Departures from the protocol during conduct of a clinical trial: a pattern from the data record consistent with a learning curve.

OBJECTIVE: Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinised. The VALsartan In Acute myocardial iNfarcTion, a large multinational, pragmatic, randomised, double-blind, multicentre trial, was retrospectively evaluated for evidence of research conduct consistent with a performance "learning curve". DESIGN: Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (eg, first, second), recruitment rate and first enrollment relative to study start date. SETTING: Computerised data from a trial coordinated by an academic research organisation collaborating with 10 academic and 2 commercial research organisations and an industry sponsor. Interventions 931 sites enrolled 14,703 patients. Departures were restricted to the first year. Exclusions included patient's death or loss to follow-up within 12 months and subjects enrolled 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment and later start date. METHODS AND RESULTS: 12,367 patients at 931 sites were analysed. Departures were more common for patients enrolled earlier at a site (p<0.0001). For example, compared with the 30th patient, the first had 47% more departures. Departures were also more common with slower enrollment and site start closer to the trial start date (p<0.0001). Similar patterns existed for queries. CONCLUSIONS: Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a "learning curve". Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct.

Cerebral embolization during cardiac surgery: impact of aortic atheroma burden.

BACKGROUND: Aortic atheromatous disease is known to be associated with an increased risk of perioperative stroke in the setting of cardiac surgery. In this study, we sought to determine the relationship between cerebral microemboli and aortic atheroma burden in patients undergoing cardiac surgery. METHODS: Transoesophageal echocardiographic images of the ascending, arch and descending aorta were evaluated in 128 patients to determine the aortic atheroma burden. Transcranial Doppler (TCD) of the right middle cerebral artery was performed in order to measure cerebral embolic load during surgery. Using multivariate linear regression, the numbers of emboli were compared with the atheroma burden. RESULTS: After controlling for age, cardiopulmonary bypass time and the number of bypass grafts, cerebral emboli were significantly associated with atheroma in the ascending aorta (R2=0.11, P=0.02) and aortic arch (P=0.013). However, there was no association between emboli and descending aortic atheroma burden (R2=0.05, P=0.20). CONCLUSIONS: We demonstrate a positive relationship between TCD-detected cerebral emboli and the atheromatous burden of the ascending aorta and aortic arch. Previously demonstrated associations between TCD-detectable cerebral emboli and adverse cerebral outcome may be related to the presence of significant aortic atheromatous disease.

The use of a postoperative morbidity survey to evaluate patients with prolonged hospitalization after routine, moderate-risk, elective surgery.

UNLABELLED: Vital healthcare resources are devoted to caring for patients with prolonged hospitalization after routine, moderate-risk surgery. Despite the significant cost, little is known about the overall incidence and pattern of complications in these patients. Four hundred thirty-eight patients undergoing a diverse group of routine, moderate-risk, elective surgical procedures were enrolled into a prospective, blinded, cohort study. Complications were assessed using a postoperative morbidity survey. The main outcome was postoperative complication, defined as either in-hospital death or prolonged postoperative hospitalization (> 7 days). The mortality rate was 1.6%. Postoperative complications occurred in 118 patients (27% [95% CI 23-31]). Complications frequently observed in these patients included: gastrointestinal 51% (42-60), pulmonary 25% (17-33), renal 21% (14-28), and infectious 13% (7-19). Most complications were not directly related to the type/site of surgery. Indices of tissue trauma (blood loss [P < 0.001], surgical duration [P = 0.001]) and tissue perfusion (arterial base deficit [P = 0.008], gastric pHi [P = 0.02]) were the strongest intraoperative predictors of complications. Despite a low mortality rate, we found that complications after routine, moderate-risk, elective surgery are common and involve multiple organ systems. Our 9-point survey can be used by healthcare providers and payers to characterize post-operative morbidity in their respective settings. IMPLICATIONS: Little is known about the overall incidence and pattern of complications in patients with prolonged hospitalization after routine, elective surgery. We prospectively assessed these complications using a novel postoperative morbidity survey. The postoperative morbidity survey can be used in future clinical outcome trials, as well as in routine hospital-based quality assurance.

Survival and outcome after endotracheal intubation for acute stroke.

OBJECTIVE: To assess survival and functional outcome in patients endotracheally intubated after ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH). BACKGROUND: Endotracheal intubation is both a necessary life support intervention and a measure of severity in IS or ICH. Knowledge of associated clinical variables may improve the estimation of early prognosis and guide management in these patients. METHODS: We reviewed 131 charts of patients with IS or ICH who were admitted to the Neurosciences Intensive Care Unit at Duke University Medical Center between July 1994 and June 1997 and required endotracheal intubation. Stroke risk factors, stroke type (IS or ICH) and location (hemispheric, brainstem, or cerebellum), circumstances surrounding intubation, neurologic assessment (Glasgow Coma Score [GCS] and brainstem reflexes), comorbidities, and disposition at discharge were documented. Survivors were interviewed for Barthel Index (BI) scores. RESULTS: Survival was 51% at 30 days and 39% overall. Variables that significantly correlated with 30-day survival in multivariate analysis included GCS at intubation (p = 0.03) and absent pupillary light response (p = 0.008). Increase in the GCS also correlated with improved functional outcome measured by the BI (p = 0.0003). In patients with IS, age and GCS at intubation predicted survival, and in patients with ICH, absent pupillary light response predicted survival. CONCLUSIONS: Predictors for mortality differ between patients with IS and ICH; however, decreased level of consciousness is the most important determinant of increased mortality and poor functional outcome. Absent pupillary light responses also correspond with a poor prognosis for survival, but further validation of this finding is needed.

