Dennis M. Davidson

Inhaled Nitric Oxide for the Early Treatment of Persistent Pulmonary Hypertension of the Term Newborn: A Randomized, Double-Masked, Placebo-Controlled, Dose-Response, Multicenter Study

Objectives. To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term infants with persistent pulmonary hypertension (PPHN), with regard to neonatal outcome, oxygenation, and safety. Methods. Randomized, placebo-controlled, double-masked, dose-response, clinical trial at 25 tertiary centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, extracorporeal membrane oxygenation (ECMO), neurologic injury, or bronchopulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [Fio 2] of 1.0, a mean airway pressure ≥10 cm H2O on a conventional ventilator, and echocardiographic evidence of PPHN. Exogenous surfactant, concomitant high-frequency ventilation, and lung hypoplasia were exclusion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or 80 ppm) treatments were administered until success or failure criteria were met. Due to slowing recruitment, the trial was stopped at N = 155 (320 planned). Results. The baseline oxygenation index (OI) was 24 ± 9 at 25 ± 17 hours old (mean ± SD). Efficacy results were similar among NO doses. By 30 minutes (no ventilator changes) the Pao 2 for only the NO groups increased significantly from 64 ± 39 to 109 ± 78 Torr (pooled) and systemic arterial pressure remained unchanged. The baseline adjusted time-weighted OI was also significantly reduced in the NO groups (-5 ± 8) for the first 24 hours of treatment. The MSI rate was 59% for the control and 50% for the NO doses (P = .36). The ECMO rate was 34% for control and 22% for the NO doses (P = .12). Elevated methemoglobin (>7%) and nitrogen dioxide (NO2) (>3 ppm) were observed only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD. Conclusion. For term infants with PPHN, early I-NO as the sole adjunct to conventional management produced an acute and sustained improvement in oxygenation for 24 hours without short-term side effects (5 and 20 ppm doses), and the suggestion that ECMO use may be reduced.

Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn

Objective. Because of case reports describing hypoxemia on withdrawal of inhaled nitric oxide (I-NO), we prospectively examined this safety issue in newborns with persistent pulmonary hypertension who were classified as treatment successes or failures during a course of I-NO therapy. Methods. Randomized, placebo-controlled, double-masked, dose-response clinical trial at 25 tertiary centers from April 1994 to June 1996. Change in oxygenation and outcome (death and/or extracorporeal membrane oxygenation) during or immediately after withdrawing I-NO were the principal endpoints. Patients (n = 155) were term infants, <3 days old at study entry with echocardiographic evidence of persistent pulmonary hypertension of the newborn. Exclusion criteria included previous surfactant treatment, high-frequency ventilation, or lung hypoplasia. Withdrawal from treatment gas (0, 5, 20, or 80 ppm) started once treatment success or failure criteria were met. Withdrawal of treatment gas occurred at 20% decrements at <4 hours between steps. Results. The patient profile was similar for placebo and I-NO groups. Treatment started at an oxygenation index (OI) of 25 ± 10 (mean ± SD) at 26 ± 18 hours after birth. For infants classified as treatment successes (mean duration of therapy = 88 hours, OI <10), decreases in the arterial partial pressure of oxygen (Pao 2) were observed only at the final step of withdrawal. On cessation from 1, 4, and 16 ppm, patients receiving I-NO demonstrated a dose-related reduction in Pao 2 (−11 ± 23, −28 ± 24, and −50 ± 48 mm Hg, respectively). For infants classified as treatment failures (mean duration of therapy = 10 hours), no change in OI occurred for the placebo group (−13 ± 36%, OI of 31 ± 11 after the withdrawal process); however a 42 ± 101% increase in OI to 46 ± 21 occurred for the pooled nitric oxide doses. One death was possibly related to withdrawal of I-NO. Conclusion. For infants classified as treatment successes, a dose response between the I-NO dose and decrease in Pao 2 after discontinuing I-NO was found. A reduction in I-NO to 1 ppm before discontinuation of the drug seems to minimize the decrease in Pao 2 seen. For infants failing treatment, discontinuation of I-NO could pose a life-threatening reduction in oxygenation should extracorporeal membrane oxygenation not be readily available or I-NO cannot be continued on transport.

