Role of individual predisposition in orthostatic intolerance before and after simulated microgravity.

Orthostatic intolerance (OI) is a major problem after spaceflight. Its etiology remains uncertain, but reports have pointed toward an individual susceptibility to OI. We hypothesized that individual predisposition plays an important role in post-bed rest OI. Twenty-four healthy male subjects were equilibrated on a constant diet, after which they underwent tilt-stand test (pre-TST). They then completed 14-16 days of head-down-tilt bed rest, and 14 of the subjects underwent repeat tilt-stand test (post-TST). During various phases, the following were performed: 24-h urine collections and hormonal measurements, plethysmography, and cardiovascular system identification (a noninvasive method to assess autonomic function and separately quantify parasympathetic and sympathetic responsiveness). Development of presyncope or syncope defined OI. During pre-TST, 11 subjects were intolerant and 13 were tolerant. At baseline, intolerant subjects had lower serum aldosterone (P < 0.01), higher excretion of potassium (P = 0.01), lower leg venous compliance (P = 0.03), higher supine parasympathetic responsiveness (P = 0.02), and lower standing sympathetic responsiveness (P = 0.048). Of the 14 subjects who completed post-TST, 9 were intolerant and 5 were tolerant. Intolerant subjects had lower baseline serum cortisol (P = 0.03) and a higher sodium level (P = 0.02) compared with tolerant subjects. Thus several physiological characteristics were associated with increased susceptibility to OI. We propose a new model for OI, whereby individuals with greater leg venous compliance recruit compensatory mechanisms (activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and withdrawal of the parasympathetic nervous system) in the face of daily postural challenges, which places them at an advantage to face orthostatic stress. With head-down-tilt bed rest, the stimulus to recruit compensatory mechanisms disappears, and differences between the two subgroups attenuate.

Effects of prolonged bed rest on the total peripheral resistance baroreflex.

Orthostatic intolerance following prolonged exposure to microgravity continues to be a primary concern of the human space program. Reduced autonomic tone has been demonstrated to contribute to this phenomenon, and the heart rate baroreflex, in particular, has been repeatedly shown to be impaired. However, only the works of Yelle et al. have attempted to address the role of the total peripheral resistance (TPR) baroreflex, a potentially more significant contributor to blood pressure regulation. We applied a previously developed method for estimating the static gains of both the arterial and cardiopulmonary TPR baroreflexes to data obtained before and after 16-day bed rest. Reductions in the estimated static gains of the arterial (statistically significant) and cardiopulmonary TPR baroreflexes were found after bed rest. This study supports the works of Yelle et al, which imply that the TPR baroreflex is reduced after spaceflight.

Midodrine prevents orthostatic intolerance associated with simulated spaceflight.

Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that alpha-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the alpha(1)-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.

Clinic dosing of beta blockers in chronic heart failure.

Beta blockers improve survival and reduce morbidity of patients with chronic heart failure. Stringent dosing guidelines calling for a 1-hour observation period after initiation or up-titration of beta-blocker therapy might limit the use of beta blockers and increase the expense involved. This study was conducted to determine the usefulness of this observation period. Data were collected from 130 in-clinic postdosing observation periods for 34 stable chronic heart failure patients started on carvedilol. The mean left ventricular ejection fraction was 0.22±0.09, and the mean functional class was 2.5±0.6. No patient had greater than first-degree heart block. Carvedilol was started at 3.125 or 6.25 mg b.i.d., and the dose was doubled every 1-3 weeks. All patients were observed for 1-2 hours after initiation or dosage increase, and blood pressure and heart rate were measured hourly. The maximal daily dose was 50±31 mg. In none of the observation periods was there a decrease in the dose of beta blockers administered in the clinic. The predosing mean blood pressure was 110±15/71±10 mm Hg, and the mean heart rate was 78±13 bpm; the 1-hour postdosing mean blood pressure was 101±14/67±10 mm Hg (p is less than 0.001), and the heart rate was 78±13 bpm. The dose was decreased in six patients and medication was discontinued in three, all consequent to symptoms reported several days after dosage increase. Beta blockers can be safely initiated and up-titrated at home in properly selected and evaluated stable patients with chronic heart failure and severe left ventricular dysfunction resulting in mild or moderate impairment of functional capacity. (c)2001 by CHF, Inc.

Effect of heart failure program on cardiovascular drug utilization and dosage in patients with chronic heart failure.

BACKGROUND: Utilization and dosage of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF) remain low. Recent data suggest that care of patients with CHF in specialized heart failure programs is associated with improved clinical outcomes. HYPOTHESIS: Specialized heart failure care is associated with better utilization and higher dose of cardiovascular drugs. METHODS: Data from 133 patients with CHF referred to a heart failure program were analyzed. Mean functional class 3.1 +/- 0.5, left ventricular ejection fraction 19 +/- 8. Utilization and doses of cardiovascular drugs were examined at initial evaluation and at last visit, after an average period of 17 +/- 14 months. Hospitalization and survival data were determined. RESULTS: Utilization of ACE inhibitors and angiotensin-receptor blockers increased from 87 to 100% (p < 0.001). Average daily dose increased by 60%, from the equivalent of captopril 105 +/- 78 mg to 167 +/- 86 mg (p < 0.001). Utilization of the following drugs increased significantly: beta blockers (16-37%, p < 0.001), metolazone (10-23%, p = 0.007), spironolactone (1-36%, p < 0.001), amiodarone (7-15%, p = 0.05), hydralazine (1-9%, p = 0.004), and nitrates (20-33%, p = 0.03). One-year survival was 90%. The 3- and 6-month hospitalization rates for heart failure were 4 and 7%, and for all cardiovascular causes they were 6 and 11%, respectively. CONCLUSIONS: Care of patients with CHF in a specialized heart failure program was associated with significant increase in the utilization and doses of all beneficial cardiovascular drugs, especially ACE inhibitors. It was also associated with excellent clinical outcomes.