Interpreting treatment effects from clinical trials in the context of real-world risk information: end-stage renal disease prevention in older adults.

IMPORTANCE: Older adults are often excluded from clinical trials. The benefit of preventive interventions tested in younger trial populations may be reduced when applied to older adults in the clinical setting if they are less likely to survive long enough to experience those outcomes targeted by the intervention. OBJECTIVE: To extrapolate a treatment effect similar to those reported in major randomized clinical trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for prevention of end-stage renal disease (ESRD) to a real-world population of older patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS: Simulation study in a retrospective cohort conducted in Department of Veterans Affairs medical centers. We included 371 470 patients 70 years or older with chronic kidney disease. EXPOSURE: Level of estimated glomerular filtration rate (eGFR) and proteinuria. MAIN OUTCOMES AND MEASURES: Among members of this cohort, we evaluated the expected effect of a 30% reduction in relative risk on the number needed to treat (NNT) to prevent 1 case of ESRD over a 3-year period. These limits were selected to mimic the treatment effect achieved in major trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for prevention of ESRD. These trials have reported relative risk reductions of 23% to 56% during observation periods of 2.6 to 3.4 years, yielding NNTs to prevent 1 case of ESRD of 9 to 25. RESULTS: The NNT to prevent 1 case of ESRD among members of this cohort ranged from 16 in patients with the highest baseline risk (eGFR of 15-29 mL/min/1.73 m(2) with a dipstick proteinuria measurement of ≥ 2+) to 2500 for those with the lowest baseline risk (eGFR of 45-59 mL/min/1.73 m(2) with negative or trace proteinuria and eGFR of ≥ 60 mL/min/1.73 m2 with dipstick proteinuria measurement of 1+). Most patients belonged to groups with an NNT of more than 100, even when the exposure time was extended over 10 years and in all sensitivity analyses. CONCLUSIONS AND RELEVANCE: Differences in baseline risk and life expectancy between trial subjects and real-world populations of older adults with CKD may reduce the marginal benefit to individual patients of interventions to prevent ESRD.

Medical practices display power law behaviors similar to spoken languages.

BACKGROUND: Medical care commonly involves the apprehension of complex patterns of patient derangements to which the practitioner responds with patterns of interventions, as opposed to single therapeutic maneuvers. This complexity renders the objective assessment of practice patterns using conventional statistical approaches difficult. METHODS: Combinatorial approaches drawn from symbolic dynamics are used to encode the observed patterns of patient derangement and associated practitioner response patterns as sequences of symbols. Concatenating each patient derangement symbol with the contemporaneous practitioner response symbol creates "words" encoding the simultaneous patient derangement and provider response patterns and yields an observed vocabulary with quantifiable statistical characteristics. RESULTS: A fundamental observation in many natural languages is the existence of a power law relationship between the rank order of word usage and the absolute frequency with which particular words are uttered. We show that population level patterns of patient derangement: practitioner intervention word usage in two entirely unrelated domains of medical care display power law relationships similar to those of natural languages, and that-in one of these domains-power law behavior at the population level reflects power law behavior at the level of individual practitioners. CONCLUSIONS: Our results suggest that patterns of medical care can be approached using quantitative linguistic techniques, a finding that has implications for the assessment of expertise, machine learning identification of optimal practices, and construction of bedside decision support tools.

Geographic information systems and chronic kidney disease: racial disparities, rural residence and forecasting.

The dynamics of health and health care provision in the United States vary substantially across regions, and there is substantial regional heterogeneity in population density, age distribution, disease prevalence, race and ethnicity, poverty and the ability to access care. Geocoding and geographic information systems (GIS) are important tools to link patient or population location to information regarding these characteristics. In this review, we provide an overview of basic GIS concepts and provide examples to illustrate how GIS techniques have been applied to the study of kidney disease, and in particular to understanding the interplay between race, poverty, rural residence and the planning of renal services for this population. The interplay of socioeconomic status and renal disease outcomes remains an important area for investigation and recent publications have explored this relationship utilizing GIS techniques to incorporate measures of socioeconomic status and racial composition of neighborhoods. In addition, there are many potential challenges in providing care to rural patients with chronic kidney disease including long travel times and sparse renal services such as transplant and dialysis centers. Geospatially fluent analytic approaches can also inform system level analyses of health care systems and these approaches can be applied to identify an optimal distribution of dialysis facilities. GIS analysis could help untangle the complex interplay between geography, socioeconomic status, and racial disparities in chronic kidney disease, and could inform policy decisions and resource allocation as the population ages and the prevalence of renal disease increases.

