Association of alpha globin gene copy number with exhaled nitric oxide in a cross-sectional study of healthy Black adults.

INTRODUCTION: The genetic determinants of fractional exhalation of nitric oxide (FeNO), a marker of lung inflammation, are understudied in Black individuals. Alpha globin (HBA) restricts nitric oxide signalling in arterial endothelial cells via interactions with nitric oxide synthase; however, its role in regulating the release of NO from respiratory epithelium is less well understood. We hypothesised that an HBA gene deletion, common among Black individuals, would be associated with higher FeNO. METHODS: Healthy Black adults were enrolled at four study sites in North Carolina from 2005 to 2008. FeNO was measured in triplicate using a nitric oxide analyzer. The -3.7 kb HBA gene deletion was genotyped using droplet digital PCR on genomic DNA. The association of FeNO with HBA copy number was evaluated using multivariable linear regression employing a linear effect of HBA copy number and adjusting for age, sex and serum immunoglobulin-E levels. Post-hoc analysis employing a recessive mode of inheritance was performed. RESULTS: 895 individuals were in enrolled in the study and 720 consented for future genetic research; 643 had complete data and were included in this analysis. Median (25th, 75th) FeNO was 20 (13, 31) ppb. HBA genotypes were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa and 8 (1.2%) aa/aaa. Subjects were 35% male with median age 20 (19, 22) years. Multivariable linear regression analysis revealed no association between FeNO and HBA copy number (ß=-0.005 (95% CI -0.042 to 0.033), p=0.81). In the post-hoc sensitivity analysis, homozygosity for the HBA gene deletion was associated with higher FeNO (ß=0.107 (95% CI 0.003 to 0.212); p=0.045). CONCLUSION: We found no association between HBA copy number and FeNO using a prespecified additive genetic model. However, a post hoc recessive genetic model found FeNO to be higher among subjects homozygous for the HBA deletion.

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans.

Introduction: People with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene (HBA) deletion would be associated with reduced risk of incident ischemic stroke. Methods: We evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determine HBA copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of HBA copy number on time to first ischemic stroke. Results: Four-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years' follow-up. HBA copy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with HBA copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66. Conclusions: Although a reduction in HBA copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, HBA copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans.

Introduction: People with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene ( HBA) deletion would be associated with reduced risk of incident ischemic stroke. Methods: We evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determine HBA copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of HBA copy number on time to first ischemic stroke. Results: Four-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years' follow-up. HBA copy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with HBA copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66. Conclusions: Although a reduction in HBA copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, HBA copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Alpha globin gene copy number and hypertension risk among Black Americans.

BACKGROUND: Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension. METHODS: Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression. RESULTS: Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR = 1.00; 95%CI 0.98,1.02), resistant hypertension (PR = 0.95; 95%CI 0.86,1.05), or incident hypertension (RR = 0.96; 95%CI 0.86,1.07). CONCLUSIONS: There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that variation in alpha globin gene copy number does not modify the risk of hypertension among Black American adults.

Indications of recent warm and dry summers' impact on private wells for drinking-water supply in Germany: a review of press articles.

Climatic changes lead to seasonal droughts with declining groundwater levels, and - especially in rural regions - private wells in the upper aquifer might fall dry. However, only limited information and no systematic administrative reporting of the extent are available for Germany yet. Therefore, a systematic analysis of newspaper articles as a promising source of information was conducted for the extraordinarily hot summers of 2018, 2019 and 2020. The results of the database searches were analysed with respect to frequency and local and regional hotspots, relations to climatic data, extent of the reported dry-fallings and emergency water supply. The analysis indicates hotspots particularly for the federal states of Saxony, where a subsidy programme for connecting to the public water supply was reissued in 2019, for Bavaria and North Rhine-Westphalia. Emergency supply was realised through various approaches. It was partly required until the winter months and did not always have drinking-water quality. As private wells are particularly vulnerable to the effects of climate change, their operators should be involved as a stakeholder group in future discussions about allocating water resources to increasingly competing uses in periods of scarcity.

Alpha Globin Gene Copy Number Is Associated with Prevalent Chronic Kidney Disease and Incident End-Stage Kidney Disease among Black Americans.

BACKGROUND: α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic-mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P<0.0001). While HBA copy number was not associated with incident reduced eGFR (RR, 1.06; 95% CI, 0.94 to 1.19; P=0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR, 1.32; 95% CI, 1.09 to 1.61; P=0.005). CONCLUSIONS: Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.

Identifying Clinical and Research Priorities in Sickle Cell Lung Disease. An Official American Thoracic Society Workshop Report.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality.Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus.Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation.Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

Catheter-related right atrial thrombus in sickle cell disease.

