Eloise Harman

A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults

Abstract Background. Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. Methods. We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of ≥5.0 mmol per liter and either an arterial-blood pH of ≤7.35 or a base deficit of ≥6 mmol per liter. The mean (±SD) arterial-blood lactate concentrations before treatment were 11.6±7.0 mmol per liter in the dichloroacetate-treated patients and 10.4±5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24±0.12 and 7.24±0...

Treatment of lactic acidosis with dichloroacetate.

We administered dichloroacetate, which prevents or reverses hyperlactatemia in animals and lowers plasma lactate levels in human beings, to 13 patients with lactic acidosis of various causes. All had hypotension, and their acidemia had resisted treatment with sodium bicarbonate. The metabolic effects of dichloroacetate were evaluated in 11 patients. In seven dichloroacetate significantly reduced the level of arterial blood lactate (P less than 0.005) from the base-line value and raised the levels of arterial blood bicarbonate (P less than 0.02) and arterial pH (P less than 0.005). In six of these seven, the acidemia resolved completely with therapy. In 10 of the 13 patients systolic blood pressure increased by 10 to 40 mm Hg, and 4 patients had a 21 per cent increase in cardiac output (P less than 0.02). Despite improvement in their lactic acidemia, all patients but one died of their underlying disease. No serious drug-related toxicity occurred. We conclude that dichloroacetate is a safe and effective adjunct in the treatment of patients with lactic acidosis, although the ultimate prognosis may depend on the underlying disease.

Natural history and course of acquired lactic acidosis in adults

Abstract study objective: To determine the pathogenesis and clinical course of lactic acidosis in adults receiving standard medical care. design: Placebo arm of a 5-year prospective, randomized, blinded study comparing placebo and dichloroacetate as specific lactate-lowering therapy. Each patient received intravenous saline placebo in addition to conventional therapy. setting: Intensive care units of 10 tertiary care hospitals in North America. patients: One hundred twenty-six patients with lactic acidosis, defined as arterial blood lactate greater than or equal to 5 mmol/L and either arterial pH of less than or equal to 7.35 or base deficit greater than 6mmol/L. Patients were followed for up to 6 months. measurements and main results: Mean ± SD demographic entry data for 126 patients included: age 56 ± 17 years, lactate 10.4 ± 5.5 mmol/L, pH 7.24 ± 0.14, calculated base deficit 14.1 ± 5.4, arterial systolic blood pressure 103 ± 29 mm Hg, Glasgow Coma score 7.9 ± 4.9, and APACHE II score 19.2 ± 8.1. Despite fluids and pressors, 32% of patients had systolic blood pressures of less than or equal to 90 mm Hg in association with sepsis (59%), cardiac failure (18%), or hemorrhage (18%). The most common causes of lactic acidosis in the absence of shock were sepsis (49%), liver disease (15%), and respiratory failure (12%). The median survival was 38.5 hours. Survival at 24 hours was 59%. Arterial pH predicted 24-hour survival better than base deficit or bicarbonate level. Percent survival was 41% at 3 days and 17% at 30 days. Only 21% of patients survived to leave the intensive care unit, and 17% were discharged from the hospital. In patients receiving sodium bicarbonate, neither acid-base nor hemodynamic status improved. conclusions: In this first prospective study of the clinical course of acute lactic acidosis in adults, nearly all subjects had both hemodynamic and nonhemodynamic (metabolic) underlying causes, many of which independently predicted survival and most of which were refractory to standard care.

Inspiratory muscle strength training improves weaning outcome in failure to wean patients: a randomized trial

