The cascading origin of the 2018 Kilauea eruption and implications for future forecasting.

The 2018 summit and flank eruption of Kilauea Volcano was one of the largest volcanic events in Hawai'i in 200 years. Data suggest that a backup in the magma plumbing system at the long-lived Pu'u 'O'o eruption site caused widespread pressurization in the volcano, driving magma into the lower flank. The eruption evolved, and its impact expanded, as a sequence of cascading events, allowing relatively minor changes at Pu'u 'O'o to cause major destruction and historic changes across the volcano. Eruption forecasting is inherently challenging in cascading scenarios where magmatic systems may prime gradually and trigger on small events.

The 2018 rift eruption and summit collapse of Kilauea Volcano.

In 2018, Kilauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'O'o vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 kilometers. A 4 May earthquake [moment magnitude (M w) 6.9] produced ~5 meters of fault slip. Lava erupted at rates exceeding 100 cubic meters per second, eventually covering 35.5 square kilometers. The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M w 4.7 to 5.4 earthquakes. Activity declined rapidly on 4 August. Summit collapse and lava flow volume estimates are roughly equivalent-about 0.8 cubic kilometers. Careful historical observation and monitoring of Kilauea enabled successful forecasting of hazardous events.

Effect of nabumetone on hemostasis during arthroscopic knee surgery.

The known effects of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) on hemostatic parameters have led to concern over their use in the perioperative period. Nabumetone, unlike other NSAIDs, has little effect on collagen-induced platelet aggregation. To evaluate the effect of nabumetone 2000 mg daily on other hemostatic parameters (e.g., bleeding time, prothrombin time, and partial thromboplastin time) in the clinical setting, this double-masked study was conducted in patients with osteoarthritis undergoing arthroscopic knee surgery. After a 1-week placebo washout period, 58 patients were randomized to receive nabumetone and 53 were randomized to receive placebo. They were assessed before surgery (after 1 to 2 weeks of treatment) and again after surgery (after an additional 3 weeks of treatment). The study was designed to have 90% power to show equivalence in bleeding time to within 1.5 minutes, a difference assumed to be of no clinical importance. No meaningful differences were observed between the groups in any of the measured hemostatic parameters. Before surgery, the bleeding time increased by only 0.3 minutes with nabumetone and decreased by 0.2 minutes with placebo. The mean (+/- SD) difference between the groups in change from baseline was 0.5 +/- 0.3 minutes. After surgery, the changes were 0.1 minutes and 0.0 minutes, respectively, and the difference between groups was 0.2 +/- 0.3 minutes. These differences were neither statistically nor clinically significant, and maximum individual increases were similar in each group. Furthermore, there were no reports of abnormal bleeding in the operative knees. The results of this study show that nabumetone had little or no effect on hemostasis and suggest that this drug can be used safely in the perioperative period.

A multicenter double-blind study of the efficacy and safety of once and twice daily dilevalol compared to propranolol.

Dilevalol, the R,R isomer of labetalol, is a non-selective beta-adrenergic blocking drug with vasodilator properties which differ from those of labetalol in that they are attributable to beta-2 agonism rather than alpha-1 blockade. This multicenter, double-blind, randomized study compares the antihypertensive efficacy and safety of dilevalol with propranolol and, in addition, compares the efficacy of dilevalol when given once daily with twice daily. Caucasian patients with mild and moderate essential uncomplicated hypertension were divided into three treatment groups and received either propranolol twice daily (N = 59), dilevalol twice daily (N = 60), or dilevalol once daily (N = 53). Patients were given increasing doses of these medications over a 2 to 10 week period to achieve a supine diastolic blood pressure (SuDBP) of less than 90 mm Hg. The three regimens were equally effective in lowering supine blood pressure (dilevalol daily and twice daily reduced SuDBP by 14 Hg and propranolol by 13 mm Hg). Patients with at least a 5 mm Hg reduction in SuDBP then entered a two month maintenance phase. Dilevalol, whether given once (N = 40) or twice daily (N = 55) maintained the supine systolic blood pressure more effectively (dilevalol daily--15 mm Hg, twice daily--13 mm Hg, P less than .05) than propranolol (N = 53, 11 mm Hg) and dilevalol given once daily maintained diastolic blood pressure more effectively than propranolol (17 mm Hg v 14 mm Hg, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dilevalol, metoprolol and atenolol on left ventricular mass and function in nonelderly and elderly hypertensive patients.

