Isosorbide dinitrate and nifedipine treatment of achalasia: a clinical, manometric and radionuclide evaluation. The effect of terbutaline sulfate, nitroglycerin, and aminophylline on lower esophageal sphincter pressure and radionuclide esophageal emptying in patients with achalasia. Comparative effects of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation. Haemodynamic advantages of isosorbide dinitrate over frusemide in acute heart-failure following myocardial infarction. Intracervical application of the nitric oxide donor isosorbide dinitrate for induction of cervical ripening: a randomised controlled trial to determine clinical efficacy and safety prior to first trimester surgical evacuation of retained products of conception. Attenuation of hypertensive response to tracheal intubation with nitroglycerin. 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. The I-NO/PPHN Study Group. Pressure and volume changes of tracheal tube cuff following inflation with various inflating agents during nitrous oxide anesthesia. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.
The effects of sublingual isosorbide dinitrate (5 mg) and nifedipine (20 mg) were compared in 15 patients with achalasia. The parameters examined included the manometric measurement of the lower esophageal sphincter pressure, the radionuclide assessment of esophageal emptying and the clinical response. The mean basal lower esophageal sphincter pressure fell significantly after both drugs (p less than 0.01), with a maximum fall of 63.5% 10 min after receiving isosorbide dinitrate, but by only 46.7% 30 min after nifedipine. The esophageal radionuclide test meal retention was significantly less (p less than 0.01) only after receiving isosorbide dinitrate. The drug improved initial esophageal emptying by its effect on the lower esophageal sphincter and by relieving the test meal hold-up noted to occur at the junction of the upper and midesophagus. Eight patients cleared their test meal within 10 min after isosorbide dinitrate administration while only two did so after nifedipine. Subjectively, 13 patients had their dysphagia relieved by isosorbide dinitrate and 8 by nifedipine. However, this relief was not confirmed in 4 patients by the radionuclide study and they, as well as the other 3 patients who did not respond to therapy, were referred to pneumatic dilatation. Side effects were more prominent after nitrates. Three of the patients are currently receiving nifedipine and 5 patients received isosorbide dinitrate therapy for 8-14 mo. The radionuclide test meal is currently the best way of objectively evaluating drug therapy in patients with achalasia. Isosorbide dinitrate is more effective than nifedipine in relieving their symptoms. We studied the effects of three smooth muscle relaxants on lower esophageal sphincter (LES) pressure and radionuclide esophageal emptying in 15 untreated patients with achalasia. LES pressures were determined before and after the administration of normal saline subcutaneously, terbutaline sulfate subcutaneously, nitroglycerin sublingually, and aminophylline intravenously. All smooth muscle relaxants significantly decreased LES pressures when compared with normal saline controls and pretreatment baseline pressures (p less than 0.01). However, in normal saline controls, LES pressure actually increased over time (p less than 0.01). Control radionuclide esophageal emptying studies were performed in all patients. Subsequent esophageal emptying studies were carried out only in patients responding to smooth muscle relaxants by decreasing LES pressures by greater than or equal to 25% (terbutaline sulfate, n = 8; nitroglycerin, n = 7; and aminophylline, n = 4). Significant improvement in esophageal emptying was observed after nitroglycerin and terbutaline sulfate (p less than 0.05) but not after aminophylline. We conclude that in patients with achalasia (a) terbutaline sulfate, nitroglycerin, and aminophylline can significantly decrease LES pressure; (b) resting LES pressures vary over time; and (c) terbutaline sulfate and nitroglycerin significantly improve esophageal emptying in some subjects. To compare the safety and efficacy of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation.
                Randomized, placebo-controlled, double-blind study.
                University-affiliated VA medical center.
                40 ASA physical status I and II patients undergoing electric surgery with general endotracheal anesthesia.
                Anesthesia was induced with thiopental sodium 5 mg/kg, and intubation was facilitated with vecuronium 0.15 mg/kg. Isoflurane (0.5% to 1%) and 50% nitrous oxide in oxygen were used for maintenance of anesthesia. In addition, patients received one of the following four study drugs intravenously (i.v.) prior to laryngoscopy: Group 1 (control) = saline 5 ml; Group 2 = lidocaine 1.5 mg/kg; Group 3 = esmolol 1.4 mg/kg; Group 4 = nitroglycerin 2 micrograms/kg.
                Mean arterial pressure (MAP) and heart rate (HR) were recorded every minute for 20 minutes following induction of anesthesia. Following laryngoscopy and intubation, MAP increased significantly in all four treatment groups (control 49% +/- 19%, lidocaine 55% +/- 26%, esmolol 25% +/- 11%, nitroglycerin 45% +/- 21%) compared with preinduction baseline values. In the esmolol-pretreated patients, the increase in HR was significantly lower (20% +/- 3%) compared with the nitroglycerin (37% +/- 8%), lidocaine (52% +/- 8%), and control (29% +/- 4%) groups.
