Rubin I. Cohen

Effect of obesity on clinical presentation and response to treatment in asthma.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.

Randomized trial of the effect of drug presentation on asthma outcomes: The American Lung Association Asthma Clinical Research Centers

BACKGROUND Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. OBJECTIVE The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit. METHODS A randomized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups. Participants were randomly assigned to one of 4 treatment groups in a factorial design (ie, placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages) or to usual care. Assignment to study drug was double masked, assignment to message content was single masked, and usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control. RESULTS Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo; no differences were noted between the neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect. CONCLUSIONS Optimistic drug presentation augments the placebo effect for patient-reported outcomes (asthma control) but not lung function. However, the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.

The impact of do-not-resuscitate order on triage decisions to a medical intensive care unit

PURPOSE To determine whether the presence of a do-not-resuscitate (DNR) order impacts on triage decisions to a medical intensive care unit (MICU) of an academic medical center. METHODS Data were collected on 179 patients in whom MICU consultation was sought and included demographic, clinical information, diagnoses, ICU admission decision, Acute Physiological and Chronic Health Evaluation II (APACHE II) score, and the presence of DNR order. Functional status was determined retrospectively using the Modified Rankin Score. RESULTS The only factor that influenced MICU admission was the presence of DNR order at the time of MICU consultation (odds ratio, 0.25; 95% confidence interval, 0.09-0.71, P < .006). There was no difference between the age, APACHE II scores, or functional status between admitted or refused. Medical intensive care unit admission was associated with increased length of stay without difference in mortality. CONCLUSION The presence of a DNR order at the time of MICU consultation was significantly associated with the decision to refuse a patient to the MICU.

Impact of Asthma Controller Medications on Clinical, Economic, and Patient-Reported Outcomes

OBJECTIVE To comprehensively evaluate clinical, economic, and patient-reported outcomes associated with various therapeutic classes of asthma controller medications. PATIENTS AND METHODS This observational study, which used administrative claims data from US commercial health plans, included patients with asthma aged 18 through 64 years who filled a prescription for at least 1 asthma controller medication from September 1, 2003, through August 31, 2005. Outcome metrics included the use of short-acting β-agonists (SABAs), the use of oral corticosteroids, inpatient (INP)/emergency department (ED) visits, and asthma-related health care costs. A subset of 5000 patients was randomly selected for a survey using the Mini-Asthma Quality of Life Questionnaire, the Work Productivity and Activity Impairment questionnaire, and the Asthma Therapy Assessment Questionnaire. RESULTS Of 56,168 eligible patients, 823 returned completed questionnaires. Compared with inhaled corticosteroids (ICSs), leukotriene modifiers (LMs) were associated with lower odds of INP/ED visits (odds ratio [OR], 0.80; P P P P =.04), lower odds of using 6 or more SABA canisters (OR, 0.46; P P CONCLUSION Inhaled corticosteroids were associated with a lower risk of INP/ED visits, and a lower cost if adherence was achieved. When adherence cannot be achieved, LMs may be a reasonable alternative. Combination therapy with ICS plus a long-acting β-agonist was associated with better or equivalent clinical, economic, and patient-reported outcomes.

Time course of nitric oxide, peroxynitrite, and antioxidants in the endotoxemic heart.

