Strategic application of modular risk components to safely increase lung transplantation volume.

OBJECTIVES: Considerable growth of individual lung transplant programs remains challenging. We hypothesized that the systematic implementation of modular risk components to a lung transplantation program would allow for expeditious growth without increasing mortality. METHODS: All consecutive patients placed on the lung transplantation waitlist were reviewed. Patients were stratified by an 18-month period surrounding the systematic implementation of the modular risk components Era 1 (1/2014-6/2015) and Era 2 (7/2015-12/2016). Modular risk components were separately evaluated for donors, recipients, and perioperative features. RESULTS: One hundred and thirty-two waitlist patients (Era 1: 48 and Era 2: 84) and 100 transplants (Era 1: 32 and Era 2: 68) were identified. There was a trend toward decreased waitlist mortality (P = .07). In Era 2, the use of ex vivo lung perfusion (P = .05) and donor-recipient over-sizing (P = .005) significantly increased. Moreover, transplantation with a lung allocation score greater than 70 (P = .05), extracorporeal support (P = .06), and desensitization (P = .008) were more common. Transplant rate significantly improved from Era 1 to Era 2 (325 vs 535 transplants per 100 patient years, P = .02). While primary graft dysfunction (PGD) grade 3 at 72 hours (P = .05) was significantly higher in Era 2, 1-year freedom from rejection was similar (86% vs 90%, P = .69) and survival (81% vs 95%, P = .02) was significantly greater in Era 2. CONCLUSIONS: The systematic implementation of a modular risk components to a lung transplantation program can result in a significant increase in center volume. However, measures to mitigate an expected increase in the incidence of PGD must be undertaken to maintain excellent short and midterm outcomes.

Early tracheostomy after initiation of venovenous extracorporeal membrane oxygenation is associated with decreased duration of extracorporeal membrane oxygenation support.

Timing of tracheostomy placement for patients with respiratory failure requiring venovenous extracorporeal membrane oxygenation support is variable and continues to depend on surgeon preference. We retrospectively reviewed all consecutive adult patients supported with peripheral venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome at a single institution with the hypothesis that early tracheostomy (within 7 days of extracorporeal membrane oxygenation initiation) decreases the duration of extracorporeal membrane oxygenation support. The primary endpoint was duration of extracorporeal membrane oxygenation support. Secondary endpoints included mortality, overall and intensive care unit length of stay, duration of mechanical ventilation, and time from extracorporeal membrane oxygenation initiation to liberation from ventilator, intensive care unit discharge, and hospital discharge. Overall and extracorporeal membrane oxygenation-associated hospital costs were compared. A total of 50 patients were identified for inclusion (early n = 21; late n = 29). Baseline characteristics including indices of disease severity were similar between groups. Duration of extracorporeal membrane oxygenation support was significantly shorter in the early tracheostomy group (12 vs. 21 days; p = 0.005). Median extracorporeal membrane oxygenation-related costs were significantly decreased in the early tracheostomy group ($3,624 vs. $5,603, p = 0.03). Early tracheostomy placement is associated with decreased time on extracorporeal membrane oxygenation support and reduced extracorporeal membrane oxygenation-related costs in this cohort. Validation in a prospective cohort or a clinical trial is indicated.

Current state of ex-vivo lung perfusion.

PURPOSE OF REVIEW: The purpose of the current report is to review the ex-vivo peer-reviewed literature published in the last 5 years and to summarize the findings. RECENT FINDINGS: Encouraging data have been published by several centers utilizing ex-vivo lung perfusion (EVLP) as a means to identify viable grafts from the high-risk donor pool. The outcomes of transplanted lungs that were initially declined because of poor quality, but reevaluated with ex-vivo perfusion, are equivalent to standard criteria donor lungs. Further, research reports have emphasized the role of ex-vivo perfusion as a platform to improve graft quality and reduce the injurious effects of ischemia-reperfusion. SUMMARY: Over the last 10 years, EVLP has proved its value as a reassessment tool to increase donor utilization. As short- and long-term data demonstrate the safety of EVLP, its use as a therapeutic platform is emerging, along with the promise of a new era in lung transplantation.

