Efficacy and safety of oral propranolol premedication to reduce reflex tachycardia during hypotensive anesthesia with sodium nitroprusside in orthognathic surgery: a double-blind randomized clinical trial.

PURPOSE: The present study sought to determine whether premedication with oral propranolol 10 mg before hypotensive anesthesia with sodium nitroprusside could reduce reflex tachycardia, the amount of sodium nitroprusside used, and blood loss during hypotensive anesthesia for orthognathic surgery. PATIENTS AND METHODS: A total of 60 patients undergoing bimaxillary surgery were studied in a prospective, randomized, and double-blind study of oral propranolol 10 mg or placebo as premedication before hypotensive anesthesia with sodium nitroprusside. Hemodynamic variables, the amount of sodium nitroprusside used, and blood loss were statistically analyzed. RESULTS: The heart rate and amount of sodium nitroprusside used were highly significantly less (P < .01) in the propranolol group, but no significant difference was found in blood loss between the 2 groups. No clinically significant complications were observed in either group. CONCLUSION: Premedication with oral propranolol 10 mg before hypotensive anesthesia with sodium nitroprusside is safe and effective to reduce reflex tachycardia and the amount of sodium nitroprusside used.

Cortisol rapidly increases baroreflex sensitivity of heart rate control, but does not affect cardiac modulation of startle.

Cortisol, the final product of human HPA axis activation, rapidly modulates the cortical processing of afferent signals originating from the cardiovascular system. While peripheral effects have been excluded, it remains unclear whether this effect is mediated by cortical or subcortical (e.g. brainstem) CNS mechanisms. Cardiac modulation of startle (CMS) has been proposed as a method to reflect cardio-afferent signals at subcortical (potentially brainstem-) level. Using a single blind, randomized controlled design, the cortisol group (n = 16 volunteers) received 1 mg cortisol intravenously, while the control group (n = 16) received a placebo substance. The CMS procedure involved the assessment of eye blink responses to acoustic startle stimuli elicited at six different latencies to ECG-recorded R-waves (R + 0, 100, 200, 300, 400 and 500 ms). CMS was assessed at four measurement points: baseline, -16 min, +0 min, and +16 min relative to substance application. Baroreflex sensitivity (BRS) of heart rate (HR) control was measured non-invasively based on spontaneous beat-to-beat HR and systolic blood pressure changes. In the cortisol group, salivary cortisol concentration increased after IV cortisol administration, indicating effective distribution of the substance throughout the body. Furthermore, BRS increased in the cortisol group after cortisol infusion. There was no effect of cortisol on the CMS effect, however. These results suggest that low doses of cortisol do not affect baro-afferent signals, but central or efferent components of the arterial baroreflex circuit presumably via rapid, non-genomic mechanisms.

Effects of peritoneal dialysis fluid biocompatibility on baroreflex sensitivity.

Conventional low biocompatibility peritoneal dialysis (PD) fluid composition has been driven by manufacturing expediency and cost limitations. PD is associated with significant acute changes in cardiovascular functional parameters, at least in part influenced by fluid composition. Short-term control of blood pressure (BP) is under control of the baroreflex arc. The aim of this study was to investigate the effects of PD fluid biocompatibility on baroreflex sensitivity (BRS). We studied 10 non-diabetic established continuous ambulatory PD patients, in a randomized crossover trial comparing conventional and biocompatible PD fluids. Systemic hemodynamics were continuously monitored using digital pulse-wave analysis. Plasma glucose and insulin were assessed during treatment with both 1.36% and 3.86% glucose-containing fluids. BRS was calculated offline from continuous BP and interbeat interval data. BRS was significantly higher with conventional PD fluid during both 1.36% (P<0.001) and 3.86% (P<0.001) dwells. Systolic BP was higher; heart rate, stroke volume, and cardiac output were lower; and total peripheral resistance increased during exposure to either fluid. There were significant differences between fluids with respect to the magnitude of these responses. Plasma glucose and insulin concentrations, and ultrafiltration volumes were significantly higher during the 3.86% dwell than the 1.36% dwell, but there were no differences between standard and biocompatible fluids. We have demonstrated for the first time that PD fluid biocompatibility rapidly affects BRS. These changes occur against a background of cardiovascular variability, hyperinsulinemia, and hyperglycemia. Further research is needed to explore the mechanism and, more importantly, the consequences of these findings.

In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats.

Imidafenacin (KRP-197) is a novel antimuscarinic agent for overactive bladder treatment. The inhibitory effect of imidafenacin on detrusor contraction has been adopted for assessing their bladder selectivity, but this is becoming less convincing as an effectiveness index. We, therefore, reevaluated the bladder selectivity of imidafenacin and other antimuscarinics using their effects on the bladder capacity as an effectiveness index. Bladder capacity was measured by intermittent cystometry in urethane-anesthetized rats. In the tissues related to antimuscarinic side effects, the inhibitory actions were measured each on salivary secretion by electrical stimulation of chorda tympani, on rhythmical contractions in colon, and on carbamylcholine-induced bradycardia. Imidafenacin, solifenacin succinate, tolterodine tartrate, and propiverine hydrochloride significantly increased the bladder capacity, with minimum effective doses of 0.003, 1, 0.03, and 3 mg/kg (i.v.), respectively. The antimuscarinics tested, except for propiverine hydrochloride, shared a common property of increasing bladder capacity at a dose which did not affect micturition pressure. The relative bladder selectivity of imidafenacin, solifenacin succinate, and tolterodine tartrate was 15-, 1.7-, and 2.5-fold higher over salivary gland; 150-, 1.9-, and 9.2-fold higher over colon; and 50-, 12-, and 4.6-fold higher over heart, respectively, than that of propiverine hydrochloride. Thus, imidafenacin shows the most highly selective for bladder over the tissues related to major antimuscarinic side effects, compared to the other three well-known antimuscarinics tested in the rat.