ObjectivesTo determine the time course for myocardial production of nitric oxide, peroxynitrite, and glutathione, to determine the activities of the myocardial antioxidant enzymes glutathione peroxidase, superoxide dismutase, and glutathione reductase throughout endotoxemia and into recovery, and to correlate the levels of these variables to left ventricular contractility in endotoxemia. DesignRats were treated with lipopolysaccharide. Endotoxemic hearts were examined at baseline, 4, 16, 24, and 48 hrs after lipopolysaccharide. Saline time-control groups were treated identically. SettingA pulmonary research laboratory of a university teaching hospital. Measurements and Main ResultsLipopolysaccharide administration resulted in decreased contractility at 16 hrs as assessed by the isolated papillary muscle technique. Contractility recovered by 24 hrs. Myocardial glutathione content initially increased, but it was decreased from baseline by 16 hrs, as was glutathione peroxidase activity. Both superoxide dismutase and glutathione reductase activities were increased early (4 hrs) and remained elevated throughout the course of the experiment. Myocardial nitric oxide content (assessed by the chemiluminescence technique) was increased by 4 hrs and was markedly elevated by 16 hrs. Nitric oxide levels remained elevated despite recovery of contractility at 24 hrs. Similarly, peroxynitrite (assessed by measurement of 3-nitrotyrosine by high-pressure liquid chromatography) was elevated at 16 hrs and remained elevated despite normalization of contractility at 24 and 48 hrs. ConclusionsMyocardial dysfunction in endotoxemia correlates mainly with decreased glutathione content and glutathione peroxidase activity rather than nitric oxide or peroxynitrite formation. These data indicate that lipopolysaccharide-induced myocardial dysfunction is not solely caused by elevated myocardial nitric oxide levels but rather caused by the sum of complex interactions between various oxygen- and nitrogen-derived radicals.

Criteria To Screen for Chronic Sinonasal Disease

BACKGROUND Sinusitis and rhinitis are associated with uncontrolled asthma. There are no simple, validated tools to screen for these diseases. The objective of this study was to assess instruments to assist in the diagnosis of chronic sinonasal disease. METHODS Participants without acute sinonasal symptoms underwent an extensive evaluation. The results were submitted to an expert panel that used the Delphi method to achieve consensus. Using the consensus diagnosis of the panel, we determined the sensitivity and specificity of test procedures to diagnose chronic sinonasal disease. We determined the reproducibility of the most sensitive and specific instrument in a separate cohort. RESULTS Fifty-nine participants were evaluated, and the expert panel reached consensus for all (42 participants with chronic sinonasal disease, 17 participants without chronic sinonasal disease). A six-item questionnaire based on the frequency of nasal symptoms was the most sensitive tool used to diagnose sinonasal disease (minimum specificity, 0.90). Reproducibility testing in a separate cohort of 63 participants (41 chronic sinonasal disease with asthma, 22 chronic sinonasal disease without asthma) showed a concordance correlation coefficient of 0.91 (95% CI, 0.85 to 0.94) when this questionnaire was limited to five items (ie, excluding a question on smell). This five-item questionnaire had a sensitivity of 0.90 (95% CI, 0.77 to 0.97), a specificity of 0.94 (95% CI, 0.71 to 1.00), and an area under the receiver operating characteristic curve of 0.97 (95% CI, 0.93 to 1.0). Sinus CT scans and nasal endoscopy lacked sensitivity for use in the diagnosis of chronic sinonasal disease. CONCLUSIONS We have developed a sensitive, specific, and reproducible instrument to screen for chronic sinonasal disease. Validation studies of this five-item questionnaire are needed, including in patients with asthma.

Scorpion venom leads to gastrointestinal ischemia despite increased oxygen delivery in pigs.