IntroductionMost patients are readily liberated from mechanical ventilation (MV) support, however, 10% - 15% of patients experience failure to wean (FTW). FTW patients account for approximately 40% of all MV days and have significantly worse clinical outcomes. MV induced inspiratory muscle weakness has been implicated as a contributor to FTW and recent work has documented inspiratory muscle weakness in humans supported with MV.MethodsWe conducted a single center, single-blind, randomized controlled trial to test whether inspiratory muscle strength training (IMST) would improve weaning outcome in FTW patients. Of 129 patients evaluated for participation, 69 were enrolled and studied. 35 subjects were randomly assigned to the IMST condition and 34 to the SHAM treatment. IMST was performed with a threshold inspiratory device, set at the highest pressure tolerated and progressed daily. SHAM training provided a constant, low inspiratory pressure load. Subjects completed 4 sets of 6-10 training breaths, 5 days per week. Subjects also performed progressively longer breathing trials daily per protocol. The weaning criterion was 72 consecutive hours without MV support. Subjects were blinded to group assignment, and were treated until weaned or 28 days.ResultsGroups were comparable on demographic and clinical variables at baseline. The IMST and SHAM groups respectively received 41.9 ± 25.5 vs. 47.3 ± 33.0 days of MV support prior to starting intervention, P = 0.36. The IMST and SHAM groups participated in 9.7 ± 4.0 and 11.0 ± 4.8 training sessions, respectively, P = 0.09. The SHAM groups pre to post-training maximal inspiratory pressure (MIP) change was not significant (-43.5 ± 17.8 vs. -45.1 ± 19.5 cm H2O, P = 0.39), while the IMST groups MIP increased (-44.4 ± 18.4 vs. -54.1 ± 17.8 cm H2O, P < 0.0001). There were no adverse events observed during IMST or SHAM treatments. Twenty-five of 35 IMST subjects weaned (71%, 95% confidence interval (CI) = 55% to 84%), while 16 of 34 (47%, 95% CI = 31% to 63%) SHAM subjects weaned, P = .039. The number of patients needed to be treated for effect was 4 (95% CI = 2 to 80).ConclusionsAn IMST program can lead to increased MIP and improved weaning outcome in FTW patients compared to SHAM treatment.Trial RegistrationClinicalTrials.gov: NCT00419458

Moving a Graveyard: How One School Prepared the Way for Continuous Curriculum Renewal

From 1991 to 1996, the faculty at the University of Florida College of Medicine initiated several significant changes in its curriculum. These changes, included the introduction of early clinical experience in primary care settings; the enhancement of active learning experiences in small-group settings; production and use of computer-based interactive learning materials; increased clinical teaching in the ambulatory care training in an interdisciplinary primary care clerkship; effective course and faculty evaluation; establishment and use of an assessment center for instruction and performance-based evaluations utilizing standardized patients; creation of a medical education center as the focal point for logistics support of the teaching faculty and education data handling; creation of a faculty development program; and initiation of mission-based budgeting based on the facultys teaching effort and quality. Because the faculty were relatively conservative, it was important to identify variables that would facilitate the introduction of changes and those that might hinder it. The following factors were most important: interest and support by the dean and clearly defined delegation of authority to an associate dean; introduction of a mission-based budgeting process that allocates education funds on the basis of faculty teaching effort and its quality; a clear understanding of the empowerment of the curriculum committee; and an identification of the principles that should guide educational planning and implementation. These efforts are considered the beginning of the continuous renewal needed to respond to information networking, scientific and technological innovations, and the fundamental changes in health care delivery. As these changes have taken place, a shift toward greater institutional control of the educational program leading to the MD degree has been evident.

Theophylline attenuation of airway responses to allergen: Comparison with cromolyn metered-dose inhaler

BACKGROUND The purpose of this study was to compare the protection afforded by individualized doses of theophylline and a cromolyn metered-dose inhaler (MDI) during allergen challenge. METHODS The study design was randomized, double-blind, and crossover. Responses to inhaled allergen were measured in 16 subjects with allergic asthma (age range, 18 to 35 years) after 7 days of treatment with either placebo, once daily slow-release theophylline producing a mean +/- SD serum concentration of 16 +/- 5 micrograms/ml during the late phase, or 2 mg of cromolyn administered by MDI four times daily. Forced expiratory volume in 1 second was measured at frequent intervals, and airway responsiveness to histamine was measured before and 3 hours after allergen challenge. RESULTS The mean +/- SD maximum decrease in forced expiratory volume in 1 second during the late phase was 30% +/- 14% during placebo treatment, 16% +/- 13% during theophylline treatment, and 13% +/- 14% during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). The geometric mean fold increase in airway responsiveness was 3.0 +/- 1.7 during placebo treatment, 1.7 +/- 1.7 during theophylline treatment, and 1.5 +/- 1.6 during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). CONCLUSIONS Theophylline, when administered once daily as a slow-release formulation, was as effective as cromolyn, administered four times daily through an MDI, in attenuating airway responses to inhaled allergen. The protection afforded by both treatments, however, was modest when compared with the results of similar studies with inhaled corticosteroids or other cromolyn formulations that deliver more drug to the lungs than the MDI available in the United States.