Dose-response effects of spectrum research cigarettes.

INTRODUCTION: Experimental cigarettes are needed to conduct studies examining the effects of varying doses of nicotine content on smoking behavior. The National Institute on Drug Abuse contracted with Research Triangle Institute to make such cigarettes available to researchers. The goal of this study was to determine whether cigarettes that vary in nicotine content produce an expected dose-response effect. METHOD: Two studies were conducted. The first study recruited subjects from 3 sites and consisted of a single, within-subject laboratory session. Subjects first smoked 4 puffs on their usual-brand cigarette and then in double-blind, random-order, smoked 4 puffs on each experimental cigarette that contained either low nicotine (LN, 0.4 mg/g), intermediate nicotine (IN, 5.7-5.8 mg/g), or high nicotine (HN, 11.4-12.8 mg/g). Each puffing bout was separated by a 30-min interval. Subjects completed questionnaires and were assessed for vital signs after each cigarette. The second study involved 1 site and used a between-subject design in which subjects were assigned to 1 of the 3 experimental cigarettes for 1 week. Subjective responses and biomarkers of exposure were assessed. RESULTS: In the first study, significant dose-response effects were observed, particularly between the LN and HN cigarettes. The second study showed decreases in cigarette smoking and exposure biomarkers predominantly in the LN group, with no changes in the HN cigarette group. CONCLUSIONS: These results are similar to those observed in prior literature, confirming that these experimental cigarettes can be used safely and with the expected pharmacological effects.

Treatment of tobacco dependence in people with mental health and addictive disorders.

People with mental health and addictive disorders (MHADs) have higher rates of cigarette smoking, and less success in quitting smoking compared with the general population. Moreover, tobacco-related medical illness may be the leading cause of death in the MHAD population. We discuss the scope of this comorbidity, and approaches to the treatment of tobacco dependence in people with MHAD, including schizophrenia, mood disorders, anxiety disorders, and alcohol and substance use disorders. Finally, at the level of health systems, we emphasize the importance of integrated treatment of tobacco dependence in MHADs.

Early Decompressive Laparotomy for Intra-Abdominal Hypertension Following Initiation of Venovenous Extracorporeal Membrane Oxygenation.

Patients supported with venovenous extracorporeal membrane oxygenation are at risk for intra-abdominal hypertension and abdominal compartment syndrome. Flow through the return cannula may be compromised in these patients, resulting in inadequate support and end-organ malperfusion. Early decompressive laparotomy can mitigate these complications and potentially improve outcomes. Here we review a series of nine patients undergoing early decompressive laparotomy for abdominal compartment syndrome at a single institution and propose an algorithmic approach to the management of these patients.

Ambulation With Femoral Arterial Cannulation Can Be Safely Performed on Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) support can be associated with significant deconditioning due to the requirement for strict bedrest as a result of femoral arterial cannulation. To address this issue, we evaluated our experience with ambulation in patients with peripheral femoral cannulation for VA-ECMO. METHODS: All patients that were peripherally cannulated for VA-ECMO over a 2-year period were retrospectively reviewed. Patients that ambulated at least once while supported with VA-ECMO were included in the analysis. The primary outcomes were safety and feasibility of ambulation, defined as the absence of major bleeding, vascular, or decannulation events. RESULTS: Of 104 patients placed on VA-ECMO, 15 ambulated with a femoral arterial cannula. Forty-six percent of patients were placed on VA-ECMO for decompensated heart failure, and 54% for massive pulmonary embolism. Twenty-seven percent of patients were cannulated during active cardiopulmonary resuscitation. The median length of time from cannulation to out of bed was 3 (range, 0 to 26) days. The median length of time from cannulation to initial ambulation was 4 (range, 1 to 42) days. The median distance of the first postcannulation walk was 300 feet. Neither flow nor speed decreased during or after ambulation. There were no major bleeding events, vascular complications, or decannulation events associated with ambulation. The median intensive care unit length of stay and hospital length of stay were 12 and 21 days, respectively. One-year survival was 100% for ambulating patients. CONCLUSIONS: Ambulating patients supported with VA-ECMO, despite femoral arterial cannulation, appears feasible and safe in carefully selected patients.

