Morphometric analysis of the splenic artery using contrast-enhanced computed tomography (CT).

PURPOSE: To evaluate the morphology and course of the splenic artery, which might impact the surgical implantation of systems that stimulate the nerves surrounding the splenic artery. Experimental studies indicate that these nerves play an important part in immune modulation, and might be a potential target in the treatment of autoimmune diseases. METHODS: This retrospective cohort study made use of contrast-enhanced CT images from 40 male and 40 female patients (age 30-69) that underwent a CT examination of the aorta, kidneys or pancreas. Anatomic features were described including total splenic artery length, calibers, tortuosity, the presence of arterial loops and the branching pattern of the splenic artery. RESULTS: No age-gender-related differences could be found related to tortuosity or branching pattern. The length of splenic artery in contact with pancreatic tissue decreased with increasing age, but was not different between genders. Artery diameters were wider in male compared to female subjects. Loops of variable directions, that represent a part of the artery that curls out of the pancreatic tissue, were identified in each age-gender category and were present in nearly all subjects (86%). CONCLUSION: This study suggests that although some anatomic features of the splenic artery are subject to factors as age and gender, the tortuosity of the splenic artery is not age dependent. Most subjects had one or multiple loops, which can serve as a target for neuromodulatory devices. Future studies should investigate whether splenic nerve stimulation is safe and feasible.

Prolonged Baroreflex Activation Abolishes Salt-Induced Hypertension After Reductions in Kidney Mass.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated for therapy in patients with resistant hypertension. However, patients with significant impairment of renal function have been largely excluded from clinical trials. Thus, there is little information on blood pressure and renal responses to baroreflex activation in subjects with advanced chronic kidney disease, which is common in resistant hypertension. Changes in arterial pressure and glomerular filtration rate were determined in 5 dogs after combined unilateral nephrectomy and surgical excision of the poles of the remaining kidney to produce ≈70% reduction in renal mass. After control measurements, sodium intake was increased from ≈45 to 450 mol/d. While maintained on high salt, animals experienced increases in mean arterial pressure from 102±4 to 121±6 mm Hg and glomerular filtration rate from 40±2 to 45±2 mL/min. During 7 days of baroreflex activation, the hypertension induced by high salt was abolished (103±6 mm Hg) along with striking suppression of plasma norepinephrine concentration from 139±21 to 81±9 pg/mL, but despite pronounced blood pressure lowering, there were no significant changes in glomerular filtration rate (43±2 mL/min). All variables returned to prestimulation values during a recovery period. These findings indicate that after appreciable nephron loss, chronic suppression of central sympathetic outflow by baroreflex activation abolishes hypertension induced by high salt intake. The sustained antihypertensive effects of baroreflex activation occur without significantly compromising glomerular filtration rate in remnant nephrons.

Prediction of blunt traumatic injuries and hospital admission based on history and physical exam.

BACKGROUND: We evaluated the ability of experienced trauma surgeons to accurately predict specific blunt injuries, as well as patient disposition from the emergency department (ED), based only on the initial clinical evaluation and prior to any imaging studies. It would be hypothesized that experienced trauma surgeons' initial clinical evaluation is accurate for excluding life-threatening blunt injuries and for appropriate admission triage decisions. METHODS: Using only their history and physical exam, and prior to any imaging studies, three (3) experienced trauma surgeons, with a combined Level 1 trauma experience of over 50 years, predicted injuries in patients with an initial GCS (Glasgow Coma Score) of 14-15. Additionally, ED disposition (ICU, floor, discharge to home) was also predicted. These predictions were compared to actual patient dispositions and to blunt injuries documented at discharge. RESULTS: A total of 101 patients with 92 blunt injuries were studied. 43/92 (46.7 %) injuries would have been missed by only performing an initial history and physical exam ("Missed injury"). A change in treatment, though often minor, was required in 19/43 (44.2 %) of the missed injuries. Only 1/43 (2.3 %) of these "missed injuries" (blunt aortic injury) required surgery. Sensitivity, specificity, and accuracy for injury prediction were 53.2, 95.9, and 92.3 % respectively. Positive and negative predictive values were 53.8 and 95.8 % respectively. Prediction of disposition from the ED was 77.8 % accurate. In 7/34 (20.6 %) patients, missed injuries led to changes in disposition. "Undertriage" occurred in 9/99 (9.1 %) patients (Predicted for floor but admitted to ICU). Additionally, 8/84 (9.5 %) patients predicted for floor admission were sent home from the ED; and 5/13 (38.5 %) patients predicted for ICU admission were actually sent to the floor after complete evaluations, giving an "overtriage" rate of 13/99 (13.1 %) patients. CONCLUSIONS: In a neurologically-intact group of trauma patients, experienced trauma surgeons would have missed 46.7 % of the actual injuries, based only on their history and physical exam. Once accurate diagnoses of injuries were completed, usually with the help of CT scans, admission dispositions changed in 20.6 % of patients. Treatment changes occurred in 44.2 % of the missed injuries, though usually minimal. Broad elimination of early imaging studies in alert, blunt trauma patients cannot be advocated.

