Daniel W. Byrne

Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial

CONTEXT Gamma-aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the alpha(2) agonist dexmedetomidine may have distinct advantages. OBJECTIVE To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients. DESIGN, SETTING, AND PATIENTS Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU. INTERVENTIONS Dexmedetomidine (0.2-1.4 microg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between -2 and +1) from enrollment until extubation or 30 days. MAIN OUTCOME MEASURES Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events. RESULTS There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, -3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02). CONCLUSIONS There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00216190 Published online February 2, 2009 (doi:10.1001/jama.2009.56).

Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: a prospective randomized double-blind clinical trial.

Objective:We sought to determine the impact of the addition of Dor fundoplication on the incidence of postoperative gastroesophageal reflux (GER) after Heller myotomy. Summary Background Data:Based only on case series, many surgeons believe that an antireflux procedure should be added to the Heller myotomy. However, no prospective randomized data support this approach. Patients and Methods:In this prospective, randomized, double-blind, institutional review board-approved clinical trial, patients with achalasia were assigned to undergo Heller myotomy or Heller myotomy plus Dor fundoplication. Patients were studied via 24-hour pH study and manometry at 6 months postoperatively. Pathologic GER was defined as distal esophageal time acid exposure time greater than 4.2% per 24-hour period. The outcome variables were analyzed on an intention-to-treat basis. Results:Forty-three patients were enrolled. There were no differences in the baseline characteristics between study groups. Pathologic GER occurred in 10 of 21 patients (47.6%) after Heller and in 2 of 22 patients (9.1%) after Heller plus Dor (P = 0.005). Heller plus Dor was associated with a significant reduction in the risk of GER (relative risk 0.11; 95% confidence interval 0.02–0.59; P = 0.01). Median distal esophageal acid exposure time was lower in the Heller plus Dor (0.4%; range, 0–16.7) compared with the Heller group (4.9%; range, 0.1–43.6; P = 0.001). No significant difference in surgical outcome between the 2 techniques with respect to postoperative lower-esophageal sphincter pressure or postoperative dysphagia score was observed. Conclusions:Heller Myotomy plus Dor Fundoplication was superior to Heller myotomy alone in regard to the incidence of postoperative GER.

Major risk factors for pressure ulcers in the spinal cord disabled: a literature review

Pressure ulcers remain a dominant health problem for persons with spinal cord injury despite abundant published research describing risk factors. Although information on these factors is plentiful, its usefulness to the spinal cord disabled is limited by three problems. First, the sheer volume is overwhelming; more than 200 risk factors for pressure ulcers have been described in the published literature. For most health care professionals, finding, no less reading and evaluating, the hundreds of articles published on this topic would be difficult. Second, most studies focused on elderly patients in nursing homes. Pressure ulcer risk factors for the spinal cord disabled are often different from those for the elderly; yet many findings from studies of the elderly provide valuable information. Third, inadequate sample sizes often hamper the usefulness of research on the spinal cord disabled. Drawing valid conclusions from these small studies, especially concerning potential risk factors is difficult. To address these three problems, we critically evaluated the medical, nursing, and nutritional research literature that pertained to risk factors for pressure ulcer development. The purpose of this paper is to provide a review of published reports on the principal risk factors for pressure ulcers in persons with spinal cord injury.

Effects of Chemical Form of Selenium on Plasma Biomarkers in a High-Dose Human Supplementation Trial

Intervention trials with different forms of selenium are under way to assess the effects of selenium supplements on the incidence of cancer and other diseases. Plasma selenium biomarkers respond to selenium administration and might be useful for assessing compliance and safety in these trials. The present study characterized the effects of selenium supplementation on plasma selenium biomarkers and urinary selenium excretion in selenium-replete subjects. Moderate (∼200 μg/d) to large (∼600 μg/d) selenium supplements in the forms sodium selenite, high-selenium yeast (yeast), and l-selenomethionine (selenomethionine) were administered. Subjects were randomized into 10 groups (placebo and three dose levels of each form of selenium). Plasma biomarkers (selenium concentration, selenoprotein P concentration, and glutathione peroxidase activity) were determined before supplementation and every 4 weeks for 16 weeks. Urinary selenium excretion was determined at 16 weeks. Supplementation with selenomethionine and yeast raised the plasma selenium concentration in a dose-dependent manner. Selenite did not. The increased selenium concentration correlated with the amount of selenomethionine administered. Neither glutathione peroxidase activity nor selenoprotein P concentration responded to selenium supplementation. Urinary selenium excretion was greater after selenomethionine than after selenite, with excretion after yeast being intermediate and not significantly different from either of the other two. We conclude that plasma selenium concentration is useful in monitoring compliance and safety of selenium supplementation as selenomethionine but not as selenite. Plasma selenium seems to reflect the selenomethionine content of yeast but not the other yeast selenium forms. As judged by urinary selenium excretion, selenium in the form of selenomethionine is better absorbed than selenite. (Cancer Epidemiol Biomarkers Prev 2006;15(4):804–10)