                Lidocaine 1.5 mg/kg i.v. and nitroglycerin 2 micrograms/kg i.v. were ineffective in controlling the acute hemodynamic response following laryngoscopy and intubation. Esmolol 1.4 mg/kg i.v. was significantly more effective than either lidocaine or nitroglycerin in controlling the HR response to laryngoscopy and intubation (p < 0.05). Esmolol also was significantly more effective than lidocaine in minimizing the increase in MAP (25% vs. 55%). The immediate haemodynamic effects of intravenous frusemide (1 mg/kg) and intravenous isosorbide dinitrate (50-200 micrograms/kg/h) were compared in a prospective, randomised, between-group study in 28 men with radiographic and haemodynamic evidence of left ventricular failure following acute myocardial infarction. The diuresis induced by frusemide reduced the left heart filling pressure and cardiac output and transiently raised systemic blood-pressure. In contrast, isosorbide dinitrate was accompanied by a reduction in systemic blood-pressure and peripheral resistance with the result that the cardiac output was not decreased despite a large fall in the pulmonary vascular and left heart filling pressures. These results indicate that reduction of excessive preload by venodilatation may be haemodynamically superior to that induced by diuresis in terms of both reducing myocardial oxygen consumption and maintaining peripheral perfusion. The influence of these contrasting treatments on the prognosis of these high-risk patients warrants further study. To determine the therapeutic efficacy and safety of a nitric oxide (NO) isosorbide dinitrate donor to induce cervical ripening of women with missed abortions before surgical evacuation of the uterus.
                A prospective, randomised, double-blind controlled trial.
                Tertiary referral maternity teaching hospital. Population Sixty women with missed abortions and no cervical dilation.
                Women requesting surgical evacuation of the uterus were randomly selected to receive endocervical 80 mg/1.5 mL isosorbide dinitrate gel solution (n= 30) or 400 mug/1.5 mL misoprostol gel solution (n= 30) every 3 hours to a maximum of four doses or until reaching cervical ripening. Vital signs and symptoms were recorded at baseline and then every 3 hours until finishing therapy. Adverse events, such as headache, abdominal pain, pelvic pain, backache, nausea and vomiting, were evaluated.
                Probability of reaching cervical ripening >8 mm Hegar dilator; evaluated at 3, 6, 9 and 12 hours after application of isosorbide dinitrate or misoprostol.
                The probabilities of induction of cervical ripening by isosorbide dinitrate and misoprostol after four repeated doses at 3-hour intervals were significantly different (P<0.001). Efficacy of therapy after 12 hours was 97% for the isosorbide dinitrate group and 70% for the misoprostol group. Systolic and diastolic blood pressures were lower after administration of isosorbide dinitrate than prostaglandin analogues. The difference in the mean systolic and diastolic blood pressure between treatment groups was greatest at 3 hours, with a difference of 7.7 mmHg (P<0.001) and 5.9 mmHg (P<0.003), respectively. The most frequent side effect associated with isosorbide dinitrate administration was headache, which occurred in 18 out of 30 patients, compared with only 5 out of 30 women in the misoprostol group [relative risk (RR) 2.41, 95% confidence interval (CI) 1.45-4.03, P<0.001). Women treated with misoprostol reported mainly pelvic pain (RR 3.24, 95% CI 1.99-5.27, P<0.001).
                Intracervical administration of 80 mg isosorbide dinitrate in women with missed abortions appears to be effective for cervical ripening prior to surgical evacuation of the uterus. Differences in the incidence of non-serious adverse events are not likely to be clinically significant. To evaluate the efficacy and safety of intravenous (IV) nitroglycerin in attenuating the hypertensive response to laryngoscopy and intubation as a new application of the drug.
                Controlled, randomized, double-blind study.
                University hospital.
                Thirty normotensive patients (ASA physical status I) undergoing elective surgery were divided into three groups of ten patients each.
                Anesthesia was induced with thiopental sodium 5 mg/kg i.v., and tracheal intubation was facilitated with vecuronium 0.2 mg/kg i.v. During anesthesia, ventilation was assisted or controlled with 1% enflurane and 50% nitrous oxide in oxygen. Either 1.5 micrograms/kg of nitroglycerin, 2.5 micrograms/kg of nitroglycerin, or saline (control) was administered IV simultaneously with the start of laryngoscopy (lasting 30 seconds), which was attempted 2 minutes after administration of thiopental sodium and vecuronium.
                Patients receiving saline showed a significant increase in mean arterial pressure and rate-pressure product associated with tracheal intubation. These increases following tracheal intubation were significantly reduced in nitroglycerin-treated patients compared with those in the control group (p < 0.05).
                A single, rapid IV dose of nitroglycerin is a simple, practical, effective, and safe method to attenuate the hypertensive response to laryngoscopy and tracheal intubation. 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.
                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 [FIO2] 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).
                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 PaO2 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.
                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. The study was designed to investigate the changes in pressure and volume of a tracheal tube-cuff inflated with air, mixture of N2O + O2, saline and 4% lidocaine during nitrous oxide anesthesia. This study was conducted in 80 patients (33 male & 47 female). The pressure and volume of a tracheal tube cuff increased with air, decreased with mixture of N2O + O2 and almost remained the same with saline and 4% lidocaine. The complications were more in the air group. Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients.
                We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients.
                Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 microg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production.
                L-Arginine improved the pain-free walking distance by 230+/-63% and the absolute walking distance by 155+/-48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209+/-63% and 144+/-28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r=0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 (L-arginine) and 7.0+/-0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3+/-0.4).
                Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.
From most of the single reports we found, after intake of nitrates (either nitroglycerin or isosorbide dinitrate), there was a fall in lower oesophageal pressure and improvement of radionuclide esophageal emptying compared to the baseline. From the available evidence, we cannot provide any implications for practice. Appropriately designed, parallel group, randomised controlled trials with long term follow-up are needed to determine the effects of nitrates for achalasia.