Chronic Interactions Between Carotid Baroreceptors and Chemoreceptors in Obesity Hypertension.

Carotid bodies play a critical role in protecting against hypoxemia, and their activation increases sympathetic activity, arterial pressure, and ventilation, responses opposed by acute stimulation of the baroreflex. Although chemoreceptor hypersensitivity is associated with sympathetically mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remain unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35% to 40% weight gain and increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (arterial partial pressure of oxygen=81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electric stimulation of the carotid sinus, tachypnea was attenuated, and hypertension was abolished before these variables returned to prestimulation values during a recovery period. After subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in arterial partial pressure of oxygen (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45%-50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex.

Non-weight-based enoxaparin dosing subtherapeutic in trauma patients.

BACKGROUND: We report our experience dosing and monitoring enoxaparin with anti-factor Xa activity (anti-FXaA) levels for venous thromboembolism prophylaxis in trauma patients (TP). MATERIALS AND METHODS: TP receiving standard, non-weight-based dosed enoxaparin administered every 12 h for venous thromboembolism prophylaxis with peak anti-FXaA levels measured were prospectively monitored and evaluated and those whose first anti-FXaA levels ≥ or <0.2 IU/mL were compared. Anti-FXaA levels and enoxaparin dose (mg/kg actual body weight) were evaluated for correlation. RESULTS: Of the fifty-one TP included, initial anti-FXaA levels were <0.2 IU/mL in 37 (72.5%) whose dose was lower than those within target range (0.38 [0.32-0.42] mg/kg versus 0.45 [0.39-0.48] mg/kg, P = 0.003). Thirty-seven TP achieved anti-FXaA level ≥0.2 IU/mL (23 requiring dose increases) at a dose of 0.49 [0.44-0.54] mg/kg. Correlation between dose and anti-FXaA levels for the initial 51 anti-FXaA levels (r = 0.360, P = 0.009) and for all 103 anti-XaA levels (r = 0.556, P < 0.001) was noted. CONCLUSIONS: Non-weight-based enoxaparin dosing did not achieve target anti-FXaA levels in most TP. Higher anti-FXaA levels correlated with larger weight-based enoxaparin doses. Weight-based enoxaparin dosing (i.e., 0.5 mg/kg subcutaneously every 12 h) would better achieve target anti-FXaA levels.

Global- and renal-specific sympathoinhibition in aldosterone hypertension.

Recent technology for chronic electric activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12 µg/kg per day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ≈40% and arterial pressure by 16±2 mm Hg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mm Hg) was diminished (≈55%) during aldosterone hypertension when compared with control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy.

Computed tomography scans with intravenous contrast: low incidence of contrast-induced nephropathy in blunt trauma patients.

BACKGROUND: Computed tomography (CT) with intravenous (IV) contrast is an important step in the evaluation of the blunt trauma patient; however, the risk for contrast-induced nephropathy (CIN) in these patients still remains unclear. The goal of this study was to describe the rate of CIN in blunt trauma patients at a Level 1 trauma center and identify the risk factors of developing CIN. METHODS: After internal review board approval, we reviewed our Level 1 trauma registry to identify blunt trauma patients admitted during a 1-year period. Chart review was used to identify patient demographics, creatinine levels, and vital signs. CIN was defined as an increase in creatinine by 0.5 mg/dL from admission after undergoing CT with IV contrast. RESULTS: Four percent of patients developed CIN during their admission following receipt of IV contrast for CT; 1% had continued renal impairment on discharge. No patients required dialysis during their admission. Diabetic patients had an increased rate of CIN, with 10% rate of CIN during admission and 4% at discharge. In multivariate analysis, only preexisting diabetes and Injury Severity Score (ISS) of greater than 25 were independently associated with risk for CIN. CONCLUSION: The rate of CIN in trauma patients following CT scan with IV contrast is low. Diabetes and ISS were independent risk factors of development of CIN in trauma patients. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III.