A common β1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to β-blockade

A common polymorphism of the β1‐adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance.

A new pressure ulcer risk assessment scale for individuals with spinal cord injury.

Each year, one-fourth of the 200,000 individuals with spinal cord injury in the United States develop pressure ulcers. No method currently exists, however, to accurately identify which of these individuals are at increased risk for development of pressure ulcers. We studied 219 spinal cord-injured patients, seen at a Veterans Affairs Medical Center, during a 6-yr period. Our goal was to develop a pressure ulcer risk assessment scale, specifically for persons with SCI. Each risk factor had to meet four criteria: (1) statistical association with pressure ulcer development; (2) biologically plausible mechanism; (3) literature support; (4) improved prediction. Among the 219 spinal cord-injured patients evaluated, 176 (80.4 percent) had a history of one or more pressure ulcers. Fifteen risk factors met the four criteria for inclusion into the risk assessment scale. They were as follows: restricted activity level, degree of immobility, complete spinal cord injury, urinary disease, impaired cognitive function, diabetes, cigarette smoking, residence in a nursing home or hospital, hypoalbuminemia, and anemia. Compared with the more general scales available, for quantifying the risk of pressure ulcer development, preliminary results suggest that this new scale is a significant improvement for the spinal cord-disabled.

Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome

Background—Patients with postural tachycardia syndrome (POTS) experience considerable disability, but in most, the pathophysiology remains obscure. Plasma volume disturbances have been implicated in some patients. We prospectively tested the hypothesis that patients with POTS are hypovolemic compared with healthy controls and explored the role of plasma renin activity and aldosterone in the regulation of plasma volume. Methods and Results—Patients with POTS (n=15) and healthy controls (n=14) underwent investigation. Heart rate (HR), blood pressure (BP), plasma renin activity, and aldosterone were measured with patients both supine and upright. Blood volumes were measured with 131I-labeled albumin and hematocrit. Patients with POTS had a higher orthostatic increase in HR than controls (51±18 versus 16±10 bpm, P<0.001). Patients with POTS had a greater deficit in plasma volume (334±187 versus 10±250 mL, P<0.001), red blood cell volume (356±128 versus 218±140 mL, P=0.010), and total blood volume (689±270 versus 228±353 mL, P<0.001) than controls. Despite the lower plasma volume in patients with POTS, there was not a compensatory increase in plasma renin activity (0.79±0.58 versus 0.79±0.74 ng · mL−1 · h−1, P=0.996). There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L; P=0.017). Conclusions—Patients with POTS have paradoxically unchanged plasma renin activity and low aldosterone given their marked reduction in plasma volume. These patients also have a significant red blood cell volume deficit, which is regulated by the renal hormone erythropoietin. These abnormalities suggest that the kidney may play a key role in the pathophysiology of POTS.