Neurocognitive endophenotypes in schizophrenia: modulation by nicotinic receptor systems.

Cigarette smoking is the leading preventable cause of death in the Western world, with a considerably higher prevalence observed in schizophrenia compared to the general population. Despite the negative health consequences of smoking heavily, it has been proposed that individuals with schizophrenia may maintain smoking behaviors to remediate symptoms associated with the disorder. Neurocognitive deficits are a core feature of schizophrenia and are present in approximately 80% of patients. Further, these deficits constitute an endophenotype of schizophrenia, as they are stable across disease phases, and are heritable. The neurocognitive deficits that are present in schizophrenia are especially debilitating, since they are associated with poor clinical and functional outcomes and community integration. Interestingly, these deficits may also constitute a vulnerability factor towards the initiation and maintenance of tobacco use. Contributing to the potential shared vulnerability between schizophrenia and tobacco dependence is a dysregulation of the nicotinic acetylcholine receptor (nAChR) system. Pre-clinical evidence has shown that nicotine affects several neurotransmitter systems, including dopamine (DA), glutamate, and γ-aminobutyric acid (GABA), and certain neuropsychological deficits associated with these neurotransmitters (reaction time, spatial working memory, sustained attention, and sensory gating) are improved after nicotine administration in patients with schizophrenia. These positive effects on neurocognition appear to be more pronounced in smokers with schizophrenia, and may be an important mechanism that explains the co-morbidity of schizophrenia and tobacco dependence.

Mu Opioid Receptor Binding Correlates with Nicotine Dependence and Reward in Smokers.

The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.

Clinical characteristics of heavy and non-heavy smokers with schizophrenia.

Up to 50-90% of persons with schizophrenia smoke cigarettes. Limited data and theories suggest persons with schizophrenia may smoke for different reasons than persons without schizophrenia, making smoking cessation interventions particularly challenging in this population. Although health consequences of smoking are widely known, less information is available regarding characteristics of different amounts of smoking exposure in this population. This study was performed to investigate differences between heavy (≥ 1 pack per day) and non-heavy (<1 pack per day) smoking in patients with schizophrenia. Data from 745 patients, mean age 41.3+/-12.6 years, were drawn from a population of smokers admitted to State of Maryland inpatient mental health facilities (1994-2000). Records were reviewed to obtain demographic information, diagnosis, medication, smoking and substance use. 43% of patients were characterized as heavy smokers. Heavy and non-heavy groups did not differ in age, GAF, weight, or BMI. No differences were found in race, gender or antipsychotic treatments. However, patients smoking ≥ 1 packs per day were more likely to use other substances such as alcohol (χ(2)=6.67, df=1, p=0.01), cocaine (χ(2)=6.66, df=1, p=0.01), and other substances (χ(2)=9.95, df=1, p=0.003) compared to non-heavy smokers. No differences in cannabis or heroin use were found by smoking category. Controlling for age, race, sex and BMI, heavy smokers had higher total cholesterol (190.7(51.6)mg/dL) compared to non-heavy smokers (178.2 (43.0)mg/dL, p=0.03), but no differences were found in glucose or blood pressure. Heavy smoking may be a particular health risk in schizophrenia and significant efforts for smoking cessation or reduction are needed.

Illicit drug use in heavy smokers with and without schizophrenia.