Catheter-related right atrial thrombus (CRAT) can occur in patients with sickle cell disease, particularly if additional risk factors for thrombosis are present. Cardiac MRI may differentiate thrombi from other types of atrial masses. Treatment should include anticoagulation and the timing of catheter removal should balance the potential risk of embolization.

Healthcare utilization and costs in ARDS survivors: a 1-year longitudinal national US multicenter study.

PURPOSE: To evaluate (1) post-discharge healthcare utilization and estimated costs in ARDS survivors, and (2) the association between patient and intensive care-related variables, and 6-month patient status, with subsequent hospitalization and costs. METHODS: Longitudinal cohort study enrolling from four ARDSNet trials in 44 US hospitals. Healthcare utilization was collected via structured interviews at 6 and 12 months post-ARDS, and hospital costs estimated via the Medical Expenditure Panel Survey. Adjusted odds ratios for hospitalization and adjusted relative medians for hospital costs were calculated using marginal two-part regression models. RESULTS: Of 859 consenting survivors, 839 (98%) reported healthcare utilization, with 52% female and a mean age of 49 years old. Over 12 months, 339 (40%) patients reported at least one post-discharge hospitalization, with median estimated hospital costs of US$18,756 (interquartile range $7852-46,174; 90th percentile $101,500). Of 16 patient baseline and ICU variables evaluated, only cardiovascular comorbidity and length of stay were associated with hospitalization, and sepsis was associated with hospital costs. At 6-month assessment, better patient-reported physical activity and quality of life status were associated with fewer hospitalizations and lower hospital costs during subsequent follow-up, and worse psychiatric symptoms were associated with increased hospitalizations. CONCLUSIONS: This multicenter longitudinal study found that 40% of ARDS survivors reported at least one post-discharge hospitalization during 12-month follow-up. Few patient- or ICU-related variables were associated with hospitalization; however, physical, psychiatric, and quality of life measures at 6-month follow-up were associated with subsequent hospitalization. Interventions to reduce post-ARDS morbidity may be important to improve patient outcomes and reduce healthcare utilization.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.

Healthcare Resource Use and Costs in Long-Term Survivors of Acute Respiratory Distress Syndrome: A 5-Year Longitudinal Cohort Study.

OBJECTIVE: To evaluate the time-varying relationship of annual physical, psychiatric, and quality of life status with subsequent inpatient healthcare resource use and estimated costs. DESIGN: Five-year longitudinal cohort study. SETTING: Thirteen ICUs at four teaching hospitals. PATIENTS: One hundred thirty-eight patients surviving greater than or equal to 2 years after acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postdischarge inpatient resource use data (e.g., hospitalizations, skilled nursing, and rehabilitation facility stays) were collected via a retrospective structured interview at 2 years, with prospective collection every 4 months thereafter, until 5 years postacute respiratory distress syndrome. Adjusted odds ratios for hospitalization and relative medians for estimated episode of care costs were calculated using marginal longitudinal two-part regression. The median (interquartile range) number of inpatient admission hospitalizations was 4 (2-8), with 114 patients (83%) reporting greater than or equal to one hospital readmission. The median (interquartile range) estimated total inpatient postdischarge costs over 5 years were $58,500 ($19,700-157,800; 90th percentile, $328,083). Better annual physical and quality of life status, but not psychiatric status, were associated with fewer subsequent hospitalizations and lower follow-up costs. For example, greater grip strength (per 6 kg) had an odds ratio (95% CI) of 0.85 (0.73-1.00) for inpatient admission, with 23% lower relative median costs, 0.77 (0.69-0.87). CONCLUSIONS: In a multisite cohort of long-term acute respiratory distress syndrome survivors, better annual physical and quality of life status, but not psychiatric status, were associated with fewer hospitalizations and lower healthcare costs.

The benefits of powdered activated carbon recirculation for micropollutant removal in advanced wastewater treatment.

PAC adsorption is a widespread option for the removal of organic micropollutants (OMP) from secondary effluent. For an optimal exploitation of the adsorption capacity, PAC recirculation is nowadays a common practice, although the mechanistic interrelations of the complex recirculation process are not fully resolved. In this work, extensive multi-stage batch adsorption testing with repeated PAC and coagulant dosage was performed to evaluate the continuous-flow recirculation system. Partly loaded PAC showed a distinct amount of remaining capacity, as OMP and DOC removals considerably increased with each additional adsorption stage. At a low PAC dose of 10 mg PAC L(-1), removals of benzotriazole and carbamazepine were shown to rise from <40% in the first stage up to >80% in the 11th stage at 30 min adsorption time per stage. At a high PAC dose of 30 mg PAC L(-1), OMP and DOC removals were significantly higher and reached 98% (for benzotriazole and carbamazepine) after 11 stages. Coagulant dosage showed no influence on OMP removal, whereas a major part of DOC removal can be attributed to coagulation. Multi-stage adsorption is particularly beneficial for small PAC doses and significant PAC savings are feasible. A new model approach for predicting multi-stage OMP adsorption on the basis of a single-stage adsorption experiment was developed. It proved to predict OMP removals and PAC loadings accurately and thus contributes towards understanding the PAC recirculation process.