Regulation of renin secretion and arterial pressure during prolonged baroreflex activation: influence of salt intake.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake.

Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal.

INTRODUCTION: Prothrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation. METHODS: Data were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety. RESULTS: Seventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p =0.001). The follow-up INR was lower after LDrFVIIa (1.25 vs. 1.75, p < 0.05) and the percent change in INR was larger after LDrFVIIa (54.1% vs. 38.8%, p = 0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, p = 1.00), mortality, length of hospital stay, or cost. CONCLUSIONS: Based on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa.

A prospective study of the role of sleep related disordered breathing as a risk factor for motor vehicle crashes and the development of systemic complications in non-commercial drivers.

INTRODUCTION: Sleep related disordered breathing (SRDB), is an established risk factor for motor vehicle crashes (MVCs) involving commercial drivers. The role of SRDB in motor vehicle crashes involving non-commercial drivers is not well established. METHODS: Drivers involved in MVCs who were admitted to an American College of Surgeons accredited Level I trauma center for treatment of their injuries, and who could give informed consent and provide verbal responses to screening questionnaires were eligible for enrolment in this study. Two questionnaires previously validated for screening patients at risk for sleep disturbances (The Epworth Sleepiness Scale (ESS) and The Berlin Questionnaire (BQ)) were administered. Questionnaire results associated with an 85% sensitivity for predicting obstructive sleep apnea were considered positive. In this study we tested the hypothesis that patients at risk for SRDB, as measured by validated questionnaires, are at an increased risk being involved in MVCs. RESULTS: Between March and October 2010, 71 consecutive patients were offered enrolment in this study with 56 agreeing to participate in this study. Six were previously diagnosed with SRDB with only one being compliant and effectively treated at the time of their MVC. Forty-two patients (75%) had responses to the questionnaires that indicated that the patients were at high risk for SRDB. Six patients suffered systemic complications, including pleural effusions, pneumonia and arrhythmias, during their hospitalization with five (83%) having abnormal questionnaire responses indicating that the patient was at high risk for SRDB. CONCLUSIONS: The high incidence of positive responses to the sleep questionnaires is consistent with the hypothesis that SRDB is potentially a significant risk factor for MVCs. Furthermore the observation that systemic complications were seen more commonly in those with SRDB, while not unexpected, is a novel observation. Further studies are needed to validate these findings in a larger cohort of patients as well as determining if these patients are truly at a greater risk for systemic complications. If replicated these observations would suggest that effective therapy for disordered sleep could play a significant role in an injury prevention process.

Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension.

The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation-current therapies in patients with resistant hypertension, who are commonly obese-restore cardiovascular dynamic control. Increases in body weight to ∼150% of control led to a gradual increase in mean arterial pressure to 17 ± 3 mmHg above control (100 ± 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1-4 days on high-fat intake, reaching 130 ± 4 beats per minute (bpm) (control = 86 ± 3 bpm) and ∼45% and <20%, respectively, of control levels. Subsequently, both baroreflex activation and renal denervation abolished the hypertension. However, only baroreflex activation effectively attenuated the tachycardia and restored cardiac baroreflex sensitivity and heart rate variability. These findings suggest that baroreflex activation therapy may reduce the risk factors for cardiac arrhythmias as well as lower arterial pressure.

Renal responses to chronic suppression of central sympathetic outflow.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs, we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combination with the calcium channel blocker amlodipine, which is commonly used in the treatment of resistant hypertension. During baroreflex activation alone, there were sustained decreases in mean arterial pressure (17±1 mmHg) and plasma (norepinephrine; ≈35%), with no change in plasma renin activity. Despite low pressure, sodium balance was achieved because of decreased tubular reabsorption, because glomerular filtration rate and renal blood flow decreased 10% to 20%. After 2 weeks of amlodipine, arterial pressure was also reduced 17 mmHg, but with substantial increases in norepinephrine and plasma renin activity and no change in glomerular filtration rate. In the presence of amlodipine, baroreflex activation greatly attenuated neurohormonal activation, and pressure decreased even further (by 11±2 mmHg). Moreover, during amlodipine administration, the fall in glomerular filtration rate with baroreflex activation was abolished. These findings suggest that the chronic blood pressure-lowering effects of baroreflex activation are attributed, at least in part, to sustained inhibition of renal sympathetic nerve activity and attendant decreases in sodium reabsorption before the macula densa. Tubuloglomerular feedback constriction of the afferent arterioles may account for reduced glomerular filtration rate, a response abolished by amlodipine, which dilates the preglomerular vasculature.

Systemic and renal-specific sympathoinhibition in obesity hypertension.

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electric activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat, whereas sodium intake was held constant. After 4 weeks on the high-fat diet, when body weight had increased ≈50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite an approximately 35% increase in glomerular filtration rate. The importance of increased tubular reabsorption to sodium retention was further reflected by ≈35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, glomerular filtration rate increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.

Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin.

BACKGROUND: Prothrombin complex concentrate (PCC) is recommended as a therapy to be considered for the reversal of warfarin's effects. Few published data are available on the use of PCC for this indication in traumatically injured patients. OBJECTIVE: To determine whether the addition of PCC to standard approaches to warfarin reversal more rapidly corrects the international normalized ratio (INR) in injured patients. METHODS: A retrospective analysis was performed in trauma patients who were on warfarin preinjury from January 2007 to September 2009 at North Memorial Medical Center. Data were collected from medical records and the trauma registry. Patients were separated based on whether or not they received PCC. The groups were compared on the basis of demographics, units of fresh frozen plasma (FFP), vitamin K use, units of PCC, number of patients achieving an INR of 1.5 or less, time to an INR of 1.5 or less, mortality, intensive care unit (ICU) and hospital length of stay, and the incidence of thromboembolic events during hospitalization. RESULTS: Thirty-one patients were included in the analysis; 13 patients who received a total mean (SD) dose of 2281 (1053) units (25.6 [12.2] units/kg) of PCC (Profilnine SD) were compared to 18 patients who did not receive PCC. There was no significant difference between groups in FFP units received or the number of patients who received vitamin K. Most patients in both groups achieved an INR of 1.5 or less (92% PCC vs 89% no PCC). However, the mean time to achieve an INR of 1.5 or less was 16:59 (20:53) hours in the PCC group versus 30:03 (23:10) hours in the no PCC group (p = 0.048). There were 3 deaths in the PCC group and no deaths in the no PCC group (p = 0.06). ICU and hospital length of stay and number of thromboembolic events did not differ significantly between the 2 groups. CONCLUSIONS: PCC, when added to FFP and vitamin K, resulted in a more rapid time to reversal of the INR.

Chronic electrical stimulation of the carotid sinus baroreflex improves left ventricular function and promotes reversal of ventricular remodeling in dogs with advanced heart failure.

BACKGROUND: Autonomic abnormalities exist in heart failure and contribute to disease progression. Activation of the carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure. METHODS AND RESULTS: Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) and 6 were not and served as controls. All dogs were followed for 3 months, and none received other background therapy. During follow-up, treatment with CSB increased LV ejection fraction 4.0±2.4% compared with a reduction in control dogs of −2.8±1.0% (P<0.05). Similarly, treatment with CSB decreased LV end-systolic volume -2.5±2.7 mL compared with an increase in control dogs of 6.7±2.9 mL (P<0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac ß(1)-adrenergic receptors, ß-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy. CONCLUSIONS: In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.

Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex.

