Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

Effect of N(G)-nitro-L-arginine methyl ester on autonomic modulation of heart rate variability during hypovolemic shock.

OBJECTIVE: To study the changes in neuroautonomic regulation of heart rate and the effects of N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of nitric oxide synthase, on efferent sympathetic cardiac activity and blood pressure during hypovolemic shock. Hypotension during hypovolemic shock may be attributable, in part, to the failure of neuroautonomic regulation of heart rate and blood pressure. In addition, the release of nitric oxide may contribute to hypotension through vasodilation and inhibition of efferent sympathetic activity. DESIGN: Prospective, controlled trial. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Seventeen anesthetized adult male New Zealand White rabbits. INTERVENTIONS: The rabbits were divided into four groups: control (n = 3), control plus L-NAME (n = 5), hypovolemic (n = 4), and hypovolemic plus L-NAME (n = 5). Hypovolemic rabbits were bled of 10% of their circulating blood volume (85 mL/kg) every 10 mins until 30% cumulative hypovolemia was reached. Rabbits received either three doses of saline 1 mL/kg every 10 mins or L-NAME 10 mg/kg in 1 mL/kg of saline solution administered after each hemorrhage for a total of three doses. Changes in heart rate, respiratory rate, mean arterial pressure, plasma catecholamine levels, and heart rate power spectra were recorded every 10 mins during serial hypovolemia and during a 30-min recovery period. MEASUREMENTS AND MAIN RESULTS: During hypovolemic shock there was a decrease in log low-frequency heart rate power (p = .001) and in systolic (p = .003), diastolic (p < .001), and mean (p < .001) blood pressures compared with control rabbits. Treatment with L-NAME during hypovolemia resulted in increased log low-frequency heart rate power (p = .03) and systolic (p = .01), diastolic (p = .007), and mean (p = .009) blood pressures compared with hypovolemic rabbits who received saline placebo. CONCLUSIONS: We found that treatment with L-NAME increased efferent sympathetic cardiac activity and mean arterial pressure during hypovolemic shock compared with control rabbits. We conclude that L-NAME may blunt hypotension during hypovolemic shock by inhibiting nitric oxide synthase and may act to restore neuroautonomic cardiovascular reactivity. Spectral analysis of heart rate variability may allow for insights into the pathophysiology of shock and provide a means of monitoring the neuroautonomic cardiovascular response to therapy.

Decomplexification in critical illness and injury: relationship between heart rate variability, severity of illness, and outcome.

OBJECTIVES: To determine if decomplexification of heart rate dynamics occurs in critically ill and injured pediatric patients. We hypothesized that heart rate power spectra, a measure of heart rate dynamics, would inversely correlate with measures of severity of illness and outcome. DESIGN: A prospective clinical study. SETTING: A 12-bed pediatric intensive care unit (ICU) in a tertiary care children's hospital. PATIENTS: One hundred thirty-five consecutive pediatric ICU admissions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared heart rate power spectra with the Pediatric Risk of Mortality (PRISM) score, the Pediatric Cerebral Performance Category (PCPC), and the Pediatric Overall Performance Category (POPC). We found significant negative correlations between minimum low-frequency and high-frequency heart rate power spectral values recorded during ICU stay and the maximum PRISM score (log low-frequency heart rate power vs. PRISM, r2 = .293, p < .001; and log high-frequency heart rate power vs. PRISM, r2 = .243, p < .001) and outcome at ICU discharge (log low-frequency heart rate power vs. POPC or PCPC, r2 = .429, p < .001; and log high-frequency heart rate power vs. POPC or PCPC, r2 = .271, p < .001). CONCLUSIONS: Our data support the hypothesis that measures of heart rate power spectra are inversely related and negatively correlated to severity of illness and outcome in critically ill and injured children. The phenomenon of decomplexification of physiologic dynamics may have important clinical implications in critical illness and injury.

Evaluation of the autonomic cardiovascular response in Arnold-Chiari deformities and cough syncope syndrome.

OBJECTIVE: To study the autonomic control of heart rate in patients with Arnold-Chiari deformity types I and II who exhibit the signs and symptoms of cough syncope syndrome. DESIGN: Prospective, clinical descriptive study. SETTING: University clinical research center. PATIENTS: Nine patients with Arnold-Chiari deformity and cough syncope syndrome. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Changes in heart rate, blood pressure, and electrocardiograms for power spectral analysis of heart rate variability were studied in the supine and standing positions, preoperatively (n = 9) and postoperatively (n = 5). RESULTS: Preoperatively, 8 (89%) of 9 patients increased their heart rate after postural change from supine to standing (mean +/- SD delta = 13 +/- 13 beats per minute [bpm]). Postoperatively, 4 (80%) of the 5 patients exhibited a greater increase in standing heart rate (mean delta = 19 +/- 16 bpm) compared with preoperative values. Changes in systolic, diastolic, and mean blood pressure with postural change were variable. Preoperatively, all patients exhibited abnormal control of heart rate in response to postural change. Three patients (33%) showed an abnormal decrease in low-frequency heart rate power (mean delta = -27 +/- 35 bpm2); the remaining 6 (67%) demonstrated an abnormal increase in high-frequency heart rate power (mean delta = 25 +/- 41 bpm2). All patients were clinically asymptomatic at 2 months after surgery. A normal spectral response to postural change was demonstrated in heart rate power in all 5 patients who were reevaluated postoperatively, with an increase in low-frequency power (mean delta = 33 +/- 21 bpm2) and a decrease in high-frequency power (mean delta = -21 +/- 23 bpm2). CONCLUSIONS: Patients with cervicomedullary anatomic abnormalities caused by Arnold-Chiari deformities may exhibit abnormal autonomic control of heart rate, and the autonomic control of their heart rate returns to a normal pattern after surgical palliation in conjunction with resolution of clinical symptoms.