Cyclohexanone contamination from extracorporeal circuits impairs cardiovascular function.

Extracorporeal circulation provides critical life support in the face of cardiopulmonary or renal failure, but it also introduces a host of unique morbidities characterized by edema formation, cardiac insufficiency, autonomic dysfunction, and altered vasomotor function. We tested the hypothesis that cyclohexanone (CHX), a solvent used in production of extracorporeal circuits and intravenous (IV) bags, leaches into the contained fluids and can replicate these clinical morbidities. Crystalloid fluid samples from circuits and IV bags were analyzed by gas chromatography-mass spectrometry to provide a range of clinical CHX exposure levels, revealing CHX contamination of sampled fluids (9.63-3,694 microg/l). In vivo rat studies were conducted (n = 49) to investigate the effects of a bolus IV infusion of CHX vs. saline alone on cardiovascular function, baroreflex responsiveness, and edema formation. Cardiovascular function was evaluated by cardiac output, heart rate, stroke volume, vascular resistance, arterial pressure, and ventricular contractility. Baroreflex function was assessed by mean femoral arterial pressure responses to bilateral carotid occlusion. Edema formation was assessed by the ratio of wet to dry organ weights for lungs, liver, kidneys, and skin. CHX infusion led to systemic hypotension; pulmonary hypertension; depressed contractility, heart rate, stroke volume, and cardiac output; and elevated vascular resistance (P < 0.05). Mean arterial pressure responsiveness to carotid occlusion was dampened after CHX infusion (from +17.25 +/- 1.8 to +5.61 +/- 3.2 mmHg; P < 0.05). CHX infusion led to significantly higher wet-to-dry weight ratios vs. saline only (3.8 +/- 0.06 vs. 3.5 +/- 0.05; P < 0.05). CHX can reproduce clinical cardiovascular, neurological, and edema morbidities associated with extracorporeal circulatory treatment.

Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate.

Systemic corticosterone (Cort) modulates arterial baroreflex control of both heart rate and renal sympathetic nerve activity. Because baroreceptor afferents terminate in the dorsal hindbrain (DHB), an area with dense corticosteroid receptor expression, we tested the hypothesis that prolonged activation of DHB Cort receptors increases the midpoint and reduces the gain of arterial baroreflex control of heart rate in conscious rats. Small (3-4 mg) pellets of Cort (DHB Cort) or Silastic (DHB Sham) were placed on the surface of the DHB, or Cort was administered systemically by placing a Cort pellet on the surface of the dura (Dura Cort). Baroreflex control of heart rate was determined in conscious male Sprague Dawley rats on each of 4 days after initiation of treatment. Plots of arterial pressure vs. heart rate were analyzed using a four-parameter logistic function. After 3 days of treatment, the arterial pressure midpoint for baroreflex control of heart rate was increased in DHB Cort rats (123 +/- 2 mmHg) relative to both DHB Sham (108 +/- 3 mmHg) and Dura Cort rats (109 +/- 2 mmHg, P < 0.05). On day 4, baseline arterial pressure was greater in DHB Cort (112 +/- 2 mmHg) compared with DHB Sham (105 +/- 2 mmHg) and Dura Cort animals (106 +/- 2 mmHg, P < 0.05), and the arterial pressure midpoint was significantly greater than mean arterial pressure in the DHB Cort group only. Also on day 4, maximum baroreflex gain was reduced in DHB Cort (2.72 +/- 0.12 beats x min(-1) x mmHg(-1)) relative to DHB Sham and Dura Cort rats (3.51 +/- 0.28 and 3.37 +/- 0.27 beats x min(-1) x mmHg(-1), P < 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function.

Promethazine affects autonomic cardiovascular mechanisms minimally.

Promethazine hydrochloride, Phenergan, is a phenothiazine derivative with antihistaminic (H1), sedative, antiemetic, anticholinergic, and antimotion sickness properties. These properties have made promethazine a candidate for use in environments such as microgravity, which provoke emesis and motion sickness. Recently, we evaluated carotid baroreceptor-cardiac reflex responses during two Space Shuttle missions 18 to 20 hr after the 50 mg intramuscular administration of promethazine. Because the effects of promethazine on autonomic cardiovascular mechanisms in general and baroreflex function in particular were not known, we were unable to exclude a possible influence of promethazine on our results. Our purpose was to determine the ground-based effects of promethazine on autonomic cardiovascular control. Because of promethazine's antihistaminic and anticholinergic properties, we expected that a 50-mg intramuscular injection of promethazine would affect sympathetically and vagally mediated cardiovascular mechanisms. Eight healthy young subjects, five men and three women, were studied at rest in recumbency. All reported drowsiness as a result of the promethazine injection; most also reported nervous excitation, dry mouth, and fatigue. Three subjects had significant reactions: two reported excessive anxiety and one reported dizziness. Measurements were performed immediately prior to injection and 3.1 +/- 0.1 and 19.5 +/- 0.4 hr postinjection. We found no significant effect of promethazine on resting mean R-R interval, arterial pressure, R-R interval power spectra, carotid baroreflex function, and venous plasma catecholamine levels.