Systemic Absorption of Topical Lidocaine in Elderly and Young Adults Undergoing Bronchoscopy

This study compared the systemic absorption of topically administered lidocaine in elderly and young adult patients who were undergoing fiberoptic bronchoscopy. Fourteen elderly subjects aged 60–72 years (mean 67 yrs) and five young subjects age 31–48 years (mean 42 yrs) were compared with respect to dosage requirements to achieve satisfactory local anesthesia, rate and extent of lidocaine systemic absorption, plasma drug levels, elimination half‐life, and drug side effects. Blood samples were drawn prior to, during, and for an average of 3 hours after the completion of bronchoscopy. Lidocaine plasma concentrations averaged in the range of 3.04–0.88 μg/ml from the beginning of the procedure to the end of blood sampling. Despite high cumulative amounts of 19 mg/kg (1200 mg) of lidocaine administered topically, the regimen proved relatively safe and achieved satisfactory anesthesia. In patients without known risk factors either for delayed hepatic lidocaine clearance or for enhanced mucosal absorption, the regimen is suitable for both young and old individuals.

Pulmonary risk factors in surgery.

The altered pattern of ventilation and the diminution in lung vol-mes after general anesthesia and surgery predispose the postoperative patient to develop serious pulmonary complications. Many additional risk factors are readily identifiable and often reversible. Careful attention to these allows the institution of therapy which can greatly diminish the incidence of serious postoperative pulmonary complications. In patients for whom thoracic surgery is contemplated, the identification and quantification of risk factor helps identify those individuals in whom surgical risk is prohibitively great, or who will not likely tolerate lung resections of major or minor extent.

The effect of inhaled gallopamil, a potent calcium channel blocker, on the late-phase response in subjects with allergic asthma

The effect of gallopamil on the late-phase response to inhaled allergen was evaluated in six young adults with allergic asthma in a crossover manner. During 2 study days, subjects received 20 mg of inhaled gallopamil or placebo 30 minutes before challenge with the same dose of allergen. In addition, a histamine challenge was performed 1 1/2 hours before and 24 hours after allergen challenge. On 2 additional study days, in the absence of allergen, basal airway responsiveness to histamine was measured before and after gallopamil or placebo administration. During the early phase, the mean +/- SD decrease in FEV1 was 28.0% +/- 11.3% after placebo and 25.1% +/- 8.4% after gallopamil administration (p greater than 0.05; beta = 0.14). During the late phase, the maximum decrease in FEV1 was 26.9% +/- 11.9% after placebo and 25.3% +/- 10.3% after gallopamil administration (p greater than 0.05; beta = 0.21). Airway reactivity to histamine 24 hours after allergen challenge could not be measured in three subjects after gallopamil administration and in one subject after placebo administration because of persistent bronchospasm. In contrast, basal responsiveness to histamine in the absence of allergen was modestly decreased by gallopamil. Since gallopamil is one of the most potent calcium channel blockers when it is administered by the inhaled route, it is unlikely that this group of drugs will be clinically useful for allergic asthma.

Novel therapies in asthma: leukotriene antagonists, biologic agents, and beyond.

Asthma is one of the most common conditions seen in clinical practice and carries both a significant disease burden in terms of patient morbidity and a high economic burden in both direct and indirect costs. Despite this, it remains a comparatively poorly understood disease, with only modest advances in treatment over the past decade. Corticosteroids remain the cornerstone of therapy. Both patient compliance with medications and physician adherence to evidence-based guidelines are often poor, and a high percentage of patients continue to have inadequately controlled disease even with optimal therapy. Following a contextual overview of the current treatment guidelines, this review focuses on novel asthma therapies, beginning with the introduction of the leukotriene receptor antagonist zafirlukast in the 1990s, continuing through advanced endoscopic therapy and into cytokine-directed biologic agents currently in development. Along with clinically relevant biochemistry and pharmacology, the evidence supporting the place of these therapies in current guidelines will be highlighted along with data comparing these agents with more conventional treatment. A brief discussion of other drugs, such as those developed for unrelated conditions and subsequently examined as potential asthma therapies, is included.