OBJECTIVE: The prevalence of cigarette smoking among people with schizophrenia is greater than that of the general population. Because smoking and use of other drugs covary, we examined illicit drug use in current smokers not trying to quit or reduce their tobacco use. We recruited outpatient participants who had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder (schizophrenia, n=70) and a control group who had no Axis I psychiatric disorders (control, n=97). During a 2-3-hour session, participants completed demographic and research questionnaires, including the Drug Use Survey (DUS). RESULTS: Participants with schizophrenia were older than controls (p<0.001) and smoked more cigarettes per day (p=0.01), but did not differ in degree of nicotine dependence. Ever using a drug was similar between the groups, except that significantly more participants with schizophrenia reported ever using hallucinogens (p<0.001) and inhalants (p=0.001). For alcohol, cocaine, and marijuana, fewer participants with schizophrenia were current users, but more participants with schizophrenia were past users (ps<0.0001). Heavy smokers from the general population continued to use illicit drugs throughout their lives, while schizophrenia participants had the highest period of illicit drug use in their 20s. CONCLUSIONS: These data suggest that illicit drug use tends to be high in heavy cigarette smokers, regardless of a schizophrenia diagnosis. However, while illicit drug use is high across the lifespan of heavy smokers in the general population, heavy smokers with schizophrenia use illicit drugs mostly in the first decade of their illness.

Alcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders.

The impact of co-morbid substance use on mortality is not well studied in psychotic disorders. The objective of this study was to examine the impact of substance use on mortality in people with psychotic disorders and alcohol and/or drug use. We examined the rate of substance use and the risk of substance use on mortality risk over a 4-10 year period in 762 people with psychotic disorders. Deceased patients were identified from the Social Security Death Index and the Maryland Division of Vital Records. Substance use was defined as regular and heavy use or abuse or dependence. Seventy seven percent had co-morbid lifetime substance use, with co-morbid cannabis and alcohol use occurring most commonly. Out of 762 subjects, 62 died during follow up. In a Cox model, predicted mortality risk was higher in age group 35-55 compared to <35 years and in males, but reduced in cannabis users. Overall five- (3.1% vs 7.5%) and ten-year mortality risk (5.5% vs. 13.6%) was lower in cannabis users than in non-users with psychotic disorders (p = 0.005) in a survival model. Alcohol use was not predictive of mortality. We observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments. Future research is warranted to replicate these findings and to shed light on the anti-inflammatory properties of the endocannabinoid system and its role in decreased mortality in people with psychotic disorders.

Cigarette smoking and mortality risk in people with schizophrenia.

This study examined effects of cigarette smoking on mortality risk in 1213 persons aged 19-69 years with schizophrenia-related psychotic disorders admitted to State of Maryland Hospitals between 1994 and 2000. Inpatient medical records from 7 hospitals were reviewed to obtain demographic information, diagnosis, medication use, as well as smoking and other substance use. Social Security Death Index data were used to identify deaths in the study group between 1994 and 2004. Death records were reviewed to obtain manner of death and underlying disorders. Of the 1213, 55% were smokers and 71% abused substances. There was an age × smoking interaction (χ(2) = 14.6, df = 1, P = .0001) for mortality, with estimated hazard ratios (HRs) for smokers vs nonsmokers of 2.1 among 35- to 54-year olds and HR of 0.7 among those aged 55-69 years. Five- and 10-year mortality rates for smokers aged 35-54 years were 7.0% and 14.2%, compared with 3.3% and 10.0% for nonsmokers, respectively (χ(2) = 5.53, df = 1, P = .019). Cardiac causes were identified in 43% of deaths in smokers but only 19% of deaths in nonsmokers (P < .006). For those aged 35-54 years, the odds of cardiac related death was increased by 12 fold in smokers relative to nonsmokers (HR = 12.4, χ(2) = 12.0, df = 1, P = .0005). Among people aged 35-54 years, those smoking greater than one pack daily have a significantly increased total mortality risk (HR = 2.7) vs nonsmokers. Cigarette smoking, particularly in people aged 35-54 years, contributes to an increased risk of death. Greater smoking severity significantly increases this risk. Smoking cessation in people with schizophrenia deserves significant attention.