OBJECTIVES Scorpion envenomation may be accompanied by metabolic acidosis even in the absence of hypoxia and cardiovascular derangement. We tested the hypothesis that venom causes ischemia of the gastrointestinal tract rather than failure of delivery of oxygen to the periphery. DESIGN Repeated measures, prospective study in experimental animals. SETTING University-affiliated hospital research laboratory. INTERVENTIONS In ten spontaneously breathing, intubated, sedated pigs, purified dried venom (Leiurus quinquestriatus), 0.05 mg/kg, was administered intravenously. Measurements were obtained before (baseline), and 5, 15, 30, 60, 120, 180, and 240 mins after injection. MEASUREMENTS AND MAIN RESULTS Variables measured included: mean arterial pressure (MAP), heart rate (HR), mean pulmonary arterial pressure, pulmonary artery occlusion pressure, cardiac output, stroke volume, right ventricular ejection fraction (rapid thermistor), left ventricular dimensions (echocardiography), arterial gas tensions, lactate and catecholamine concentrations, gastric interstitial mucosal pH (tonometry), as well as systemic and pulmonary vascular resistances. Within 5 mins after venom injection, there was a hyperdynamic state accompanied by significantly increased MAP (97 +/- 18 to 136 +/- 47 mm Hg, p < .0003), HR (70 +/- 12 to 121 +/- 24 beats/min, p < .00006), and cardiac output (1.88 +/- 0.35 to 2.95 +/- 0.53 L/min, p < .0003), with no change in stroke volume, or pulmonary artery occlusion pressure. Right ventricular ejection fraction increased from 38.1 +/- 4.3 to 48.6 +/- 9.0% (p < .0009) by 15 mins. No change in left ventricular function was observed. There were significant decreases in systemic vascular resistance and pulmonary vascular resistance following envenomation. Arterial and gastric mucosal pH significantly decreased from 7.40 +/- 0.04 to 7.25 +/- 0.07 (p < .0001) for arterial pH, and 7.33 +/- 0.08 to 7.17 +/- 0.13 (p < .00001) for gastric mucosal pH by 30 mins after envenomation. The decrease in arterial pH was not sufficient to account for the change in gastric mucosal pH, indicating gastric mucosal ischemia. Arterial lactate increased from 2.6 +/- 1.4 to 7.4 +/- 1.9 (p < .05 x 10(-8)). There were significant increases in serum epinephrine and norepinephrine values by 5 mins. All hemodynamic variables and catecholamine concentrations returned to baseline by 4 hrs. However, there was persistent arterial and gastric mucosal acidosis and increased lactate concentrations even at 4 hrs. Oxygen delivery remained normal or supernormal for 4 hrs following envenomation. However, despite this finding, systemic and gastric mucosal pH changes indicate impaired gastrointestinal oxygen delivery. CONCLUSIONS Despite increased peripheral oxygen delivery, scorpion envenomation was associated with evidence of ischemia of the gastrointestinal tract. This association could be due to shunting of blood from metabolically active areas, possibly associated with massive catecholamine release, or a direct toxic effect of the venom on regional oxygen transport at the cellular level.

Efficacy of nasal mometasone for the treatment of chronic sinonasal disease in patients with inadequately controlled asthma

BACKGROUND Chronic sinonasal disease is common in asthmatic patients and associated with poor asthma control; however, there are no long-term trials addressing whether chronic treatment of sinonasal disease improves asthma control. OBJECTIVE We sought to determine whether treatment of chronic sinonasal disease with nasal corticosteroids improves asthma control, as measured by the Childhood Asthma Control Test and Asthma Control Test in children and adults, respectively. METHODS A 24-week multicenter, randomized, placebo-controlled, double-blind trial of placebo versus nasal mometasone in adults and children with inadequately controlled asthma was performed. Treatments were randomly assigned, with concealment of allocation. RESULTS Two hundred thirty-seven adults and 151 children were randomized to nasal mometasone versus placebo, and 319 participants completed the study. There was no difference in the Childhood Asthma Control Test score (difference in change with mometasone - change with placebo [ΔM - ΔP], -0.38; 95% CI, -2.19 to 1.44; P = .68; age 6-11 years) or the Asthma Control Test score (ΔM - ΔP, 0.51; 95% CI, -0.46 to 1.48; P = .30; age ≥12 years) in those assigned to mometasone versus placebo. In children and adolescents (age 6-17 years) there was no difference in asthma or sinus symptoms but a decrease in episodes of poorly controlled asthma defined by a decrease in peak flow. In adults there was a small difference in asthma symptoms measured by using the Asthma Symptom Utility Index (ΔM - ΔP, 0.06; 95% CI, 0.01 to 0.11; P < .01) and in nasal symptoms (sinus symptom score ΔM - ΔP, -3.82; 95% CI, -7.19 to -0.45; P = .03) but no difference in asthma quality of life, lung function, or episodes of poorly controlled asthma in adults assigned to mometasone versus placebo. CONCLUSIONS Treatment of chronic sinonasal disease with nasal corticosteroids for 24 weeks does not improve asthma control. Treatment of sinonasal disease in asthmatic patients should be determined by the need to treat sinonasal disease rather than to improve asthma control.

