Stanley B. Higgins

High-Dose Corticosteroids in Patients with the Adult Respiratory Distress Syndrome

Corticosteroids are widely used as therapy for the adult respiratory distress syndrome (ARDS) without proof of efficacy. We conducted a prospective, randomized, double-blind, placebo-controlled trial of methylprednisolone therapy in 99 patients with refractory hypoxemia, diffuse bilateral infiltrates on chest radiography and absence of congestive heart failure documented by pulmonary-artery catheterization. The causes of ARDS included sepsis (27 percent), aspiration pneumonia (18 percent), pancreatitis (4 percent), shock (2 percent), fat emboli (1 percent), and miscellaneous causes or more than one cause (42 percent). Fifty patients received methylprednisolone (30 mg per kilogram of body weight every six hours for 24 hours), and 49 received placebo according to the same schedule. Serial measurements were made of pulmonary shunting, the ratio of partial pressure of arterial oxygen to partial pressure of alveolar oxygen, the chest radiograph severity score, total thoracic compliance, and pulmonary-artery pressure. We observed no statistical differences between groups in these characteristics upon entry or during the five days after entry. Forty-five days after entry there were no differences between the methylprednisolone and placebo groups in mortality (respectively, 30 of 50 [60 percent; 95 percent confidence interval, 46 to 74] and 31 of 49 [63 percent; 95 percent confidence interval, 49 to 77]; P = 0.74) or in the reversal of ARDS (18 of 50 [36 percent] vs. 19 of 49 [39 percent]; P = 0.77). However, the relatively wide confidence intervals in the mortality data make it impossible to exclude a small effect of treatment. Infectious complications were similar in the methylprednisolone group (8 of 50 [16 percent]) and the placebo group (5 of 49 [10 percent]; P = 0.60). Our data suggest that in patients with established ARDS due to sepsis, aspiration, or a mixed cause, high-dose methylprednisolone does not affect outcome.

The effects of ibuprofen on the physiology and survival of patients with sepsis

BACKGROUND In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. METHODS From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. RESULTS In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo). CONCLUSIONS In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.

Total suppression of ventricular arrhythmias by encainide. Pharmacokinetic and electrocardiographic characteristics.

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis.

ObjectiveStarling’s equation indicates that reduced oncotic pressure gradients will favor edema formation, and the current consensus definition of acute respiratory distress syndrome (ARDS) excludes only the hydrostatic pressure contribution. We hypothesized that low serum total protein levels might correlate with the likelihood of ARDS in at-risk patients because serum total protein is the chief determinant of oncotic pressure in humans. DesignRegression analysis to compare outcomes in patients with low serum total protein levels with outcomes in patients with normal serum total protein levels with respect to weight change, development of ARDS, and mortality. SettingIntensive care units (ICUs) of seven clinical centers in North America. PatientsA total of 455 ICU patients who met consensus criteria for severe sepsis (178 of whom developed ARDS) from a recently completed prospective clinical trial. InterventionNone. Measurements and Main ResultsWe found that 92% of the patients developing ARDS had low or borderline serum total protein levels (<6 g/dL). Logistic and multiple regression analyses confirmed that of 18 clinical variables, initial serum total protein level and protein change over time were the most statistically significant predictors of weight gain, prolonged mechanical ventilation, ARDS development, and mortality in the study population. This correlation remained significant after adjustment for the other major predictors of outcome present at baseline (ie, Acute Physiology and Chronic Health Evaluation II score). ConclusionsHypoproteinemia is significantly correlated with fluid retention and weight gain, development of ARDS and poor respiratory outcome, and mortality in patients with sepsis. Prospective, randomized trials of serum protein manipulation are needed to establish whether there is a cause-effect relationship to this association.

Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide

Abstract Flecainide acetate is a new antiarrhythmic agent whose pharmacokinetics have suggested that effective therapy could be achieved with twice daily dosing. The antiarrhythmic and electrocardiographic effects of flecainide were evaluated in 11 patients with chronic ventricular ectopic beats. Nine patients had been resistant or intolerant to at least three antiarrhythmic agents and eight had recurrent nonsustained ventricular tachycardia. The antiarrhythmic efficacy of increasing doses of flecainide was determined by comparison with results during administration of a placebo 2 days before and 3 days after increasing doses of flecainide. All 11 patients had an antiarrhythmic response with a mean 97 percent (range 88 to 100) rate of suppression of ventricular ectopic beats and mean 100 percent rate of suppression of ventricular tachycardia with a mean daily dose of 410 mg (range 200 to 600) of flecainide. Effective therapy was accompanied by lengthening of the P-R (+ 29 percent), QRS (+ 27 percent) and Q-Tc (+ 11 percent) intervals. These changes were not associated with a deterioration in exercise tolerance or a reduction in ejection fraction (0.52 ± 0.08 with placebo, 0.53 ± 0.12 with flecainide) as assessed with two dimensional echocardiography. Increasing doses of flecainide were associated with progressive prolongation of the ventricular ectopic coupling interval before suppression of ventricular ectopic beats. During the placebo washout period after multiple oral doses, the terminal (postabsorptive) phase plasma half-life of flecainide was found to range from 13 to 27 hours (mean 20.3). The minimal effective plasma levels of flecainide (resulting in greater than 90 percent suppression of ventricular etopic beats) ranged from 245 to 980 ng/ml (mean 631). Adverse effects during the inpatient evaluation were limited to blurring of vision in three patients, which resolved with smaller but still effective doses. Suppression of ventricular ectopic beats at a mean rate of 95 percent continued during outpatient therapy. During a mean of 12 months of outpatient follow-up in nine patients, regularly scheduled evaluation of ambulatory arrhythmia frequency continued to document suppression of arrhythmia. Outpatient follow-up occurred monthly for the first 6 months and every 2nd month thereafter. In three patients it was necessary to administer flecainide every 8 hours because blurring of vision occurred at the time of peak plasma levels when the drug was administered every 12 hours. Flecainide was highly effective in suppressing ventricular arrhythmias when administered twice daily.

Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.

The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patients procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.

Human Metapneumovirus Infection Plays an Etiologic Role in Acute Asthma Exacerbations Requiring Hospitalization in Adults

We determined the prevalence of human metapneumovirus (hMPV) infection in adults with asthma who were prospectively enrolled after hospitalization for an acute asthma exacerbation. Nasal wash specimens collected at admission and 3 months after discharge were tested for hMPV by real-time reverse-transcription polymerase chain reaction assays. hMPV was detected in 7 (6.9%) of 101 subjects at hospitalization and in 1 (1.3%) of 75 subjects at follow-up (odds ratio, 7 [95% confidence interval, 0.9-312]; P=.03). None of the patients with hMPV infection at hospitalization tested positive at follow-up, strongly suggesting that hMPV plays a direct etiologic role in acute asthma exacerbations.

Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.

In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.

The Relationship of Rhinovirus-Associated Asthma Hospitalizations with Inhaled Corticosteroids and Smoking

Abstract BackgroundAlthough rhinovirus (RV) respiratory infections trigger asthma exacerbations, the etiologic association between this virus and severe exacerbations, as well as the clinical characteristics of adults at risk for RV-associated asthma that necessitates hospitalization, have not been established MethodsDuring 1999–2003, we conducted a cohort study of 101 adults prospectively enrolled at hospital admission for an asthma exacerbation. Patient characteristics and frequencies of RV in nasal specimens were analyzed, by reverse-transcription polymerase chain reaction (RT-PCR), at asthma-related hospital admission and at a 3-month convalescent follow-up visit ResultsRV was detected by RT-PCR in 21% of hospitalized patients over a 4-year period and in 1.3% of patients who returned for a 3-month follow-up visit. RV detection was strongly associated with hospitalization for asthma (adjusted odds ratio [OR], 15.1 [95% confidence interval {CI}, 1.88–121.4]). After adjustment for baseline asthma severity, RV-positive patients were more likely than RV-negative patients to be current smokers and nonusers of inhaled corticosteroids (ICSs) (adjusted OR, 11.18 [95% CI, 2.37–52.81]; P=.002) ConclusionsRV respiratory infection is an etiologic agent in severe asthma exacerbations necessitating hospitalization in adults. Compared with hospitalized patients with asthma who were RV negative, RV-positive patients were significantly more likely to be smokers and nonusers of ICSs

Tocainide therapy for refractory ventricular arrhythmias

Tocainide, a congener of lidocaine, was used to treat symptomatic ventricular arrhythmias in 19 patients resistant to or unable to tolerate conventional agents. In this highly selected group, 15 showed good initial responses to oral therapy. Ventricular tachycardia was suppressed to a greater extent than isolated ventricular ectopic depolarizations at any plasma concentration, and upward dose-ranging showed progressive suppression of both. Arrhythmia responsiveness to lidocaine was found to be an excellent predictor of tocainide response. Of the 15 responders, one died 24 hours after stopping therapy, three died while receiving tocainide, nine stopped because of adverse reactions (five allergic), and two continue on therapy at 1 and 4 years. We conclude that tocainide is an effective agent for the short-term suppression of ventricular arrhythmias, particularly ventricular tachycardia sensitive to lidocaine, but a high incidence of adverse effects limits its application to chronic therapy in many patients.