Using serial M-mode echocardiographic determinations of left ventricular (LV) mass and function, the effects of dilevalol, a selective beta 2 agonist with nonselective beta-antagonist properties, were compared with those of metoprolol in 2 centers in double-blind, randomized clinical trials using similar protocols in nonelderly hypertensive patients (aged less than 65 years) (study 1). In a separate bicenter study with a similar design, dilevalol was compared with atenolol in elderly hypertensive patients (aged greater than or equal to 65 years) (study 2). Patients in both studies received placebo for 2 to 4 weeks, and were then randomized to receive increasing doses of dilevalol (200, 400, 800, 1,600 mg) or metoprolol (100, 200, 300, 400 mg) in study 1, and dilevalol (100, 200, 400, 800 mg) or atenolol (50, 100 mg) in study 2, to achieve a supine diastolic blood pressure (BP) of less than 90 mm Hg. In both studies, LV function and mass (Penn convention) were determined by echocardiographic examinations performed before randomization and at the end of the active treatment phase. Dilevalol, metoprolol and atenolol significantly reduced BP compared with placebo. In the nonelderly patients, a modest reduction in LV mass was observed with dilevalol (p less than 0.03) but not with metoprolol. Indexes of LV function--as assessed by end-diastolic and end-systolic dimensions, LV ejection time and ejection fraction--were better preserved by dilevalol than by metoprolol. In the elderly, neither dilevalol nor atenolol affected LV mass; however, indexes of LV function were better preserved with dilevalol than with atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Dilevalol compared with propranolol and placebo for systemic hypertension.

Dilevalol is a new antihypertensive agent that is both a vasodilator, through its beta 2-agonist action, and a nonselective beta antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placebo. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 105 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during which doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of less than 90 mm Hg and a decrease from baseline of greater than or equal to 10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p less than 0.001) (study 2). In both studies, dilevalol given once daily was effective and well tolerated. The side-effect profile of dilevalol was similar to that of placebo and different from that of propranolol. Treatment with dilevalol resulted in significantly less fatigue (p less than 0.05), bradycardia (less than 50 beats/minute) and mental depression than with propranolol, but significantly (p less than 0.05) more diarrhea/loose stools.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of antihypertensive action of dilevalol compared with that of "cardioselective" beta-blocking agents.

The hemodynamic effects of dilevalol, a nonselective beta-adrenergic blocking agent with vasodilating properties, were evaluated in 34 hypertensive patients and compared with those of the "cardioselective" beta blockers atenolol and metoprolol in 21 patients. Hemodynamic measurements were obtained at baseline, after acute treatment (first dose) with dilevalol (400 mg) and atenolol (50 mg) or metoprolol (100 mg), and again after subchronic treatment with these agents. After both acute and subchronic treatment (mean daily dose 1,042 mg), dilevalol significantly reduced mean arterial pressure (MAP, p less than 0.0001), by significantly reducing systemic vascular resistance index (SVRI, p less than 0.001), and by not significantly altering cardiac index (CI). In contrast, atenolol and metoprolol significantly reduced MAP (p less than 0.002) by significantly reducing CI (p less than 0.0001), with a concomitant increase in SVRI (p less than 0.007). Heart rate (HR) was reduced significantly less (p less than 0.006) with dilevalol than with the cardioselective agents. Correlation of the decrease in MAP with other hemodynamic parameters revealed that the effects on MAP of acute treatment with the cardioselective drugs are related to a decrease in HR (r = 0.63, p = 0.002), whereas those of subchronic treatment are correlated to a decrease in CI (r = 0.59, p = 0.01). The decrease in MAP after acute and subchronic dilevalol treatment is correlated primarily with SVRI (r = 0.46 to 0.49, p less than 0.01) and only secondarily with HR (r = 0.34, p less than 0.05). Therefore, the main mechanism of antihypertensive action for dilevalol is vasodilation, in contrast to the cardioselective agents, which is beta blockade.

Multicenter comparison of dilevalol to placebo in patients with mild hypertension.