Serial ambulatory electrocardiography and treadmill exercise testing after uncomplicated myocardial infarction

To compare the diagnostic and prognostic utility of ambulatory electrocardiography and treadmill exercise testing after clinically uncomplicated myocardial infarction, 90 men (mean age 52 years) were evaluated 3 weeks after the acute event and a variable number were evaluated 11, 26 and 52 weeks after the acute event. The prevalence of “any” premature ventricular complex and of “complex” ventricular ectopic activity was greater with ambulatory electrocardiography than with treadmill testing (78 versus 49 percent; p

Optimal methods for identifying depression following hospitalization for myocardial infarction

Abstract Methods for detecting depression were evaluated in 64 men mean age 53 ± 4 yr who underwent treadmill exercise testing 3 and 7 weeks after clinically uncomplicated myocardial infarction. Following an open-ended interview, a therapist rated 9 33 patients as moderately to severely depressed, of whom 3 33 (9%) were judged to require treatment for depression. Two self report scales identified only 2 of the 9 patients with moderate to severe depression and only 1 of the 3 patients requiring treatment. Following a standardized interview, a technician rated 4 of the next 31 patients as moderately to severely depressed, all of whom ( 4 31 , 13%) were judged by the therapist to require treatment for depression. Self report identified only 2 of the 4 patients judged by the therapist to require treatment. A trained technician and a therapist detect about the same proportion of patients requiring treatment for depression after myocardial infarction. Both methods of interview are superior to self report scales for the detection of moderately severe depression requiring treatment.

School-based blood Cholesterol screening

Coronary artery disease, the major cause of death in developed countries, begins early in childhood. Elevated blood cholesterol, a major risk for coronary artery disease in adults, has been associated at autopsy with atherosclerotic disease in children. To explore the feasibility of mass screening of blood cholesterol levels in children, a school-based screening and education program for fourth-graders was carried out in a Southern California school district. Approximately 10% of the children had blood cholesterol levels of 200 mg/dl or more, the upper limit of desirable levels for adults. These children and their parents returned for repeat cholesterol testing and nutrition counseling. A family history of early coronary artery disease was present in only one third of the children with high cholesterol levels; this fact, coupled with consumable costs less than

The effect of a standardized psychological stressor on the cardiovascular response to physical effort soon after uncomplicated myocardial infarction

2 per child, suggests that cholesterol screening is a practical, cost-effective addition to school health programs.

Echocardiographic changes during a 1 year exercise program in previously sedentary middle aged men

To determine whether a standardized psychological stressor combined with physical stress might disclose ischemic abnormalities not evident with physical stress alone, 30 men, mean age 54, were evaluated seven weeks after clinically uncomplicated myocardial infarction. In the first 20 patients, two symptom-limited treadmill tests (TM) were performed on the same day, with and without superimposed psychological quiz (Q). In the next 10 consecutive patients, the Q was administered at a submaximal level (4 METs). When TM and TM + Q responses were compared, no significant differences were noted in the maximal levels of heart rate (HR), systolic blood pressure (SBP), rate pressure product, or in the prevalence of ischemic ST segment depression or angina pectoris. The HR and double product at which ischemic ST segment depression and angina pectoris appeared were similar for the two types of testing. The psychological stress of a psychological quiz may not, of course, approximate the effect of the more severe stressors individuals may encounter in their daily routines.

Cholesterol screening in children during office visits

Previous echocardiographic studies of the effects of physical conditioning have focused primarily on persons aged 35 and younger who undergo exercise training for six months or less [1, 2, 3, 4]. In this study, 81 healthy but previously sedentary men, aged 35–55, were randomly assigned to exercise and control groups, to examine the effects on cardiac dimensions and plasma lipoproteins of a year-long running program.

Long-term results of coronary artery bypass surgery for unstable angina: incidence of mortality, myocardial infarction, and angina resumption†

Elevated blood cholesterol levels, a major risk for coronary artery disease in adults, has been associated with atherosclerotic disease in children. More than 10% of North American children have blood cholesterol levels higher than the desirable levels for adults. Current guidelines recommend screening only in children who have a family history of hyperlipidemia or myocardial infarction at an early age; however, this method fails to identify most children with hypercholesterolemia. Office-based cholesterol screening is an effective means to identify children and family members for dietary assessment and counseling. Should these measures be insufficient to lower the childs cholesterol level, referral for pharmacologic treatment is indicated.

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide

To determine if routine treadmill testing would be helpful in identifying patients at high risk for subsequent events, the first 81 patients to undergo coronary artery bypass0 surgery for unstable angina pectoris at Stanford University Medical Center were reevaluated at four intervals after surgery. Evaluations, including assessment of angina pectoris and a treadmill test, were done at mean times of 18,40, and 72 months after surgery. At a mean time of 90 months postoperatively, angina status was determined in survivors. The prevalence of angina rose from 19% during the first year to 53% during the fourth and fifth postoperative years. Cardiac deaths and myocardial infarctions were frequent during the first postoperative year, and were more frequent in patients with three‐vessel disease and those with one or more severely narrowed coronary arteries which were not bypassed. Cardiac events were rare between 12 and 36 months after operation; clinical and treadmill variables did not predict these events. During the fourth and subsequent postoperative years, the incidence of cardiac events increased. While the presence of stable angina pectoris was the clinical variable most useful prognostically, treadmill testing added additional independent prognostic information (p<0.0001). During the intervals between visits 1 and 2, and visits 2 and 3, cardiac events were ten times more frequent in persons with a maximal heart rate of 130 beats/min or less on the treadmill at 18 and 40 months.