The limits of evidence-based medicine.

The importance of clinical research for the practice of clinical medicine is immense and undeniable. Yet the type of knowledge gained from clinical research, referred to here as "empirical evidence," is itself insufficient to provide for optimal clinical care. A gap exists between empirical evidence and clinical practice. Proponents of evidence-based medicine have clearly acknowledged one aspect of this gap: the part that requires the consideration of values, both patient and professional, prior to arriving at medical decisions. Not as clearly recognized, however, is the gap that exists due to the fact that empirical evidence is not directly applicable to individual patients, as the knowledge gained from clinical research does not directly answer the primary clinical question of what is best for the patient at hand. Proponents of evidence-based medicine have made a conceptual error by grouping knowledge derived from clinical experience and physiologic rationale under the heading of "evidence" and then have compounded the error by developing hierarchies of "evidence" that relegate these forms of medical knowledge to the lowest rungs. Empirical evidence, when it exists, is viewed as the "best" evidence on which to make a clinical decision, superseding clinical experience and physiologic rationale. But these latter forms of medical knowledge differ in kind, not degree, from empirical evidence and do not belong on a graded hierarchy. As they differ in kind, these other forms of medical knowledge can be viewed as complementary to empirical evidence and their incorporation necessary to overcome the intrinsic gap noted above. Clinicians, then, need to incorporate knowledge from 5 distinct areas into each medical decision: (1) empirical evidence, (2) experiential evidence, (3) physiologic principles, (4) patient and professional values, and (5) system features. The relative weight given to each of these areas is not predetermined, but varies from case to case.

Why alternative medicine cannot be evidence-based.

The concept of evidence-based medicine (EBM) has been widely adopted by orthodox Western medicine. Proponents of EBM have argued that complementary and alternative medicine (CAM) modalities ought to be subjected to rigorous, controlled clinical trials in order to assess their efficacy. However, this does not represent a scientific necessity, but rather is a philosophical demand: promoters of EBM seek to establish their particular epistemology as the primary arbiter of all medical knowledge. This claim is problematic. The methods for obtaining knowledge in a healing art must be coherent with that art's underlying understanding and theory of illness. Thus, the method of EBM and the knowledge gained from population-based studies may not be the best way to assess certain CAM practices, which view illness and healing within the context of a particular individual only. In addition, many alternative approaches center on the notion of non-measurable but perceptible aspects of illness and health (e.g., Qi) that preclude study within the current framework of controlled clinical trials. Still, the methods of developing knowledge within CAM currently have limitations and are subject to bias and varied interpretation. CAM must develop and defend a rational and coherent method for assessing causality and efficacy, though not necessarily one based on the results of controlled clinical trials. Orthodox medicine should consider abandoning demands that CAM become evidence-based, at least as "evidence" is currently narrowly defined, but insist instead upon a more complete and coherent description and defense of the alternative epistemic methods and tools of these disciplines.

A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.

New and emerging therapies for pulmonary complications of cystic fibrosis.

In the decade since the gene for cystic fibrosis (CF) was discovered, research into potential therapeutic interventions has progressed on a number of different fronts. The vast majority of morbidity and mortality in CF results from inflammation and infection of the airways. Direct delivery of antibacterials to the airway secretions via a nebuliser is an attractive therapeutic option, and a novel formulation of tobramycin designed for such a purpose has been demonstrated to improve spirometry and decrease the need for intravenous antibacterials. In addition, early clinical trials are studying the effects of small peptides with antibiotic properties (defensins) delivered directly to the airways. Inflammation, whether secondary to infection or an independent feature of CF, leads to progressive bronchiectasis. Anti-inflammatories such as prednisone and possibly ibuprofen have been shown to decrease the rate of respiratory decline in patients with CF but have tolerability profiles that limit clinical usefulness. Macrolides also have anti-inflammatory properties and clinical trials are now ongoing to assess the efficacy of these agents in CF. Multiple agents, including uridine triphosphate (UTP), genistein, phenylbutyrate and CPX (cyclopentyl dipropylxanthine), have been demonstrated in cell culture to at least partially correct the primary defect of ion transport related to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). No agent of this class has yet demonstrated clinical effectiveness, but several are in preclinical and early clinical trials. Finally, gene therapy that allows for the incorporation and expression of wild-type CFTR in respiratory epithelial cells would be definitive therapy for CF. However, multiple barriers to delivery and expression need to be overcome. With research proceeding on these multiple fronts, new therapies for pulmonary complications promise to continue to increase the life expectancy of individuals with CF.

Sputum induction as a research tool for sampling the airways of subjects with cystic fibrosis.

BACKGROUND: Sputum induction (SI) has proved to be a reliable non-invasive tool for sampling inflammatory airway contents in asthma, with distinct advantages over collection of expectorated sputum (ES) and bronchoalveolar lavage (BAL). A study was undertaken to evaluate the safety of SI and to assess if it might be an equally valuable outcome tool in patients with cystic fibrosis (CF). METHODS: The safety of the procedure was examined and sample volume, cell counts, cytokine concentrations, and bacterial culture results obtained by SI, spontaneous ES, and fibreoptic bronchoscopy were compared in 10 adults with CF. RESULTS: SI was well tolerated and was preferred to BAL by all subjects. The mean (SE) sample volume obtained by SI was significantly greater than ES (6.74 (1.46) ml v 1.85 (0.33) ml, p = 0.005). There was no significant difference in the number of cells per ml of sample collected. There was a difference in the mean (SD) percentage of non-epithelial, non-squamous cells collected (67 (28)%, 86 (21)%, and 99 (1)% for ES, SI, and BAL, respectively). These percentage counts were different between ES and both SI and BAL (p=0.03 and p=0.006, respectively). Cell differential counts (excluding squamous cells) from all collection methods were similar (mean (SD) 84 (9)%, 87 (7)%, and 88 (11)% polymorphonuclear cells for ES, SI, and BAL, respectively). The concentrations of interleukin (IL)-8 and tumour necrosis factor (TNF)-alpha were the same in all three samples when corrected for dilution using urea concentration. The test specific detection rate for recovery of bacteriological pathogens was 79% for SI, 76% for ES, and 73% for BAL. CONCLUSION: SI offers safety advantages over BAL and may be a more representative airway outcome measurement in patients with CF.

Complications of indwelling catheters in cystic fibrosis: a 10-year review.

STUDY OBJECTIVE: Patients with cystic fibrosis (CF) frequently require recurrent courses of IV antibiotics to treat acute exacerbations of their pulmonary disease. Over time, CF patients often lose peripheral access, and indwelling central venous catheters are placed. We attempted to determine the type and incidence of catheter complications so that CF patients could be fully informed of the risks prior to placement of these catheters. DESIGN: The charts of all CF patients who attended the Adult Cystic Fibrosis Clinic of the University of Washington Medical Center from January 1989 through December 1998 were reviewed. Demographic information was obtained along with the type and duration of catheter, type and number of complications, and the use of anticoagulant medication. MEASUREMENTS AND RESULTS: Of the 218 CF patients who attended the clinic, 65 patients (30%) had indwelling catheters in place at some time during the study period. A total of 87 catheters were placed into these 65 patients. The total number of catheter-days for first indwelling catheters was 68,220. The total number of catheter-days for all catheters was 75,660 (210 catheter-years). Thirty-five catheter-related complications were identified, occurring in 26 patients. Complications included thrombosis (n = 14), infections (n = 9), mechanical problems (n = 6), pneumothorax (n = 3), superior vena cava syndrome/stenosis (n = 2), and air embolism (n = 1), for an overall complication rate of 0. 463/1,000 catheter-days. CONCLUSION: We conclude that indwelling catheters are relatively safe in patients with CF. Good infection control policies appear to prevent most infectious complications. The most common complication is that of thrombosis, which may be recurrent in some patients. Consideration should be given to prophylactic warfarin therapy despite the potential risk of significant hemoptysis in this patient population.

In defense of expert opinion.

Evidence-based medicine, centered on the incorporation of evidence from clinical trials and systematic reviews into the teaching and practice of clinical medicine, explicitly attempts to supplant expert opinion, which is viewed as an antiquated and unreliable form of medical authority. The epistemology of evidence-based medicine categorizes expert opinion as the lowest form of medical evidence, superseded even by methodologically flawed clinical research. When derived from direct clinical experience, however, expert opinion represents an alternative form of medical knowledge, one that may be complementary to empirical evidence. Input from clinical experts is vital to informing the context of clinical research and an appeal to alternate forms of medical knowledge, including expert opinion, is necessary to overcome the intrinsic gap between clinical research and the care of individual patients. Even when the quality and quantity of empirical medical evidence are ideal, expert opinion will remain an integral part of the multifaceted knowledge required for the optimal practice of clinical medicine.

Pseudomonal pericarditis complicating cystic fibrosis.

Patients with advanced cystic fibrosis typically have chronic bacterial infection of the upper and lower respiratory tracts, but rarely develop extrapulmonary sites of infection. We report a case of purulent pericarditis due to Pseudomonas aeruginosa in a patient with cystic fibrosis and no other risk factors for pericarditis. This is a previously unreported complication in cystic fibrosis prior to lung transplantation.

End-of-life care in cystic fibrosis.

Despite significant progress in therapy for cystic fibrosis (CF), most patients with the disease still die before the age of 30 years. Published discussions and descriptions of end-of-life care of patients with CF have been few, but interest in these issues is increasing. Descriptions of end-of-life care for persons with CF have begun to appear, and conflicting models of care have been proposed. Advanced care planning offers an opportunity for persons with CF to actively influence the type of care they will receive. Still, more empiric research and ethical discussion is needed to facilitate optimal end-of-life care of patients with CF.

The philosophical limits of evidence-based medicine.

Evidence-based medicine (EBM) has already had a profound effect on both medical education and clinical practice. The benefits of EBM, which defines the value of medical interventions in terms of empirical evidence from clinical trials, are enormous and well described. Not clearly acknowledged, however, are the limits of EBM. An intrinsic gap exists between clinical research and clinical practice. Failure to recognize and account for this gap may lead to unintended and untoward consequences. Under the current understanding of EBM, the individuality of patients tends to be devalued, the focus of clinical practice is subtly shifted away from the care of individuals toward the care of populations, and the complex nature of sound clinical judgment is not fully appreciated. Despite its promise, EBM currently fails to provide an adequate account of optimal medical practice. A broader understanding of medical knowledge and reasoning is necessary.

Ethical considerations in the treatment of cystic fibrosis.

Over the last several decades, rapid medical advancement in the treatment of persons with cystic fibrosis (CF) has brought with it a number of ethical concerns. The increasing life expectancy of persons with CF has made transitions in care increasingly common. This change in life expectancy along with advances in assisted reproductive technologies has focused attention on reproductive decision making in CF. Living lobar lung transplantation, although technically developed, remains ethically problematic. The understanding of ethical issues arising in the treatment of CF is crucial to providing optimal care.

Substituted judgment in medical practice: evidentiary standards on a sliding scale.

Proposes an approach to the substituted judgment standard that reflects the reality of clinical practice and circumvents shortcomings in the current legal and bioethical alternatives.

Clinical experimentation. Lessons from lung volume reduction surgery.

Although the advancement of medical science can occur only with the systematic evaluation of new interventions, novel therapies continue to be introduced and accepted prior to thorough study. The recent development of lung volume reduction surgery for emphysema provides an illustration of the unwillingness or the inability of the medical community, unconstrained by legal or reimbursement limitations, to assure the safety and efficacy of a new procedure prior to widespread utilization. Medical practitioners must learn to recognize the experimental nature of new procedures independent of the courts and third-party payers. The nature of the informed consent that must be obtained for an experimental therapy is different from that which is required for standard medical practice and this difference can provide a test of whether a new treatment is experimental. A comparison between the introduction of lung volume reduction surgery and the rigorous scrutiny required of any pharmacologic interventions for emphysema underscores the double standard that exists for evaluating new surgical (and some medical) innovations. Such a double standard cannot be defended on ethical or scientific grounds. Specific changes in the way experimental therapies are introduced and disseminated are suggested. Until all new medical and surgical interventions are required to undergo a thorough evaluation prior to becoming standard of case, the promise of evidence-based medicine can never be fulfilled.