The antihypertensive effects of oral dilevalol, a beta-blocking agent with vasodialating properties were compared with placebo in 128 mildly hypertensive patients (supine diastolic blood pressure 95 to 105 mm Hg) in a multicenter, double-blind, parallel group study. Following a 4-week placebo phase, 63 patients were randomly assigned to receive dilevalol and 65 to receive placebo. A titration phase followed during which the dose of dilevalol was increased every other week from 100 mg to 800 mg to achieve a supine diastolic blood pressure (SDBP) less than 90 mm Hg and decreased by 10 mm Hg or more from baseline. A matching number of placebo capsules for each dose level of dilevalol was dispensed for blinding purposes. Patients who had at least a 5 mm Hg reduction in SDBP entered a 1-month maintenance phase. Blood pressure and heart rate were measured weekly 20 to 24 hours after a dose. This study demonstrated that the minimally effective dose of dilevalol was 100 mg, which was shown to result in a significantly (P less than or equal to 0.05) greater reduction in systolic BP. A once-daily dose of 200 mg was superior to placebo in both systolic and diastolic BP effects (P less than 0.001 and less than 0.001, respectively), and this superiority was seen again at both the end of titration and the end of the study. The BP reduction was accompanied by a small (5 bpm) decrease in heart rate. The side effect profile of dilevalol was not different from placebo. Dilevalol appears to have no adverse effect on plasma lipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Monotherapy with labetalol in the treatment of mild hypertension: a double-blind study.

The antihypertensive effects of oral labetalol compared with placebo were evaluated in 74 mildly hypertensive patients (standing diastolic blood pressure 95 to 110 mm Hg) in a bicentric double-blind parallel group study. Following a four-week placebo phase, 36 patients were randomly assigned to receive labetalol and 38 to receive placebo. A five-week titration phase followed during which the dose of labetalol was increased weekly from 100 mg twice a day to 600 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg and decreased 10 mm Hg or more from baseline. A matching number of placebo capsules for each dose of labetalol was dispensed for blinding purposes. Patients then entered a two-month maintenance phase. A thiazide diuretic could be added when the standing diastolic blood pressure was 100 mm Hg or greater at the highest dose of the study drug. At the end of this phase, the administration of labetalol (or placebo) was abruptly discontinued and patients were given the same number of placebo capsules twice a day taken during maintenance. Blood pressure and heart rate in the supine and standing position were measured eight to 10 hours after a dose at each visit. This study demonstrated that labetalol (median daily doses of 600 mg) was significantly more effective than placebo (p less than 0.05) in lowering the supine and standing blood pressures. Significantly more (p less than 0.001) placebo-treated patients than labetalol-treated patients (six versus 20) required the addition of a thiazide diuretic. Control of hypertension (that is, standing diastolic blood pressure less than 90 mm Hg) was achieved in significantly (p less than 0.001) more labetalol-treated patients than placebo-treated patients at the monotherapy endpoint (26 of 36; 72 percent versus six of 38; 16 percent). Blood pressure overshoot did not occur when labetalol was abruptly discontinued. Not one labetalol-treated patient discontinued the study because of adverse experiences. Labetalol is a safe and effective treatment for patients with mild hypertension.

Multiclinic comparison of labetalol to metoprolol in treatment of mild to moderate systemic hypertension.

The antihypertensive effects of oral labetalol, a new alpha- and beta-adrenergic blocking agent, and metoprolol, a relatively beta1 selective adrenergic blocker, were evaluated in 91 patients with mild to moderate hypertension (standing diastolic blood pressure of 90 to 115 mm Hg) in a double-blind parallel group multicenter clinical trial. The effects of the two drugs on plasma lipids and lipoprotein fractions were also assessed. Following a four-week placebo phase, 44 patients were randomized to receive labetalol and 47 metoprolol. During a four-week titration phase, the labetalol dose was increased from 100 mg twice daily to a maximum of 600 mg twice daily to achieve a standing diastolic blood pressure of 90 mm Hg that was decreased by 10 mm Hg or more. Metoprolol was titrated from 50 mg to 200 mg twice daily. An eight-week maintenance period followed during which hydrochlorothiazide could be added. At the end of the maintenance phase, the doses of labetalol and metoprolol were tapered over a two to four day period after which patients received a placebo for one week. Blood pressure in the supine and standing position was measured at each visit. Labetalol and metoprolol both significantly (p less than 0.01) lowered the supine and standing blood pressure from baseline with no significant difference found between the two treatment groups. Both drugs lowered the heart rate; however, the rate-lowering effect was significantly greater with metoprolol (p less than 0.01). There were no significant effects of either drug on plasma lipids or lipoprotein fractions. Fatigue was the most frequently reported complaint with both drugs. Dizziness, dyspepsia, and nausea were more common with labetalol; bradycardia was more common with metoprolol. There was no blood pressure "overshoot" after withdrawing drug treatment; however, a heart rate "overshoot" was seen after metoprolol was tapered off and stopped. Labetalol is as safe and effective as metoprolol in the treatment of patients with mild to moderate hypertension.

