Paul N. Lanken

An Official American Thoracic Society Clinical Policy Statement: Palliative Care for Patients with Respiratory Diseases and Critical Illnesses

Executive Summary Introduction Methods Goals, Timing, and Settings for Palliative Care Decision-making Process Advance Directives Care Planning and Delivery Hospice Care Alternative End-of-Life Decisions Symptom Management Dyspnea Management Pain Management Management of Psychological and Spiritual Distress and Suffering Withdrawal of Mechanical Ventilation Process of Decision Making Process of Withdrawing Mechanical Ventilation Bereavement Care Barriers to Palliative Care Program Development, Education, Training, and Research in Palliative Care

Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury

We recently used positional cloning to identify the transcription factor Nrf2 (NF‐E2 related factor 2) as a susceptibility gene in a murine model of oxidant‐induced acute lung injury (ALI). NRF2 binds to antioxidant response elements (ARE) and up‐regulates protective detoxifying enzymes in response to oxidative stress. This led us to investigate NRF2 as a candidate susceptibility gene for risk of development of ALI in humans. We identified multiple single nucleotide polymorphisms (SNPs) by resequencing NRF2 in ethnically diverse subjects, and one (—617 C/A) significantly (P< 0.001) diminished luciferase activity of promoter constructs containing the SNP and significantly decreased the binding affinity (P<0.001) relative to the wild type at this locus (—617 CC). In a nested case‐control study, patients with the —617 A SNP had a significantly higher risk for developing ALI after major trauma (OR 6.44; 95% CI 1.34, 30.8;P=0.021) relative to patients with the wild type (—617 CC). This translational investigation provides novel insight into the molecular mechanisms of susceptibility to ALI and may help to identify patients who are predisposed to develop ALI under at risk conditions, such as trauma and sepsis. Furthermore, these findings may have important implications in other oxidative stress related illnesses.–Marzec J. M., Christie, J. D., Reddy, S. P., Jedlicka, A. E., Vuong, H., Lanken, P. N., Aplenc, R., Yamamoto, T., Yamamoto, M., Cho, H.‐Y., Klee‐berger S. R. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 21, 2237–2246 (2007)

Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure.

ObjectivePositive end-expiratory pressure (PEEP) and recruitment maneuvers (RMs) may partially reverse atelectasis and reduce ventilation-associated lung injury. The purposes of this study were to assess a) magnitude and duration of RM effects on arterial oxygenation and on requirements for oxygenation support (Fio2/PEEP) in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) receiving ventilation with low tidal volumes and high levels of PEEP; and b) frequency of adverse respiratory and circulatory events attributable to RMs. DesignProspective, randomized, crossover study. SettingThirty-four intensive care units at 19 hospitals. PatientsSeventy-two patients with early ALI/ARDS. Baseline PEEP and Fio2 were 13.8 ± 3.0 cm H2O and 0.39 ± 0.10, respectively (mean ± sd). InterventionsWe conducted RMs by applying continuous positive airway pressure of 35–40 cm H2O for 30 secs. We conducted sham RMs on alternate days. We monitored oxyhemoglobin saturation by pulse oximetry (SpO2), Fio2/PEEP, blood pressure, and heart rate for 8 hrs after RMs and sham RMs. We examined chest radiographs for barotrauma. Measurements and Main ResultsResponses to RMs were variable. Greatest increments from baseline SpO2 within 10 mins after RMs were larger than after sham RMs (1.7 ± 0.2 vs. 0.6 ± 0.3 %, mean ± sem, p < .01). Systolic blood pressure decreased more within 10 mins after RMs (9.4 ± 1.1 vs. 3.1 ± 1.1 mm Hg, p < .01). Changes in Fio2/PEEP requirements were not significantly different at any time after RMs vs. sham RMs. Barotrauma was apparent on first radiographs after one RM and one sham RM. ConclusionsIn ALI/ARDS patients receiving mechanical ventilation with low tidal volumes and high PEEP, short-term effects of RMs as conducted in this study are variable. Beneficial effects on gas exchange in responders appear to be of brief duration. More information is needed to determine the role of recruitment maneuvers in the management of ALI/ARDS.