Association of the Metabolic Syndrome With Pulmonary Venous Hypertension

BACKGROUND Pulmonary venous hypertension (PVH) is a well-described cause of pulmonary hypertension (PH) in patients with left heart disease associated with elevated left heart filling pressure. PVH results from a number of processes, including left-sided valvular disease, constrictive pericardial disease, restrictive cardiomyopathies, and left ventricular (LV) systolic dysfunction. PVH in patients with normal LV systolic function, commonly referred to as diastolic dysfunction, is not well characterized. We observed that many patients with PH due to PVH have obesity, hypertension, diabetes mellitus, and hypercholesterolemia, which are clinical features of the metabolic syndrome (MS), a previously identified cause for systemic vascular disease. METHODS We evaluated 122 consecutive patients referred for diagnosis and treatment of PH and compared the prevalence of features of the MS between patients with PVH and those with pulmonary arterial hypertension (PAH). We also compared clinical and hemodynamic characteristics between these two groups. RESULTS Compared to patients with PAH, patients with PVH had a higher frequency of hypertension, obesity, diabetes mellitus, and hyperlipidemia. Two or more features of the MS were found in 16 of 17 patients with PVH (94.1%) compared with 34.3% of patients with PAH (p < 0.001; odds ratio, 30.7; 95% confidence interval, 3.6 to 260.0). PH was substantial, but less severe overall, in patients with PVH compared to those with PAH (mean pulmonary artery pressure, 45 +/- 17 mm Hg [range, 26 to 71 mm Hg] vs 53 +/- 10 [range, 33 to 72 mm Hg], respectively [p = 0.041]; and pulmonary vascular resistance, 4.4 +/- 2.9 units [range, 1.2 to 10.8 units] vs 10.8 +/- 4.7 units [range, 4.8 to 21.9 units], respectively [p < 0.001]). CONCLUSION PVH is highly associated with the MS. Our results suggest that the MS may predispose patients to develop pulmonary vascular disease.

Autonomic Contribution to Blood Pressure and Metabolism in Obesity

Obesity is associated with alterations in the autonomic nervous system that may contribute to the increase in blood pressure and resting energy expenditure present in this condition. To test this hypothesis, we induced autonomic withdrawal with the ganglionic blocker trimethaphan in 10 lean (32±3 years) and 10 obese (35±3 years) subjects. Systolic blood pressure fell more in obese compared with lean subjects (−17±3 versus −11±1 mm Hg; P=0.019) because of a greater decrease in total peripheral resistance (−310±41 versus 33±78 dynes/sec/cm−5; P=0.002). In contrast, resting energy expenditure decreased less in obese than in lean subjects, (−26±21 versus −86±15 kcal per day adjusted by fat-free mass; P=0.035). We confirmed that the autonomic contribution to blood pressure was greater in obesity after including additional subjects with a wider range of blood pressures. Systolic blood pressure decreased −28±4 mm Hg (95% CI: −38 to −18.0; n=8) in obese hypertensive subjects compared with lean (−9±1 mm Hg; 95% CI: −11 to −6; n=22) or obese normotensive subjects (−14±2 mm Hg; 95% CI: −18 to −10; n=20). After removal of autonomic influences, systolic blood pressure remained higher in obese hypertensive subjects (109±3 versus 98±2 mm Hg in lean and 103±2 mm Hg in obese normotensive subjects; P=0.004) suggesting a role for additional factors in obesity-associated hypertension. In conclusion, sympathetic activation induced by obesity is an important determinant to the blood pressure elevation associated with this condition but is not effective in increasing resting energy expenditure. These results suggest that the sympathetic nervous system could be targeted in the treatment of obesity-associated hypertension.

Water Ingestion as Prophylaxis Against Syncope

Background—Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. It is unclear whether prophylactic water drinking improves orthostatic tolerance in normal healthy adults. Methods and Results—Twenty-two healthy subjects, 18 to 42 years of age, with no history of syncope underwent head-up tilt-table testing at 60° for 45 minutes or until presyncope or syncope occurred. In their initial test, participants were randomized to either 16 oz (473 mL) of water drinking 5 minutes before tilt-table testing or tilt-table testing alone, with the alternative in a second test on a different day. During the first 30 minutes of tilt, 8 of 22 subjects without water experienced presyncope but only 1 of 22 who had ingested water (P =0.016). Water drinking attenuated the heart rate increase associated with tilt (P <0.001) while accentuating the increase in total peripheral resistance (P =0.012). The average time study participants tolerated head-up tilt was 26% longer after water (41.1±8.1 versus 32.6±14.3 minutes, mean±SD), with a pairwise mean difference of 8.5±14.0 minutes (95% CI, 2.3 to 14.7 minutes; P =0.011). Conclusions—Water enhances tolerance of upright posture. The effect of water is mediated by increased peripheral vascular resistance. Water ingestion may constitute a simple and effective prophylaxis against vasovagal reactions in healthy subjects, such as those associated with blood donation.