Distinct germination response of endangered and common arable weeds to reduced water potential.

Arable weeds are one of the most endangered species groups in Europe. Modern agriculture and intensive land-use management are the main causes of their dramatic decline. However, besides the changes in land use, climate change may further challenge the adaptability of arable weeds. Therefore, we investigated the response pattern of arable weeds to different water potential and temperature regimes during the phase of germination. We expected that endangered arable weeds would be more sensitive to differences in water availability and temperature than common arable weeds. To this end, we set up a climate chamber experiment where we exposed seeds of five familial pairs of common and endangered arable weed species to different temperatures (5/15, 10/20 °C) and water potentials (0.0 to -1.2 MPa). The results revealed a significant relationship between the reaction of arable weed species to water availability and their Red List status. The effects of reduced water availability on total germination, mean germination time and synchrony were significantly stronger in endangered than in common arable weeds. Therefore, global climate change may present a further threat to the survival of endangered arable weed species.

Health care resource use and costs of two-year survivors of acute lung injury. An observational cohort study.

RATIONALE: Survivors of acute lung injury (ALI) require ongoing health care resources after hospital discharge. The extent of such resource use, and associated costs, are not fully understood. OBJECTIVES: For patients surviving at least 2 years after ALI, we evaluated cumulative 2-year inpatient admissions and related costs, and the association of patient- and intensive care unit-related exposures with these costs. METHODS: Multisite observational cohort study in 13 intensive care units at four academic teaching hospitals evaluating 138 two-year survivors of ALI. MEASUREMENTS AND MAIN RESULTS: Two-year inpatient health care use data (i.e., admissions to hospitals, and skilled nursing and rehabilitation facilities) were collected for patients surviving at least 2 years, via (1) one-time retrospective structured interview with patient and/or proxy, (2) systematic medical record review for nonfederal study site hospitals, and (3) inpatient medical record review for non-study site hospitals, as needed for clarifying patient/proxy reports. Costs are reported in 2013 U.S. dollars. A total of 138 of 142 (97%) 2-year survivors completed the interview, with 111 (80%) reporting at least one inpatient admission during follow-up, for median (interquartile range [IQR]) estimated costs of $35,259 ($10,565-$81,166). Hospital readmissions accounted for 76% of costs. Among 12 patient- and intensive care unit-related exposures evaluated, baseline comorbidity and intensive care unit length of stay were associated with increased odds of incurring any follow-up inpatient costs. Having Medicare or Medicaid (vs. private insurance) was associated with median estimated costs that were 85% higher (relative median, 1.85; 95% confidence interval, 1.01-3.45; P=0.045). CONCLUSIONS: In this multisite study of 138 two-year survivors of ALI, 80% had one or more inpatient admission, representing a median (IQR) estimated cost $35,259 ($10,565-$81,166) per patient and $6,598,766 for the entire cohort. Hospital readmissions represented 76% of total inpatient costs, and having Medicare or Medicaid before ALI was associated with increased costs. With the aging population and increasing comorbidity, these findings have important health policy implications for the care of critically ill patients.

Rapid small-scale column testing of granular activated carbon for organic micro-pollutant removal in treated domestic wastewater.

This study investigates the applicability of the rapid small-scale column test (RSSCT) concept for testing of granular activated carbon (GAC) for organic micro-pollutants (OMPs) removal from wastewater treatment plant (WWTP) effluent. The chosen experimental setup was checked using pure water, WWTP effluent, different GAC products, and variable hydrodynamic conditions with different flow velocities and differently sized GAC, as well as different empty bed contact times (EBCTs). The setup results in satisfying reproducibility and robustness. RSSCTs in combination with WWTP effluent are effective when comparing the OMP removal potentials of different GAC products and are a useful tool for the estimation of larger filters. Due to the potentially high competition between OMPs and bulk organics, breakthrough curves are likely to have unfavorable shapes when treating WWTP effluent. This effect can be counteracted by extending the EBCT. With respect to the strong competition observed in GAC treatment of WWTP effluent, the small organic acid and neutral substances are retained longer in the RSSCT filters and are likely to cause the majority of the observed adsorption competition with OMPs.

Age and decisions to limit life support for patients with acute lung injury: a prospective cohort study.

INTRODUCTION: The proportion of elderly Americans admitted to the intensive care unit (ICU) in the last month of life is rising. Hence, challenging decisions regarding the appropriate use of life support are increasingly common. The objective of this study was to estimate the association between patient age and the rate of new limitations in the use of life support, independent of daily organ dysfunction status, following acute lung injury (ALI) onset. METHODS: This was a prospective cohort study of 490 consecutive patients without any limitations in life support at the onset of ALI. Patients were recruited from 11 ICUs at three teaching hospitals in Baltimore, Maryland, USA, and monitored for the incidence of six pre-defined limitations in life support, with adjustment for baseline comorbidity and functional status, duration of hospitalization before ALI onset, ICU severity of illness, and daily ICU organ dysfunction score. RESULTS: The median patient age was 52 (range: 18 to 96), with 192 (39%) having a new limitation in life support in the ICU. Of patients with a new limitation, 113 (59%) had life support withdrawn and died, 53 (28%) died without resuscitation, and 26 (14%) survived to ICU discharge. Each ten-year increase in patient age was independently associated with a 24% increase in the rate of limitations in life support (Relative Hazard 1.24; 95% CI 1.11 to 1.40) after adjusting for daily ICU organ dysfunction score and all other covariates. CONCLUSIONS: Older critically ill patients are more likely to have new limitations in life support independent of their baseline status, ICU-related severity of illness, and daily organ dysfunction status. Future studies are required to determine whether this association is a result of differences in patient preferences by age, or differences in the treatment options discussed with the families of older versus younger patients.

A scenario-based, randomized trial of patient values and functional prognosis on intensivist intent to discuss withdrawing life support.

OBJECTIVES: To evaluate the effect of 1) patient values as expressed by family members and 2) a requirement to document patients' functional prognosis on intensivists' intention to discuss withdrawal of life support in a hypothetical family meeting. DESIGN: A three-armed, randomized trial. SETTING: One hundred seventy-nine U.S. hospitals with training programs in critical care accredited by the Accreditation Council for Graduate Medical Education. SUBJECTS: Six hundred thirty intensivists recruited via e-mail invitation from a database of 1,850 eligible academic intensivists. INTERVENTIONS: Each intensivist was randomized to review 10, online, clinical scenarios with a range of illness severities involving a hypothetical patient (Mrs. X). In control-group scenarios, the patient did not want continued life support without a reasonable chance of independent living. In the first experimental arm, the patient wanted life support regardless of functional outcome. In the second experimental arm, patient values were identical to the control group, but intensivists were required to record the patient's estimated 3-month functional prognosis. MEASUREMENTS AND MAIN RESULTS: Response to the question: "Would you bring up the possibility of withdrawing life support with Mrs. X's family?" answered using a five-point Likert scale. There was no effect of patient values on whether intensivists intended to discuss withdrawal of life support (p = 0.81), but intensivists randomized to record functional prognosis were 49% more likely (95% CI, 20-85%) to discuss withdrawal. CONCLUSIONS: In this national, scenario-based, randomized trial, patient values had no effect on intensivists' decisions to discuss withdrawal of life support with family. However, requiring intensivists to record patients' estimated 3-month functional outcome substantially increased their intention to discuss withdrawal.

Timing of limitations in life support in acute lung injury patients: a multisite study*.

OBJECTIVE: Substantial variability exists in the timing of limitations in life support for critically ill patients. Our objective was to investigate how the timing of limitations in life support varies with changes in organ failure status and time since acute lung injury onset. DESIGN, SETTING, AND PATIENTS: This evaluation was performed as part of a prospective cohort study evaluating 490 consecutive acute lung injury patients recruited from 11 ICUs at three teaching hospitals in Baltimore, MD. INTERVENTIONS: None. MEASUREMENTS: The primary exposure was proportion of days without improvement in Sequential Organ Failure Assessment score, evaluated as a daily time-varying exposure. The outcome of interest was a documented limitation in life support defined as any of the following: 1) no cardiopulmonary resuscitation, 2) do not reintubate, 3) no vasopressors, 4) no hemodialysis, 5) do not escalate care, or 6) other limitations (e.g., "comfort care only"). MAIN RESULTS: For medical ICU patients without improvement in daily Sequential Organ Failure Assessment score, the rate of limitation in life support tripled in the first 3 days after acute lung injury onset, increased again after day 5, and peaked at day 19. Compared with medical ICU patients, surgical ICU patients had a rate of limitations that was significantly lower during the first 5 days after acute lung injury onset. In all patients, more days without improvement in Sequential Organ Failure Assessment scores was associated with limitations in life support, independent of the absolute magnitude of the Sequential Organ Failure Assessment score. CONCLUSIONS: Persistent organ failure is associated with an increase in the rate of limitations in life support independent of the absolute magnitude of Sequential Organ Failure Assessment score, and this association strengthens during the first weeks of treatment. During the first 5 days after acute lung injury onset, limitations were significantly more common in medical ICUs than surgical ICUs.