Finding an alternative diagnosis does not justify increased use of CT-pulmonary angiography

BackgroundThe increased use of computed tomography pulmonary angiography (CTPA) is often justified by finding alternative diagnoses explaining patients’ symptoms. However, this has not been rigorously examined.MethodsWe retrospectively reviewed CTPA done at our center over an eleven year period (2000 – 2010) in patients with suspected pulmonary embolus (PE). We then reviewed in detail the medical records of a representative sample of patients in three index years – 2000, 2005 and 2008. We determined whether CTPA revealed pulmonary pathology other than PE that was not readily identifiable from the patient’s history, physical examination and prior chest X-ray. We also assessed whether the use of pre-test probability guided diagnostic strategy for PE.ResultsA total of 12,640 CTPA were performed at our center from year 2000 to 2010. The number of CTPA performed increased from 84 in 2000 to 2287 in 2010, a 27 fold increase. Only 7.6 percent of all CTPA and 3.2 percent of avoidable CTPAs (low or intermediate pre-test probability and negative D-dimer) revealed previously unknown findings of any clinical significance. When we compared 2008 to 2000 and 2005, more CTPAs were performed in younger patients (mean age (years) for 2000: 67, 2005: 63, and 2008: 60, (p=0.004, one–way ANOVA)). Patients were less acutely ill with fewer risk factors for PE. Assessment of pre-test probability of PE and D-dimer measurement were rarely used to select appropriate patients for CTPA (pre-test probability of PE documented in chart (% total) in year 2000: 4.1%, 2005: 1.6%, 2008: 3.1%).ConclusionsOur data do not support the argument that increased CTPA use is justified by finding an alternative pulmonary pathology that could explain patients’ symptoms. CTPA is being increasingly used as the first and only test for suspected PE.

The Madison Avenue Effect: How drug presentation style influences adherence and outcome in patients with asthma

BACKGROUND Little is known about how drug presentation influences medication adherence. OBJECTIVE To examine the effect of an educational program aimed at increasing expectations of treatment benefit on medication adherence. METHODS Data are analyzed from 99 participants who underwent electronic drug monitoring during the Trial of Asthma Patient Education, a randomized, placebo-controlled, multicenter trial. Participants with suboptimally controlled asthma were randomized to placebo or montelukast in conjunction with a presentation mode that was either neutral or designed to increase outcome expectancy. Adherence was monitored electronically over 4 weeks and was defined as ≥ 80% use of prescribed doses. Outcome expectancy, peak expiratory flow, prebronchodilator FEV₁, asthma control (Juniper asthma control questionnaire), and asthma-related quality of life were assessed at baseline and at the 4-week follow-up. RESULTS Average electronic medication adherence was 69.9%. There was a significant interaction between presentation mode and drug assignment, with participants in the enhanced/montelukast group having a higher change in outcome expectancy (Δ 2.1 points; P < .001) and better medication adherence (odds ratio, 4.0; 95% CI, 1.1-14.3) compared with those in the neutral/placebo group. There was no difference in asthma symptoms, quality of life, or clinical outcomes on the basis of presentation mode. Rather, increased outcome expectancy was associated with modest improvements in asthma symptoms after adjusting for presentation mode, drug assignment, and medication adherence. CONCLUSION The use of an enhanced presentation aimed at increasing outcome expectancy may lead to improved medication adherence.