Step II treatment with labetalol for essential hypertension.

Labetalol, a new alpha- and beta-adrenergic blocking agent, was administered to 57 patients with essential hypertension whose standing diastolic blood pressure was 105 to 120 mm Hg after three and four weeks of placebo therapy and greater than 90 mm Hg after three to four weeks of therapy with hydrochlorothiazide, 25 mg twice a day. Patients were then randomly assigned on a double-blind basis to receive either labetalol, 100 mg twice a day, or placebo combined with hydrochlorothiazide. Thereafter, the dose of labetalol was titrated weekly in both groups to a maximum of 400 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg that was also decreased from the hydrochlorothiazide baseline by 10 mm Hg or more (therapeutic goal). Labetalol was abruptly discontinued after four weeks of treatment and patients were given hydrochlorothiazide alone for two additional weeks. After one week of labetalol therapy, 100 mg twice a day (added to hydrochlorothiazide), there was a significantly greater reduction in supine systolic/diastolic blood pressure (6/5 mm Hg, p less than 0.04/less than 0.03) and standing blood pressure (9/7 mm Hg, p less than 0.01/less than 0.01) than with placebo therapy (3/0.5 and 3/1 mm Hg, respectively). The blood pressure reduction in the labetalol-treated group was associated with a 4 and 5 beats per minute reduction in the supine and standing heart rates, respectively. The median labetalol dose required to achieve the standing diastolic blood pressure goal was 400 mg twice a day. After four weeks of labetalol treatment, the mean reduction in blood pressure from the hydrochlorothiazide baseline was 12/13 mm Hg (p less than 0.01/0.01) in the standing position and 8/8 mm Hg (p less than 0.01/0.01) in the supine position. These blood pressure reductions were accompanied by a mean reduction in heart rate of 7 beats per minute. The most frequently reported complaints other than thiazide-induced nocturia included dizziness, fatigue, nausea, rash, and/or pruritus. Most of these complaints were reported at a similar incidence while patients were receiving placebo or hydrochlorothiazide alone as when receiving labetalol with hydrochlorothiazide. After abrupt withdrawal of labetalol, no evidence of rebound hypertension was observed. Labetalol is a safe and effective step II drug when added to hydrochlorothiazide for the treatment of patients with moderate to moderately severe hypertension.

Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies.

The antihypertensive effects of intravenous labetalol were evaluated in 59 patients with hypertensive crises or severe hypertension in need of rapid lowering of blood pressure in a multicenter study. Patients appearing with a supine diastolic blood pressure 125 mm Hg or greater, or a supine systolic blood pressure of more than 200 mm Hg received an initial mini-bolus injection (20 mg) of labetalol. This was followed by repeated incremental doses of 20 to 80 mg given at 10 minute intervals to achieve a supine diastolic blood pressure of less than 95 mm Hg or decrease 30 mm Hg or greater, or a satisfactory decrease in systolic blood pressure. Patients were stratified into those who had taken antihypertensive medication within 24 hours and those who had not. The initial mini-bolus injection caused rapid but not abrupt reduction in blood pressure; the baseline mean blood pressure decreased 23/14 mm Hg. Further injections were needed in the majority of patients (mean: 197 mg). The blood pressure reduction after the last dose of labetalol was 55/33 mm Hg. In pretreated patients and in those who had no medication for 24 hours prior to the intravenous labetalol, the response was similar. Heart rate decreased 10 beats per minute in the total population. In patients pretreated with beta-adrenergic blockers, blood pressure response was similar to that in the total group (59/35 versus 55/33 mm Hg), but heart rate remained essentially unchanged. The dose required to achieve the therapeutic effect was less in pretreated patients than in untreated patients, but the duration of action was shorter. No serious adverse effects were encountered even in patients with concomitant diagnoses of acute left ventricular failure, myocardial infarction, stable congestive heart failure, atrial fibrillation, angina pectoris, acute stroke, transient ischemic attack or encephalopathy. Labetalol is a safe and effective treatment for a rapid blood pressure reduction in hypertensive emergencies.