The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: Long-Term Neuropsychological Function in Survivors of Acute Lung Injury

RATIONALE Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking. OBJECTIVES To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment. METHODS As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post-hospital discharge. MEASUREMENTS AND MAIN RESULTS Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02). CONCLUSIONS Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

Objective To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Design A prospective, randomized, double-blind, placebo-controlled, multicenter study. Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network. Patients A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group). Interventions Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing. Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo. Conclusions In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Predicting Bacteremia in Patients with Sepsis Syndrome

The goal of this study was to develop and validate clinical prediction rules for bacteremia and subtypes of bacteremia in patients with sepsis syndrome. Thus, a prospective cohort study, including a stratified random sample of 1342 episodes of sepsis syndrome, was done in eight academic tertiary care hospitals. The derivation set included 881 episodes, and the validation set included 461. Main outcome measures were bacteremia caused by any organism, gram-negative rods, gram-positive cocci, and fungal bloodstream infection. The spread in probability between low- and high-risk groups in the derivation sets was from 14.5% to 60.6% for bacteremia of any type, from 9.8% to 32.8% for gram-positive bacteremia, from 5.3% to 41.9% for gram-negative bacteremia, and from 0.6% to 26.1% for fungemia. Because the model for gram-positive bacteremia performed poorly, a model predicting Staphylococcus aureus bacteremia was developed; it performed better, with a low- to high-risk spread of from 2.6% to 21.0%. The prediction models allow stratification of patients according to risk of bloodstream infections; their clinical utility remains to be demonstrated.

Underuse of lung protective ventilation: analysis of potential factors to explain physician behavior.

Objective:To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with acute lung injury (ALI) and the factors associated with the choice of tidal volume. Design:Prospective observational cohort study of patients identified with ALI or acute respiratory distress syndrome from September 2000 to November 2002. Setting:Medical and surgical intensive care unit (ICU) at an academic tertiary-care hospital. Measurements and Main Results:Measurements included the proportion for whom the ventilation tidal volume (TV) was ≤7.5 mL/kg predicted body weight (PBW) on days 2, 4, and 7 of ALI and the proportion for whom the ventilation TV was ≤6.5 and ≤8.5 mL/kg/PBW (sensitivity analysis). Demographic and clinical characteristics of patients undergoing ventilation with low and high TV were compared. Of 88 total patients studied, 39% had ventilation with TV ≤7.5 mL/kg/PBW on day 2 of ALI, 49% on day 4, and 56% on day 7. In contrast, 49% of patients had ventilation with TV >8.5 mL/kg/PBW on day 2 of ALI, 30% on day 4, and 24% on day 7. The use of low TV was significantly associated with clinical parameters indicative of worse disease severity, including low values for Pao2 (p = .01), Pao2/Fio2 (p = .08), and static compliance of the respiratory system (p = .006). Conclusions:Ventilation with a low TV was used in a minority of patients with ALI, despite results published in 1998 and 2000 supporting this approach. This may be related to clinicians’ underrecognition of less severe cases of ALI, their reserving of low-TV ventilation for more severe cases, or both.

