Jag Sunderram

Heme oxygenase-1 and chronic hypoxia.

A myriad of changes are necessary to adapt to chronic hypoxemia. Key among these changes increases in arterial oxygen carrying capacity, ventilation and sympathetic activity. This requires the induction of several gene products many of which are regulated by the activity of HIF-1α, including HO-1. Induction of HO-1 during chronic hypoxia is necessary for the continued breakdown of heme for the enhanced production of hemoglobin and the increased respiratory and sympathetic responses. Several human HO-1 polymorphisms have been identified that can affect the expression or activity of HO-1. Associations between these polymorphisms and the prevalence of hypertension have recently been assessed in specific populations. There are major gaps in our understanding of the mechanisms of how HO-1 mediates changes in the activity of the hypoxia-sensitive chemosensors and whether HO-1 polymorphisms are an important factor in the integrated response to chronic hypoxia. Understanding how HO-1 mediates cardiorespiratory responses could provide important insights into clinical syndromes such as obstructive sleep apnea.

Time-restricted feeding and the realignment of biological rhythms: translational opportunities and challenges.

It has been argued that circadian dysregulation is not only a critical inducer and promoter of adverse health effects, exacerbating symptom burden, but also hampers recovery. Therefore understanding the health-promoting roles of regulating (i.e., restoring) circadian rhythms, thus suppressing harmful effects of circadian dysregulation, would likely improve treatment. At a critical care setting it has been argued that studies are warranted to determine whether there is any use in restoring circadian rhythms in critically ill patients, what therapeutic goals should be targeted, and how these could be achieved. Particularly interesting are interventional approaches aiming at optimizing the time of feeding in relation to individualized day–night cycles for patients receiving enteral nutrition, in an attempt to re-establish circadian patterns of molecular expression. In this short review we wish to explore the idea of transiently imposing (appropriate, but yet to be determined) circadian rhythmicity via regulation of food intake as a means of exploring rhythm-setting properties of metabolic cues in the context of improving immune response. We highlight some of the key elements associated with his complex question particularly as they relate to: a) stress and rhythmic variability; and b) metabolic entrainment of peripheral tissues as a possible intervention strategy through time-restricted feeding. Finally, we discuss the challenges and opportunities for translating these ideas to the bedside.

Acute exacerbations of chronic obstructive pulmonary disease: diagnosis, management, and prevention in critically ill patients.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is a substantial source of disability in the United States. Moderate‐to‐severe acute exacerbations of COPD (AECOPD) can progress to respiratory failure, necessitating ventilator assistance in patients in the intensive care unit (ICU). Patients in the ICU with AECOPD requiring ventilator support have higher morbidity and mortality rates as well as costs compared with hospitalized patients not in the ICU. The mainstay of management for patients with AECOPD in the ICU includes ventilator support (noninvasive or invasive), rapid‐acting inhaled bronchodilators, systemic corticosteroids, and antibiotics. However, evidence supporting these interventions for the treatment of AECOPD in critically ill patients admitted to the ICU is scant. Corticosteroids have gained widespread acceptance in the management of patients with AECOPD necessitating ventilator assistance, despite their lack of evaluation in clinical trials as well as controversies surrounding optimal dosage regimens and duration of treatment. Recent studies evaluating the safety and efficacy of corticosteroids have found that higher doses are associated with increased adverse effects, which therefore support lower dosing strategies, particularly for patients admitted to the ICU for COPD exacerbations. This review highlights recent findings from the current body of evidence on nonpharmacologic and pharmacologic treatment and prevention of AECOPD in critically ill patients. In addition, the administration of bronchodilators using novel delivery devices in the ventilated patient and the conflicting evidence surrounding antibiotic use in AECOPD in the critically ill is explored. Further clinical trials, however, are warranted to clarify the optimal pharmacotherapy management for AECOPD, particularly in critically ill patients admitted to the ICU.

Unique Features of Obstructive Sleep Apnea in World Trade Center Responders With Aerodigestive Disorders

Objectives: To compare obstructive sleep apnea (OSA) in World Trade Center (WTC) responders with aerodigestive disorders and snoring with non-WTC habitual snorers, and to distinguish features of OSA in a subset of responders with worsening of snoring after 9/11 from responders with previous habitual snoring. Methods: Cross-sectional comparative study of 50 WTC Medical Monitoring and Treatment Program responders with aerodigestive disorders and snoring and 50 nonresponders with snoring. Responders with worsening of snoring after 9/11 were compared with previous habitual snorers. Results: While there was a strong correlation between body mass index (BMI), weight, and Apnea + Hypopnea Index (r = 0.36, P = 0.001; r = 0.29, P = 0.044) in the nonresponders, no correlation between either BMI or weight and Apnea + Hypopnea Index was found in the responders. Responders with worsening of snoring after 9/11 had a significantly lower BMI than previous habitual snorers. Conclusion: Mechanisms other than obesity are important in the pathogenesis of OSA in WTC responders with aerodigestive disorders.

Heme oxygenase-1 Dependent Central Cardiorespiratory Adaptations to Chronic Intermittent Hypoxia in Mice.

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1-/-). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1-/- Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1-/-; however, minute diaphragm electromyogram activity increased in WT but not HO-1-/- The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1-/- CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1-/-, and 2) the baseline sympathetic activity in WT and HO-1-/-, which remained stable subsequently in WT but not in HO-1-/- We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.

A comparison of CPAP and CPAPFLEX in the treatment of obstructive sleep apnea in World Trade Center responders: study protocol for a randomized controlled trial.

BackgroundFollowing the World Trade Center disaster, a large number of individuals involved in rescue and recovery activity were exposed to significant amounts of dust, and reported symptoms of chronic nasal and sinus inflammation. An unusually high prevalence of obstructive sleep apnea (OSA) has also been observed in this World Trade Center Responder population. This project aims to examine the relationship between nasal pathology and OSA. Our hypothesis is that increased nasal resistance due to nasal inflammation predisposes to OSA in this population. Continuous Positive Airway Pressure (CPAP) is the standard therapy for OSA but despite its efficacy has poor adherence. Subjects with high nasal resistance may have greater difficulty in tolerating this therapy than those who do not have high nasal resistance. Reduction of excess expiratory positive pressure by the modality known as Cflex™ during Continuous Positive Airway Pressure therapy (CPAPFlex) has been suggested to improve comfort without compromising efficacy. We will compare CPAP to CPAPFlex in subjects with OSA.Study DesignSubjects with new onset habitual snoring will be screened for OSA using home sleep studies and rhinomanometry will be used to determine nasal resistance. In 400 subjects with OSA we will perform a randomized double blind cross-over study comparing CPAP to CPAPflex, and relate nasal resistance to adherence to CPAP therapy.DiscussionThis is the first multicenter trial designed to test the hypothesis that adherence to CPAP therapy relates to nasal resistance and CPAPFlex will improve adherence to CPAP in those subjects with high nasal resistance.We anticipate the following results from this trial: 1. Increased nasal resistance is associated with decreased adherence to CPAP therapy. 2. Use of CPAPFlex improves adherence with CPAP therapy in subjects with high nasal resistance, but not in those with low nasal resistance. 3. The benefit of CPAPFlex on adherence is greatest when offered at CPAP therapy initiation rather than as a “rescue” therapy in subjects with high nasal resistance.Trial RegistrationClinicalTrials.gov Identifier: NCT01753999, Date: 12 December 2012

Chronic Rhinosinusitis is an independent risk factor for Obstructive Sleep Apnea in World Trade Center Responders

BACKGROUND: Many respiratory conditions have been attributed to toxic dust and fume exposure in World Trade Center (WTC) rescue and recovery workers, who frequently report symptoms of OSA. We examined the prevalence of new‐onset OSA and tested if the prevalence and severity of OSA are related to the presence of chronic rhinosinusitis (CRS). METHODS: A total of 601 subjects (83% men; age, 33‐87 years; BMI, 29.9 ± 5.5 kg/m2) enrolled in the WTC Health Program, excluding those with significant pre‐September 11, 2001, snoring or prior CRS, underwent two nights of home sleep testing. OSA was defined as Apnea Hypopnea Index 4% ≥ 5 events/h or respiratory disturbance index of ≥ 15 events/h. CRS was assessed using nasal symptom questionnaires. RESULTS: The prevalence of OSA was 75% (25% no OSA, 46% mild OSA, 19% moderate OSA, and 10% severe OSA), and the prevalence of CRS was 43.5%. Compared with no CRS, new and worsening CRS was a significant risk factor for OSA with an OR of 1.80 (95% CI, 1.18‐2.73; P = .006) unadjusted and 1.76 (95% CI, 1.08‐2.88; P = .02) after adjustment for age, BMI, sex, gastroesophageal reflux disorder, and alcohol use. CONCLUSIONS: The high prevalence of OSA in WTC responders was not explained fully by obesity and sex. Possible mechanisms for the elevated risk of OSA in subjects with CRS include increased upper airway inflammation and/or elevated nasal/upper airway resistance, but these need confirmation.

Effect of World Trade Center Dust Exposure and Chronic Intermittent Hypoxia on Macrophage Matrix Metalloproteinase-12 Expression in Mice

RATIONALE The pathophysiologic mechanisms by which World Trade Center (WTC) dust exposure leads to pulmonary disease have not been established. Matrix metalloproteinase-12 (MMP-12) is involved in the development of pulmonary fibrosis and chronic obstructive pulmonary disease. We have previously shown that exposure of mice to WTC dust results in increased expression of matrix metalloproteinase 12 by alveolar macrophages. Matrix metalloproteinase 12 expression is regulated, in part, by oxidative stress, which is also increased after WTC dust exposure. A significant percentage of WTC dust-exposed individuals have concomitant obstructive sleep apnea, which is an added source of oxidative stress, through chronic intermittent hypoxia (CIH). OBJECTIVES To determine if combined exposures of mice to WTC dust and CIH exacerbated matrix metalloproteinase 12 expression in alveolar macrophages. METHODS Male Balbc/J mice (12-24 wk) were treated intratracheally with phosphate-buffered saline (PBS) or WTC dust suspended in PBS, followed by CIH (cycles of 21 to 5% fraction of inspired oxygen, 2-min cycles) (CIH groups) or chronic intermittent air (CIA; cycles of 21 to 19% fraction of inspired oxygen, 2-min cycles) (CIA groups) 12 hours per day for 28 days. Histologic sections were then examined for macrophage expression of matrix metalloproteinase 12 by immunohistochemistry. RESULTS The mean number of positively stained alveolar macrophages from five fields per lobe was quantified. Mice exposed to WTC dust or CIH displayed increased macrophage expression of matrix metalloproteinase 12 compared with the control group. Exposure to WTC dust plus CIH was additive in effect (mean ± SD, PBS/CIA: 20.8 ± 5.2; PBS/CIH: 43.3 ± 19.8; WTC/CIA: 43.3 ± 12.5; WTC/CIH: 77.8 ± 12.2). CONCLUSIONS To our knowledge, this is the first study to suggest CIH increases macrophage matrix metalloproteinase 12 expression in mice. Combined exposures to WTC dust and CIH further increased macrophage matrix metalloproteinase 12 expression. Given the role of matrix metalloproteinase 12 in pulmonary fibrosis and chronic obstructive pulmonary disease pathogenesis, patients with obstructive sleep apnea who have been exposed to WTC dust may have added risk for pulmonary parenchymal disease.

Severe Obstructive Sleep Apnea is Associated with Alterations in the Nasal Microbiome and Increase in Inflammation

Rationale: Obstructive sleep apnea (OSA) is associated with recurrent obstruction, subepithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. Objectives: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. Methods: Two large cohorts were used: 1) a discovery cohort of 472 subjects from the WTCSNORE (Seated, Supine and Post‐Decongestion Nasal Resistance in World Trade Center Rescue and Recovery Workers) cohort, and 2) a validation cohort of 93 subjects rom the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing), and 2) biomarkers for inflammation (inflammatory cells, IL‐8, and IL‐6). Longitudinal 3‐month samples were obtained in the validation cohort, including after continuous positive airway pressure treatment when indicated. Measurements and Main Results: In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; and 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of cooccurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea‐hypopnea index. Three months of treatment with continuous positive airway pressure did not change the composition of the nasal microbiota. Conclusions: We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed.

Pharmacist-Led Workshops to Enhance Pharmacotherapy Knowledge for Medical Students

Background: Graduating medical students have reported concern regarding inadequate training in pharmacotherapy. Teaching by clinical pharmacists may improve medical students’ pharmacotherapy knowledge. Purpose: To assess the impact of pharmacist led workshops on 4th year medical students’ knowledge of pharmacotherapy and satisfaction. Methods: Senior medical students enrolled in intensive care unit rotations at a US medical school were randomized to an intervention of pharmacist led case-based workshops or a control group without an explicit pharmacotherapy curriculum. Intervention group students attended four weekly 1-hour workshops that covered topics in pharmacokinetics, pharmacodynamics, drug interactions and toxicity. A multiple-choice test of clinical vignettes assessed students’ knowledge of pharmacotherapy. An end of clerkship survey assessed student satisfaction with teaching. Results: Of 176 medical students eligible, 148 agreed to participate and were randomized to the intervention (n = 63) or control groups (n = 85). Student satisfaction with pharmacist led workshops was high. End of clerkship performance on clinical vignettes (minimum score 0, maximum 100) was similar between the groups (mean score 47 (SD = 12.2) for intervention vs 44 (SD = 13.0) for control group, p = 0.16). On end of clerkship survey, only 8% of control group students agreed or strongly agreed that the standard curriculum provided sufficient teaching in pharmacotherapy. The majority of students (82%) felt that pharmacotherapy should be taught formally in the clinical years. Conclusion: Pharmacist led workshops on pharmacotherapy were well received by senior medical students but did not improve performance on a test of pharmacotherapy knowledge. Further study is needed to define optimal strategies for improving medical students’ pharmacotherapy knowledge.