Care of the critically ill patient with advanced chronic kidney disease or end-stage renal disease.

PURPOSE OF REVIEW: The number of individuals with chronic kidney disease (CKD) and end-stage renal disease (ESRD) is rising, and these individuals often require intensive care. RECENT FINDINGS: Patients with CKD and ESRD require critical care more frequently than those without these conditions and have similar reasons for requiring critical care as the general population. However, the burden of comorbidities, overall severity of illness as assessed by standard scoring systems, and mortality are higher in patients with ESRD than in the non-ESRD critically ill. After adjustment for demographics, comorbidities, and physiologic variables, the increased mortality risk in patients with ESRD is attenuated. In comparison to patients with dialysis-requiring acute kidney injury (AKI), critically ill patients with ESRD have a more favorable prognosis. Severity of illness scoring systems such as Acute Physiology and Chronic Health Evaluation and Simplified Acute Physiology Score tend to overestimate the risk of death in critically ill ESRD patients. ICU admission does not appear to dramatically affect long-term mortality in those with ESRD who survive their initial acute illness as compared ESRD patients without critical illness. SUMMARY: Despite the manifest physiologic derangements attending CKD/ESRD, a higher burden of comorbid conditions and a greater severity of illness on presentation account for much of the increased mortality. There is no justification for therapeutic nihilism in this population.

Abnormal nocturnal heart rate variability response among chronic kidney disease and dialysis patients during wakefulness and sleep.

BACKGROUND: Dialysis patients and patients with chronic kidney disease (CKD) experience a substantial risk for abnormal autonomic function and abnormal heart rate variability (HRV). It remains unknown whether HRV changes across sleep stages in patients with different severity of CKD or dialysis dependency. We hypothesized that high-frequency (HF) HRV (vagal tone) will be attenuated from wakefulness to non-rapid eye movement (NREM) and then to rapid eye movement (REM) sleep in dialysis patients as compared to patients with CKD. METHODS: In-home polysomnography was performed in 95 patients with stages 4-5 CKD or end-stage renal disease (ESRD) on haemodialysis (HD) or peritoneal dialysis (PD). HRV was measured using fast Fourier transform of interbeat intervals during wakefulness and sleep. Low-frequency (LF) and HF intervals were generated. Natural logarithm HF (LNHF) and the logarithm LF/HF ratio (sympathovagal tone) were analysed by multivariable quantile regression and generalized estimating equations. RESULTS: Of the 95 patients, 63.2% (n = 60) was male, 35.8% (n = 34) was African American and 20.4% (n = 19) was diabetic. Average age was 51.6 ± 15.1 (range 19-82). HRV variables were significantly associated with diabetic status, higher periodic limb movement indices and lower bicarbonate levels. Patients with advanced CKD did not differ from dialysis patients in their inability to increase vagal tone during sleep. During wakefulness, female gender (P = 0.05) was associated with the increases in the vagal tone. CONCLUSIONS: Patients with CKD/ESRD exhibit dysregulation of the autonomic nervous system tone manifesting as a failure to increase HRV during wakefulness and sleep. Different patient characteristics are associated with changes in HRV at different sleep stages.

Effects of vascular flow and PEEP in a multiple hit model of lung injury in isolated perfused rabbit lungs.

BACKGROUND: High vascular flow aggravates lung damage in animal models of ventilator-induced lung injury. Positive end-expiratory pressure (PEEP) can attenuate ventilator-induced lung injury, but its continued effectiveness in the setting of antecedent lung injury is unclear. The objective of the present study was to evaluate whether the application of PEEP diminishes lung injury induced by concurrent high vascular flow and high alveolar pressures in normal lungs and in a preinjury lung model. METHODS: Two series of experiments were performed. Fifteen sets of isolated rabbit lungs were randomized into three groups (n = 5): low vascular flow/low PEEP; high vascular flow/low PEEP, and high vascular flow/high PEEP. Subsequently, the same protocol was applied in an additional 15 sets of isolated rabbit lungs in which oleic acid was added to the vascular perfusate to produce mild to moderate lung injury. All lungs were ventilated with peak airway pressure of 30 cm H2O for 30 minutes. Outcome measures included frequency of gross structural failure, pulmonary hemorrhage, edema formation, changes in static compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. RESULTS: In the context of high vascular flow, application of a moderate level of PEEP reduced pulmonary rupture, edema formation, and lung hemorrhage. The protective effects of PEEP were not observed in lungs concurrently injured with oleic acid. CONCLUSIONS: Under these experimental conditions, PEEP attenuates lung injury in the setting of high vascular flow. The protective effect of PEEP is lost in a two-hit model of lung injury.

Analyzing pathogen transmission in the dialysis unit: time for a (schedule) change?

BACKGROUND AND OBJECTIVES: Infectious diseases and antimicrobial-resistant microorganisms are a growing problem for the dialysis population. The frequency of patient visits and intimate, prolonged physical contact with the inanimate environment during dialysis treatments make these facilities potentially efficient venues for nosocomial pathogen transmission. Isolation measures and infection control practices can be inconvenient and consume limited resources. Quantitative tools for analyzing the effects of different containment strategies can help to identify optimal strategies for further study. However, spatial and temporal considerations germane to the dialysis unit greatly complicate analyses relying on conventional mathematical approaches. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A stochastic, individual-based, Monte Carlo simulation tool that predicts the effects of various infection control strategies on pathogen dissemination through the dialysis unit in the face of diagnostic uncertainty was developed. The model was configured to emulate a medium-sized dialysis unit. The predicted consequences of various policies for scheduling patients who were suspected of being infectious were then explored, using literature-based estimates of pathogen transmissibility, prevalence, and diagnostic uncertainty. RESULTS: Environmental decontamination was predicted to be of paramount importance in limiting pathogen dissemination. Temporal segregation (scheduling patients who were suspected of being infectious to dialysis shifts that are later in the day) was predicted to have the greatest effectiveness in reducing transmission, given adequate environmental decontamination between successive days. CONCLUSIONS: Decontamination of the patient's environment (chair) can markedly attenuate pathogen dissemination. Temporal segregation could be a simple, low-cost, system-level intervention with significant potential to reduce nosocomial transmission in the dialysis unit.

Modulating cofactors of acute lung injury 2005-2006: any closer to 'prime time'?

PURPOSE OF REVIEW: Considerable progress has recently been made in understanding the modulation of acute lung injury by cofactors that are not traditionally considered 'pulmonary' in nature. We will review findings regarding some of these extrapulmonary cofactors, focusing on those most readily manipulated in the current clinical setting. RECENT FINDINGS: Recent studies have demonstrated that limiting fluid administration in the setting of acute lung injury might improve surrogate outcomes; that hypercapnea and induced hypothermia might protect against or attenuate acute lung injury; that corticosteroids can improve mechanics but not mortality in acute respiratory distress syndrome; a potential role for concomitant administration of colloid and diuretic in acute lung injury; and the potential benefits of inhaled beta agonists in acute lung injury. SUMMARY: There are a number of simple, low-cost, and rapidly deployable approaches to reducing the severity of acute lung injury that are not directly pulmonary in origin. These interventions could be rapidly implemented in any intensive care unit, once evidence for their efficacy and safety is adequate.

Contributions of vascular flow and pulmonary capillary pressure to ventilator-induced lung injury.

OBJECTIVE: To evaluate the influence of vascular flow on ventilator-induced lung injury independent of vascular pressures. DESIGN: Laboratory study. SETTING: Hospital laboratory. SUBJECTS: Thirty-two New Zealand White rabbits. INTERVENTIONS: Thirty-two isolated perfused rabbit lungs were allocated into four groups: low flow/low pulmonary capillary pressure; high flow/high pulmonary capillary pressure; low flow/high pulmonary capillary pressure, and high flow/low pulmonary capillary pressure. All lungs were ventilated with peak airway pressure 30 cm H2O and positive end-expiratory pressure 5 cm H2O for 30 mins. MEASUREMENTS AND MAIN RESULTS: Outcome measures included frequency of gross structural failure (pulmonary rupture), pulmonary hemorrhage, edema formation, changes in lung compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. Lungs exposed to high pulmonary vascular flow ruptured more frequently, displayed more hemorrhage, developed more edema, suffered larger decreases in compliance, and had larger increases in vascular resistance than lungs exposed to low vascular flows (p < .05 for each pairwise comparison between groups). CONCLUSIONS: These findings suggest that high pulmonary vascular flows might exacerbate ventilator-induced lung injury independent of their effects on pulmonary vascular pressures.

Pathogen transmission and clinic scheduling.

We developed a model of pathogen dissemination in the outpatient clinic that incorporates key kinetic aspects of the transmission process, as well as uncertainty regarding whether or not each incident patient is contagious. Assigning appointments late in the day to patients suspected of being infectious should decrease pathogen dissemination.

Inhibition of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C(18)-, C(19)- and C(21)-hydroxysteroids and ketosteroids.

Epidemiologic data suggest a relationship between dietary intake of phytochemicals and a lower incidence of some cancers. Modulation of steroid hormone metabolism has been proposed as a basis for this effect. It has been shown that aromatase, 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) are inhibited by the isoflavones, genistein and daidzein, and by coumestrol. In general, the extent of inhibition has been expressed in terms of IC50-values, which do not give information as to the pattern of inhibition, i.e., competitive, non-competitive, or mixed. Less is known of the effects of these compounds on 3alpha-HSD. The human lung is known to have a high level of 17beta-HSD and 3alpha-HSD activity. During the course of studies to characterize both activities in normal and inflamed lung and lung tumors we noted that 3alpha-HSD activity with 5alpha-DHT of microsomes from normal, adult lung was particularly susceptible to inhibition by coumestrol. To clarify the pattern of inhibition, the inhibition constants Ki and K'i were evaluated from plots of 1/v versus [I] and [S]/v versus [I]. Genistein, daidzein and coumestrol gave mixed inhibition patterns versus both 5alpha-DHT and NADH. In contrast, 5alpha-androstane-3,17-dione and 5alpha-pregnane-3,20-dione were competitive with 5alpha-DHT. NAD inhibited competitively with NADH. Our findings demonstrate that phytochemicals have the potential to inhibit 5alpha-DHT metabolism and thereby affect the androgen status of the human lung. The observation of a mixed inhibition pattern suggests these compounds bind to more than one form of the enzyme within the catalytic pathway.

Massive brain injury enhances lung damage in an isolated lung model of ventilator-induced lung injury.

OBJECTIVE: To assess the influence of massive brain injury on pulmonary susceptibility to injury attending subsequent mechanical or ischemia/reperfusion stress. DESIGN: Prospective experimental study. SETTING: Animal research laboratory. SUBJECTS: Twenty-four anesthetized New Zealand White rabbits randomized to control (n = 12) or induced brain injury (n = 12) group. INTERVENTIONS: After randomization, brain injury was induced by inflation of an intracranial balloon-tipped catheter, and animals were ventilated with a tidal volume of 10 mL/kg and zero end-expiratory pressure for 120 mins. Following heart-lung block extraction, isolated and perfused lungs were subjected to injurious ventilation with peak airway pressure 30 cm H2O and positive end-expiratory pressure 5 cm H2O for 30 mins. MEASUREMENTS AND MAIN RESULTS: No difference was observed between groups in gas exchange, lung mechanics, or hemodynamics during the 2-hr in vivo period following induction of brain injury. However, after 30 mins of ex vivo injurious mechanical ventilation, lungs from the brain injury group showed greater change in ultrafiltration coefficient, weight gain, and alveolar hemorrhage (all p < .05). CONCLUSIONS: Massive brain injury might increase lung vulnerability to subsequent injurious mechanical or ischemia-reperfusion insults, thereby increasing the risk of clinical posttransplant graft failure.

An agent-based and spatially explicit model of pathogen dissemination in the intensive care unit.

OBJECTIVE: To develop and disseminate a spatially explicit model of contact transmission of pathogens in the intensive care unit. DESIGN: A model simulating the spread of a pathogen transmitted by direct contact (such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus) was constructed. The modulation of pathogen dissemination attending changes in clinically relevant pathogen- and institution-specific factors was then systematically examined. SETTING AND PATIENTS: The model was configured as a hypothetical 24-bed intensive care unit. The model can be parameterized with different pathogen transmissibilities, durations of caregiver and/or patient contamination, and caregiver allocation and flow patterns. INTERVENTIONS: Pathogen- and institution-specific factors examined included pathogen transmissibility, duration of caregiver contamination, regional cohorting of contaminated or infected patients, delayed detection and isolation of newly contaminated patients, reduction of the number of caregiver visits, and alteration of caregiver allocation among patients. MEASUREMENTS AND MAIN RESULTS: The model predicts the probability that a given fraction of the population will become contaminated or infected with the pathogen of interest under specified spatial, initial prevalence, and dynamic conditions. Per-encounter pathogen acquisition risk and the duration of caregiver pathogen carriage most strongly affect dissemination. Regional cohorting and rapid detection and isolation of contaminated patients each markedly diminish the likelihood of dissemination even absent other interventions. Strategies reducing "crossover" between caregiver domains diminish the likelihood of more widespread dissemination. CONCLUSIONS: Spatially explicit discrete element models, such as the model presented, may prove useful for analyzing the transmission of pathogens within the intensive care unit.

Intercomparison of recruitment maneuver efficacy in three models of acute lung injury.

OBJECTIVE: To compare the relative efficacy of three forms of recruitment maneuvers in diverse models of acute lung injury characterized by differing pathoanatomy. DESIGN: We compared three recruiting maneuver (RM) techniques at three levels of post-RM positive end-expiratory pressure in three distinct porcine models of acute lung injury: oleic acid injury; injury induced purely by the mechanical stress of high-tidal airway pressures; and pneumococcal pneumonia. SETTING: Laboratory in a clinical research facility. SUBJECTS: Twenty-eight anesthetized mixed-breed pigs (23.8 +/- 2.6 kg). INTERVENTIONS: The RM techniques tested were sustained inflation, extended sigh or incremental positive end-expiratory pressure, and pressure-controlled ventilation. PRIMARY MEASUREMENTS: Oxygenation and end-expiratory lung volume. MAIN RESULTS: The post-RM positive end-expiratory pressure level was the major determinant of post-maneuver PaO2, independent of the RM technique. The pressure-controlled ventilation RM caused a lasting increase of PaO2 in the ventilator-induced lung injury model, but in oleic acid injury and pneumococcal pneumonia, there were no sustained oxygenation differences for any RM technique (sustained inflation, incremental positive end-expiratory pressure, or pressure-controlled ventilation) that differed from raising positive end-expiratory pressure without RM. CONCLUSIONS: Recruitment by pressure-controlled ventilation is equivalent or superior to sustained inflation, with the same peak pressure in all tested models of acute lung injury, despite its lower mean airway pressure and reduced risk for hemodynamic compromise. Although RM may improve PaO2 in certain injury settings when traditional tidal volumes are used, sustained improvement depends on the post-RM positive end-expiratory pressure value.

Transient hemodynamic effects of recruitment maneuvers in three experimental models of acute lung injury.

OBJECTIVE: Elevated lung volumes and increased pleural pressures associated with recruitment maneuvers (RM) may adversely affect pulmonary vascular resistance and cardiac filling or performance. We investigated the hemodynamic consequences of three RM techniques after inducing acute lung injury. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Hospital research laboratory. SUBJECTS: Thirteen anesthetized, mechanically ventilated pigs. INTERVENTIONS: We induced three types of acute lung injury: oleic acid injury (n = 4); ventilator-induced lung injury (n = 4); and pneumonia (n = 5). All three models were designed to initiate a similar severity of oxygenation impairment. RM methods tested were sustained inflation, incremental positive end-expiratory pressure (PEEP) with a limited peak pressure, and pressure-controlled ventilation with increased PEEP and a fixed driving pressure. From a baseline PEEP of 8 cm H2O, all interventions were tested using post-RM PEEP levels of 8, 12, and 16 cm H2O. Cardiac output by thermodilution and systemic and pulmonary artery pressures were measured frequently during the RM and for 15 mins after its completion. MEASUREMENTS AND MAIN RESULTS: During the RM, cardiac output decreased to a greater extent in the pneumonia model (0.49 of baseline cardiac output) than in the oleic acid injury (0.67 of baseline) or ventilator-induced lung injury (0.79 of baseline) models. Cardiac output recovered to the baseline value by 5 mins post-RM in oleic acid injury and ventilator-induced lung injury models. However, cardiac output remained decreased 15 mins post-RM in the pneumonia model. There were no differences in hemodynamic parameters among RM methods in oleic acid injury and ventilator-induced lung injury models. In the pneumonia model, however, cardiac output decreased to a greater extent during the RM with sustained inflation (to 0.33 of baseline cardiac output) compared with pressure-controlled ventilation (to 0.68 of baseline). CONCLUSIONS: We conclude that RM transiently but profoundly depressed cardiac output in three models of acute lung injury. The results imply that a lung recruiting maneuver should be used with caution, especially when using sustained inflation in the setting of pneumonia.