Caffeine deprivation affects vigilance performance and mood.

The effects of brief caffeine deprivation on vigilance performance, mood, and symptoms of caffeine withdrawal were studied in habitual coffee drinkers. Thirty male and female coffee drinkers were tested twice at midday (1130 to 1330 hours) after mornings in which they either consumed caffeinated beverages ad lib or abstained. Vigilance performance was tested with a 30-min computerized visual monitoring task. Mood and withdrawal symptom reports were collected by questionnaires. Caffeine deprivation was associated with impaired vigilance performance characterized by a reduction in the percentage of targets detected and an increase in response time, and by subjective reports of decreased vigor and increased fatigue and symptoms characterized by sleepiness, headache, and reduced ability to work. Even short periods of caffeine deprivation, equivalent in length to skipping regular morning coffee, can produce deficits in sustained attention and noticeable unpleasant caffeine-withdrawal symptoms in habitual coffee drinkers. Such symptoms may be a common side-effect of habitual caffeine consumption that contributes to the maintenance of this behavior.

Caffeine raises blood pressure at work.

OBJECTIVE: The study investigated the effects of moderate doses of caffeine on ambulatory blood pressure and heart rate during workday activities. METHODS: Healthy, nonsmoking, habitual coffee drinkers (N = 21) received daily doses of 100 mg and 500 mg of caffeine on 2 days in a crossover design. Treatment order was random and counterbalanced, and administration was double-blind. Ambulatory monitoring was conducted for 6 to 9 hours during normal workday activities and diary entries were completed at each measurement. Ambulatory data were analyzed for the effects of caffeine dose, controlling for variations in posture, physical activity, and perceived stress. RESULTS: The average workday blood pressure and heart rate were significantly higher when the higher dose of caffeine was consumed. Controlling for other factors, dose-related differences were 4 mm Hg for systolic and 3 mm Hg for diastolic blood pressure, and were 3 bpm for heart rate. CONCLUSIONS: Results support earlier evidence that caffeine raises blood pressure at work, and demonstrate that these pressor effects are independent of changes in posture, physical activity, or stress. Daily blood pressure increases associated with caffeine consumption could increase the risk of developing cardiovascular diseases. In addition, caffeine consumption effects might confound ambulatory investigations of the cardiovascular effects of other psychosocial, personality, or health-behavior factors.

Caffeine withdrawal symptoms following brief caffeine deprivation.

The effects of short-term caffeine deprivation on mood, withdrawal symptoms and psychomotor performance were studied in habitual coffee drinkers. Thirty-one male and female coffee drinkers were tested twice at midday (1130 to 1330 h) 4 h after double-blind administration of 250 mg of caffeine or placebo. Mood and withdrawal symptoms reports were collected by questionnaires. Psychomotor performance was tested with a brief computerized test battery, and causal blood pressure was measured. Caffeine deprivation was associated with decreased vigor and increased fatigue and with symptoms including sleepiness and yawning. Blood pressure was lower by 5-6 mm Hg. No changes in psychomotor performance were observed. Even short periods of caffeine deprivation, equivalent in length to missing regular morning coffee, can produce noticeable unpleasant caffeine withdrawal symptoms in habitual coffee drinkers. Such symptoms may be common side effects of habitual caffeine consumption that contribute to the maintenance of this behavior.

Health-related quality of life after ileoanal pull-through evaluation and assessment of new health status measures.

BACKGROUND & AIMS: Health-related quality of life (HRQL) after proctocolectomy is a critical parameter for management decisions in patients with chronic pancolitis. The aim of this study was to evaluate the HRQL of patients with ileoanal pull-through and to validate new, easy-to-administer HRQL measures. METHODS: The Sickness Impact Profile (SIP), Short Form 36 (SF-36), Rating Form of Inflammatory Bowel Disease (IBD) Patient Concerns (RFIPC), and the time trade-off (TTO) were used to measure HRQL of pull-through patients. The SF-36 and the RFIPC were validated. RESULTS: HRQL of patients with ileoanal pull-through was better than that of a national sample of patients with IBD (SIP and RFIPC) and similar to that of a normal population (SF-36). Physical and psychosocial subscales of the SF-36 correlated with the SIP, affirming the construct validity of the SF-36. The RFIPC results correlated with the SIP and SF-36 results, suggesting that it is also a valid health status measure for these patients. TTO results correlated with the physical subscales of the SIP and SF-36, reflecting the impact of physical health on this group. CONCLUSIONS: HRQL of patients with ileoanal pull-through is excellent. The SF-36 and RFIPC are valid health status measures that can be used by clinicians and researchers in these patients.