) with cineangiographically-determined normal left ventricular volume (LVV) and 28 children (group II) with large left ventricular volumes. Conventional LV echo dimensions were compared to the cineangiographic LV anterior-posterior minor axis (LVmA) and LVV. Very good correlations were found in group I between LV enddiastolic echo dimensions (LVEDD) and cine LVmA (r = 0.91) and between LVEDD and LV end-diastolic volume (LVEDV) by cine in group I (r = 0.86). In group II correlations were less accurate between LVEDD and diastolic LVmA and between LVEDD and LVEDV. There was poor correlation between the cine and echo percent of shortening (r = 0.41) and velocity of circumferential fiber shortening (VCF) (r = 0.51). This study demonstrates that M-mode echocardiography is a very useful method for determining LV dimensions in children with normal LV volume, but is less accurate in children with left ventricular volume overload or with abnormal septal orientation or postoperative status after ventriculotomy.

Long-term follow-up of bronchopulmonary dysplasia

We observed 10 children with bronchopulmonary dysplasia, evaluated initially by cardiac catheterization (mean age 18 months), for an average of 4.4 years. Age at last evaluation averaged 5.8 years; subjects reside in and around Albuquerque, N.M. (altitude 5000 ft). At initial cardiac catheterization, mean pulmonary artery pressure was 40 mm Hg, pulmonary vascular resistance index 8.9 units, and intrapulmonary shunt fraction was high; pulmonary wedge angiograms were normal. Over the period of follow-up the group has done poorly. Four of the 10 continue to receive home oxygen therapy, but none requires inotropic or diuretic therapy; four children have marked developmental or motor delays. Nine of 10 patients have abnormalities of respiratory function on spirometric testing. Four patients underwent recatheterization because of clinical indications; two had large atrial level left-to-right shunts not found on initial study. Reductions in pulmonary artery pressure (55 to 37 mm Hg) and pulmonary vascular resistance (11.9 to 7.8 units) occurred between the two studies in these four patients (average study interval 4.0 years); the still elevated levels of pressure and resistance fell further in response to 40% O2 administration. Pulmonary wedge angiograms were abnormal in each restudied patient. Although not uniformly bleak, the long-term outlook for children with severe bronchopulmonary dysplasia is diverse and guarded.

Systemic oxygen transport in patients with congenital heart disease.

The physiology of oxygen delivery was studied in 118 stable patients from 3 months to 20 years old with congenital heart disease. During cardiac catheterization, oxygen consumption (VO2), arterial and venous blood gases and oxygen saturations (range 41% to 98%), hemoglobin concentration, diphosphoglycerate (2,3-DPG), and P50 levels were measured, and then cardiac output, systemic oxygen transport (SOT), arterial and venous oxygen contents, and the VO2/SOT ratio (fractional O2 extraction) were calculated. P50 averaged 31 mm Hg, compared with 27 mm Hg in 10 control children (p less than .01). The composite O2-hemoglobin dissociation curve in vivo was broad: Po2 varied from 37 to 65 mm Hg at 80% saturation. P50, 2,3-DPG, hemoglobin concentrations, and O2 saturation varied widely and inconsistently with Po2 and arterial and venous O2 content, but resulted in clustering of the arterial oxygen content near 165 +/- 23 (SD) ml/liter over a wide range of Po2 and hemoglobin concentrations. SOT varied in direct relation with flow (r = .82, p less than .001), but not with oxygen content, Po2, or P50. VO2 varied widely at normal or high levels of SOT, but decreased linearly at SOT levels below 400 ml/min/m2. Oxygen extraction varied inversely with venous O2 content, rising to about 50% and plateauing below venous contents of 100 ml/liter. O2 extraction did not correlate with Po2, arterial O2 content, or P50. These data suggest that: O2 saturation cannot be predicted or calculated accurately from measured Po2, but must be measured directly, 2,3-DPG, hemoglobin concentration, and P50 fluctuate to stabilize arterial oxygen content, SOT is determined primarily by cardiac output in subjects who are adapted chronically, O2 extraction rises, due to a fall in venous O2 content, to maintain VO2 as transport falls, below a critical level of SOT, O2 extraction ceases to rise and VO2 falls with further reduction in transport.

Hemodynamic consequences of neonatal polycythemia

The hemodynamic consequences of neonatal polycythemic hyperviscosity and the effects of partial exchange transfusion were evaluated in 13 infants. Mean (+/- SD) venous hematocrit was 72% +/- 2.5%. After partial exchange transfusion, whole blood viscosity at a shear rate of 11.5 sec-1 decreased from 16.2 to 8.4 centipoise. There were significant (P less than 0.05) increases in heart rate (127 +/- 7.5 to 139 +/- 7.8 beats/min), Doppler-derived cardiac index (200 +/- 35 to 263 +/- 48 ml/kg/min), left ventricular stroke volume index (1.56 +/- 0.23 to 1.89 +/- 0.33 ml/kg), systemic oxygen transport (51.4 +/- 8.4 to 57.9 +/- 11.9 ml/kg/min), and laser-Doppler peripheral (cutaneous) blood flow (+80%) after partial exchange transfusion. The increase in cardiac index probably resulted from reductions in pulmonary and systemic vascular resistance index, the latter decreasing from 0.26 to 0.19 mm Hg/ml/min/kg-1. The greater increase in cutaneous blood flow (+80%) versus cardiac index (+32%) after exchange transfusion suggests hemodynamic compromise and a redistribution of blood flow away from organs that use little oxygen during polycythemia. Our data provide a possible basis for the symptoms of neonatal polycythemia, and demonstrate the acute hemodynamic benefits of partial exchange transfusion.