Following sinoaortic denervation, which eliminates arterial baroreceptor input into the brain, there are slowly developing adaptations that abolish initial sympathetic activation and hypertension. In comparison, electrical stimulation of the carotid sinus for 1 wk produces sustained reductions in sympathetic activity and arterial pressure. However, whether compensations occur subsequently to diminish these responses is unclear. Therefore, we determined whether there are important central and/or peripheral adaptations that diminish the sympathoinhibitory and blood pressure-lowering effects of more sustained carotid sinus stimulation. To this end, we measured whole body plasma norepinephrine spillover and alpha(1)-adrenergic vascular reactivity in six dogs over a 3-wk period of baroreflex activation. During the first week of baroreflex activation, there was an approximately 45% decrease in plasma norepinephrine spillover, along with reductions in mean arterial pressure and heart rate of approximately 20 mmHg and 15 beats/min, respectively; additionally, plasma renin activity did not increase. Most importantly, these responses during week 1 were largely sustained throughout the 3 wk of baroreflex activation. Acute pressor responses to alpha-adrenergic stimulation during ganglionic blockade were similar throughout the study, indicating no compensatory increases in adrenergic vascular reactivity. These findings indicate that the sympathoinhibition and lowering of blood pressure and heart rate induced by chronic activation of the carotid baroreflex are not diminished by adaptations in the brain and peripheral circulation. Furthermore, by providing evidence that baroreflexes have long-term effects on sympathetic activity and arterial pressure, they present a perspective that is opposite from studies of sinoaortic denervation.

Prolonged activation of the baroreflex decreases arterial pressure even during chronic adrenergic blockade.

Previous studies suggest that prolonged electric activation of the baroreflex may reduce arterial pressure more than chronic blockade of alpha(1)- and beta(1,2)-adrenergic receptors. To determine whether central inhibition of sympathetic outflow has appreciable effects to chronically reduce arterial pressure by actions distinct from well-established mechanisms, we hypothesized that chronic baroreflex activation would lower arterial pressure substantially even during complete alpha(1)- and beta(1,2)-adrenergic receptor blockade. This hypothesis was tested in 6 dogs during adrenergic blockade (AB; 18 days) with and without electric activation of the carotid baroreflex (7 days). During chronic AB alone, there was a sustained decrease in the mean arterial pressure of 21+/-2 mm Hg (control: 95+/-4 mm Hg) and an approximately 3-fold increase in plasma norepinephrine concentration (control: 138+/-6 pg/mL), likely attributed to baroreceptor unloading. In comparison, during AB plus prolonged baroreflex activation, plasma norepinephrine concentration decreased to control levels, and mean arterial pressure fell an additional 10+/-1 mm Hg. Because of differences in plasma norepinephrine concentration, we also tested the acute blood pressure-lowering effects of MK-467, a peripherally acting alpha(2)-antagonist. After administration of MK-467, there was a significantly greater fall in arterial pressure during AB (15+/-3 mm Hg) than during AB plus prolonged baroreflex activation (7+/-3 mm Hg). These findings suggest that reflex-induced increases in sympathetic activity attenuate reductions in arterial pressure during chronic AB and that inhibition of central sympathetic outflow by prolonged baroreflex activation lowers arterial pressure further by previously undefined mechanisms, possibly by diminishing attendant activation of postjunctional alpha(2)-adrenergic receptors.

Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure.

Much of the current pharmacological therapy for chronic heart failure targets neurohormonal activation. In spite of recent advances in drug therapy, the mortality rate for chronic heart failure remains high. Activation of the carotid baroreceptor (BR) reduces sympathetic outflow and augments vagal tone. We investigated the effect of chronic activation of the carotid BR on hemodynamic and neurohormonal parameters and on mortality in dogs with chronic heart failure. Fifteen dogs were instrumented to record hemodynamics. Electrodes were applied around the carotid sinuses to allow for activation of the BR. After 2 weeks of pacing (250 bpm), electrical carotid BR activation was initiated in 7 dogs and continued for the remainder of the study. The start of BR activation was used as a time reference point for the remaining 8 control dogs that did not receive BR activation. Survival was significantly greater for dogs undergoing carotid BR activation compared with control dogs (68.1+/-7.4 versus 37.3+/-3.2 days, respectively; P<0.01), although arterial pressure, resting heart rate, and left ventricular pressure were not different over time in BR-activated versus control dogs. Plasma norepinephrine was lower in dogs receiving BR activation therapy 31 days after the start of BR activation (401.9+/-151.5 versus 1121.9+/-389.1 pg/mL in dogs not receiving activation therapy; P<0.05). Plasma angiotensin II increased less in dogs receiving activation therapy (plasma angiotensin II increased by 157.4+/-58.6 pg/mL in control dogs versus 10.1+/-14.0 pg/mL in dogs receiving activation therapy; P<0.02). We conclude that chronic activation of the carotid BR improves survival and suppresses neurohormonal activation in chronic heart failure.