Dying Patients in the Intensive Care Unit: Forgoing Treatment, Maintaining Care

Up to 60% of deaths in the United States occur in acute care hospitals (1), and of these, 75% occur after decisions to forgo treatment (2, 3). Although such decisions are common in the intensive care unit (ICU), the care of dying patients raises both clinical and ethical difficulties. For example, in one survey, most ICU nurses and physicians stated that ICU interventions were often burdensome and used inappropriately (4). Although ICUs present many challenges to providing excellent end-of-life care, they also have special resources available (for example, a low patientnurse ratio that allows careful titration of intravenous medication to control dyspnea during ventilator withdrawal). This paper aims to help clinicians improve the care provided to ICU patients and families when decisions are made to limit life-sustaining treatment. It challenges the misconception that such decisions are decisions to withdraw care (5). In addition, it challenges physicians and nurses to care for dying patients with the same attention to detail, critical thinking, and compassion that they use in caring for ICU patients who are expected to survive. Patient Case Mr. McGee is a 79-year-old minister admitted with acute abdominal pain. He has been well except for complete heart block, which requires a permanent pacemaker. He lives at home and cares for his disabled wife. A perforated bowel is diagnosed, and he undergoes emergency surgical repair. Postoperatively, in the ICU, he develops the acute respiratory distress syndrome, renal failure, and candidal peritonitis. Mechanical ventilation and hemodialysis are begun. During the next 3 weeks, his mental status deteriorates so that he can no longer engage in conversations or follow commands. The ICU physician tells Mrs. McGee that her husbands chance of surviving is less than 10% and that even if he does survive, he will need long-term ventilator support and dialysis. Although Mr. McGee has no written advance directive, his family is certain that he would not want ICU care continued given these prospects. Deciding To Withdraw Life-Sustaining Interventions Although the basic values underlying end-of-life decision making (6-8) are not unique to the ICU, the setting presents unique challenges to the process. The ethical aspect of forgoing treatment resides in the legal and ethical right of the patient to determine what should happen to his or her own body. An adult patient with decisional capacity must be informed of reasonable treatment options and their possible outcomes. Patients who decide to forgo life-sustaining treatment should have these decisions honored. As a rule, a patients considered decision should override contrary opinions of family or physicians, no matter how well-intentioned the opposing views may be. When patients who cannot make decisions are concerned, the issues become more complicated. Before admission, Mr. McGee was fully capable of decision making, and conversations about his preferences for life support may have helped his family make decisions on his behalf. However, 60% to 70% of seriously ill patients, like Mr. McGee, are unable to speak for themselves when decisions to limit treatment are considered (3, 9). Although advance directives allow patients to specify preferences in advance, they have limited usefulness, and only 10% to 20% of patients even complete them. Living wills generally apply only if a patient is terminally ill or permanently unconscious, categories that are inapplicable to many ICU patients. Moreover, patients with advance directives may receive the same care as those without them (8) or may not want them followed literally (10). In the absence of a proxy designated by the patient, it is helpful to identify a single surrogate decision maker [or, if decisions are made by consensus within the family, a single spokesperson]. The surrogate should know the patient well and be willing to serve as the patients representative. In order of preference, decisions should be made on the basis of 1) the patients previously stated wishes; 2) inferences based on the patients values or life goals; or 3) the patients best interests, as judged by weighing the benefits and burdens of treatment. Many states stipulate surrogates by using a legal hierarchy. However, the legally mandated person and the ethically appropriate person may sometimes differ. For example, a daughter may know much more about her fathers preferences than a separated wife. For this reason, all capable patients should be urged on admission to the ICU (if not before) to advise caregivers about how to make decisions and should designate a health care proxy. Clinicians in the ICU should guide the proxy or surrogate through the decision-making process. Information should be given by using understandable terms and avoiding jargon. In addition, ample time should be allowed for discussion and repeated conversations. If a patient is expected to remain in the ICU for more than 2 days, holding a meeting with the patient and family within 48 hours of admission (and periodically thereafter) can help identify the appropriate goals of ICU treatment. These goals should be reevaluated by considering the patients course and determining whether current interventions remain consistent with the treatment goals. Participants in such meetings vary but often include the patients ICU and primary care physicians, nurses, consultants, family, close friends, religious advisor, and, most important, the patient (if possible). Spiritual Needs and Cultural Values Spiritual and religious issues are often significant factors for patients and families who are confronted by the possibility of death. An overwhelming sense of personal loss, with associated emotional and spiritual suffering, are often at the core of a dying persons and familys experience (11). Clinicians should routinely ask patients and families whether spiritual needs are being met and, if not, how the hospitals resources might be more helpful. Chaplains, social workers, and others skilled in supporting people through personal loss can be invaluable. The importance of dealing with the grief, spiritual issues, and emotions of family members emphasizes the need for multidisciplinary approaches. In addition, clinicians in the ICU should be aware of cultural differences in making decisions at the end of life. People from some cultures may be less willing to discuss resuscitation status or to forgo life-sustaining treatment (12-14) and may be less likely to complete advance directives (15, 16). Cultural and religious knowledge, sensitivity, and respect are essential when ICU staff discuss limiting life support. Use and Limits of Prognostic Models Recent advances in the use of prognostic models have improved objective predictions of hospital mortality rates for ICU patients. However, difficulty in determining if and when an individual patient will die remains a major obstacle to providing end-of-life care in the ICU. For example, the Acute Physiology and Chronic Health Evaluation (APACHE) III prognostic system (17) provides point estimates of mortality with 95% confidence intervals for the day of ICU admission, with updated predictions for subsequent ICU days. This and other models have been validated to predict outcomes of groups of patients (17-19). No controlled evidence, however, shows that prognostic models improve end-of-life decision making for individual patients. The prognostic model developed for the Study to Understand Prognoses and Preferences for Outcomes and Risk of Treatments (SUPPORT) provides 2- and 6-month estimates of survival, but this information has been shown to have minimal impact on end-of-life care for patients with serious illnesses (20). Given these limitations, would sophisticated ICU prognostic models have aided decision making for Mr. McGee? Possibly. However, most clinicians already incorporate some type of probabilistic reasoning when discussing prognosis with patients and families. Having objective estimates of survival may complement physician estimates and may help plant the seed in the minds of family members who have difficulty accepting that their loved one may die in the ICU. Because current prognostic models have considerable limitations, however, clinicians should use them only as an adjunct to the process of shared decision making (Table 1). Table 1. Limitations of Prognostic Models for End-of-Life Decision Making in the Intensive Care Unit Withdrawing Life-Sustaining Interventions After discussions with Mrs. McGee, a do-not-resuscitate order is written and dialysis is stopped. The ICU attending physician suggests that the ventilator also be discontinued, and the family agrees. Before ventilator support is stopped, vasopressors and all medications except morphine and midazolam are withdrawn. The resident discontinues enteral feedings but restarts them an hour later at the attendings request. Practice Variations Mr. McGees care presented physicians and family with many decisions. Was the ICU the best place to care for him? Which interventions should be continued, and which should be stopped? Is artificial nutrition different from other life-sustaining treatment? The practice of withdrawing treatment in ICUs has evolved during the past 20 years. When initial recommendations for discontinuing ventilator support were published in 1983, withdrawing ventilators was rare (21). Since then, withdrawing dialysis, ventilators, and other interventions has become much more common (22, 23). A study of 136 ICUs found that 74% of 5910 dying patients had some form of treatment withheld or withdrawn before death (2). However, interinstitutional variation was striking. Individual ICUs reported that anywhere from 21% to 96% of deaths were preceded by treatment limitation, and some ICUs reported no instances of withdrawing life support. This variation raises the question of whether these practice differences reflect physician or

ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio

RATIONALE Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI. OBJECTIVES To identify ALI risk variants after major trauma using a large-scale candidate gene approach. METHODS We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot. MEASUREMENTS AND MAIN RESULTS Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038). CONCLUSIONS An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.

Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma.

Background:Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients. Methods:We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score ≥16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2–5 single nucleotide polymorphisms were conducted. Results:Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio = 1.87, 95% confidence interval 1.06–3.33; p = 0.022) and Pro147Ser (TT, odds ratio = 2.13, 95% confidence interval 1.14–4.10; p = 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio = 0.42, 95% confidence interval 0.20–0.85; p = 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2–4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008). Conclusions:Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis.