Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model.

Rationale: Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. Objectives: To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Methods: Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, in vitro differentiation ability, and transcriptional profiles. Measurements and Main Results: The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased in vitro neurosphere formation and altered neural progenitor cell transcriptional signatures. Conclusions: Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.

Can the complete blood count be used as a reliable screening tool for obstructive sleep apnea?

PURPOSE: Since hypoxia increases erythropoietin production and inflammation, the complete blood count (CBC) has been proposed as an inexpensive alternative for obstructive sleep apnea (OSA) screening. The objective of this study was to determine whether or not intermittent hypoxia and OSA severity, as measured by the mean oxygen saturation (SpO2) and apnea-hypopnea index (AHI), affect parameters measured by the CBC. METHODS: This retrospective study included a total of 941 surgical patients who had a pre-operative home sleep study. The pre-operative CBC was extracted from the electronic patient records. Patients were stratified according to their AHI scores, into mild (AHI ≥ 5 - < 15), moderate (AHI ≥ 15 - < 30), and severe (AHI ≥ 30) OSA groups. RESULTS: There were 244 patients without OSA, 294 with mild, 223 with moderate, and 180 with severe OSA. Our analysis showed that hemoglobin (P = 0.010), hematocrit (P = 0.027), and basophils (P = 0.006) showed significant changes among the different severities of OSA. For mean SpO2, there were negative associations with body mass index (r = - 0.287; P < 0.001), age (r = - 0.077; P = 0.021), hemoglobin (r = - 0.208; P < 0.001), hematocrit (r = - 0.220; P < 0.001), red blood cells (r = - 0.107; P = 0.001), mean corpuscular volume (MCV) (r = - 0.159; P < 0.001), mean corpuscular hemoglobin (r = - 0.142; P < 0.001), and basophils (r = - 0.091; P = 0.007). All analyzed parameters remained within normal clinical range. Multivariable regression identified hemoglobin, MCV, and basophils to be independent predictors of mean SpO2 and AHI. CONCLUSION: Hemoglobin, MCV, and basophils were independently associated with intermittent hypoxia defined by mean SpO2 and AHI. Adding CBC parameters to other screening tools for OSA may have additional value due to its association with changes in mean SpO2.

Early Versus Late Tracheostomy in Patients With Acute Traumatic Spinal Cord Injury: A Systematic Review and Meta-analysis.

BACKGROUND: Acute traumatic spinal cord injuries (SCIs) often result in impairments in respiration that may lead to a sequelae of pulmonary dysfunction, increased risk of infection, and death. The optimal timing for tracheostomy in patients with acute SCI is currently unknown. This systematic review and meta-analysis aims to assess the optimal timing of tracheostomy in SCI patients and evaluate the potential benefits of early versus late tracheostomy. METHODS: We searched Medline, PubMed, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, and PsycINFO for published studies. We included studies on adults with SCI who underwent early or late tracheostomy and compared outcomes. In addition, studies that reported a concomitant traumatic brain injury were excluded. Data were extracted independently by 2 reviewers and copied into R software for analysis. A random-effects meta-analysis was performed to estimate the pooled odds ratio (OR) or mean difference (MD). RESULTS: Eight studies with a total of 1220 patients met our inclusion criteria. The mean age and gender between early and late tracheostomy groups were similar. The majority of the studies performed an early tracheostomy within 7 days from either time of injury or tracheal intubation. Patients with a cervical SCI were twice as likely to undergo an early tracheostomy (OR = 2.13; 95% confidence interval [CI], 1.24-3.64; P = .006) compared to patients with a thoracic SCI. Early tracheostomy reduced the mean intensive care unit (ICU) length of stay by 13 days (95% CI, -19.18 to -7.00; P = .001) and the mean duration of mechanical ventilation by 18.30 days (95% CI, -24.33 to -12.28; P = .001). Although the pooled risk of in-hospital mortality was lower with early tracheostomy compared to late tracheostomy, the results were not significant (OR = 0.56; 95% CI, 0.32-1.01; P = .054). In the subgroup analysis, mortality was significantly lower in the early tracheostomy group (OR = 0.27; P = .006). Finally, no differences in pneumonia between early and late tracheostomy groups were noted. CONCLUSIONS: Based on the available data, patients with early tracheostomy within the first 7 days of injury or tracheal intubation had higher cervical SCI, shorter ICU length of stay, and shorter duration of mechanical ventilation compared to late tracheostomy. The risk of in-hospital mortality may be lower following an early tracheostomy. However, due to the quality of studies and insufficient clinical data available, it is challenging to make conclusive interpretations. Future prospective trials with a larger patient population are needed to fully assess short- and long-term outcomes of tracheostomy timing following acute SCI.

Perioperative adherence to continuous positive airway pressure and its effect on postoperative nocturnal hypoxemia in obstructive sleep apnea patients: a prospective cohort study.

BACKGROUND: Although continuous positive airway pressure (CPAP) is the first line treatment for obstructive sleep apnea (OSA) patients, the perioperative adherence rate is unclear. The objective of this study was to determine the perioperative adherence rate of patients with OSA with a CPAP prescription and the effect of adherence on nocturnal oxygen saturation. METHODS: This prospective cohort study included adult surgical patients with a diagnosis of OSA with CPAP prescription undergoing elective non-cardiac surgery. Patients were divided into CPAP adherent and non-adherent groups based on duration of usage (≥ 4 h/night). Overnight oximetry was performed preoperatively and on postoperative night 1 and 2 (N1, N2). The primary outcome was adherence rate and the secondary outcome was nocturnal oxygen saturation. RESULTS: One hundred and thirty-two patients completed the study. CPAP adherence was 61% preoperatively, 58% on postoperative N1, and 59% on N2. Forty-nine percent were consistently CPAP adherent pre- and postoperatively. Using a linear fixed effects regression, oxygen desaturation index (ODI) was significantly improved by CPAP adherence (p = 0.0011). The interaction term CPAP x N1 was significant (p = 0.0015), suggesting that the effect of CPAP adherence varied on N1 vs preoperatively. There was no benefit of CPAP adherence on postoperative mean SpO2, minimum SpO2, and percentage of sleep duration with SpO2 < 90%. Use of supplemental oxygen therapy was much lower in the CPAP adherent group vs non-adherent group (9.8% vs 46.5%, p <  0.001). CONCLUSIONS: Among patients with a preoperative CPAP prescription, approximately 50% were consistently adherent. CPAP adherence was associated with improved preoperative ODI and the benefit was maintained on N1. These modest effects may be underestimated by a higher severity of OSA in the CPAP adherent group and a higher rate of oxygen supplementation in the non-adherent group. TRIAL REGISTRATION: ClinicalTrials.Gov registry ( NCT02796846 ).

Risk of major cardiovascular and cerebrovascular complications after elective surgery in patients with sleep-disordered breathing: A retrospective cohort analysis.

BACKGROUND: There is limited and conflicting data on whether sleep-disordered breathing (SDB) is associated with postoperative major cardiovascular and cerebrovascular events (MACCE), and mortality. OBJECTIVES: To determine whether SDB is associated with increased risks of MACCE, mortality and length of hospital stay. DESIGN: Retrospective cohort analysis from the Nationwide Inpatient Sample. SETTING: Adults who underwent elective abdominal, orthopaedic, prostatic, gynaecological, thoracic, transplant, vascular or cardiac surgery in the United States of America between 2011 and 2014. PATIENTS: The study cohort included 1813 974 surgical patients, of whom 185 615 (10.2%) had SDB. Emergency or urgent surgical procedures were excluded. MAIN OUTCOME MEASURES: The incidences of MACCE, respiratory and vascular complications, in-hospital mortality and mean length of hospital stay were stratified by SDB. Linear and logistic regression models were constructed to determine the independent association between SDB and outcomes of interest. RESULTS: The incidences of MACCE [25.3 vs. 19.8%, odds ratio (OR) 1.20, P < 0.001] and respiratory complications (11.75 vs. 8.0%, OR 1.43, P < 0.001) were significantly higher in patients with SDB than in those without SDB. SDB was associated with higher rates of atrial fibrillation (14.7 vs. 10.8%, P < 0.001), other arrhythmias (6.0 vs. 5.4%, P < 0.001) and congestive heart failure (9.8 vs. 7.1%, P < 0.001). SDB patients had a lower rate of myocardial infarction (3.1 vs. 3.4%, OR 0.69, P < 0.001), lower mortality (0.6 vs. 1.3%, P < 0.001) and shorter length of hospital stay (4.8 vs. 5.2 days, P < 0.001). CONCLUSION: SDB was associated with increased risks of MACCE, and respiratory and vascular complications, but had a lower incidence of in-hospital mortality and shorter length of hospital stay.

Marked Strain-Specific Differences in the SU5416 Rat Model of Severe Pulmonary Arterial Hypertension.

We assessed the pulmonary hemodynamic response to vascular endothelial growth factor receptor, type 2, inhibition using SU5416 (SU) with and without chronic hypoxia (CH) in different background strains and colonies of rats. A single subcutaneous injection of SU (20 mg/kg) or vehicle was administered to different substrains of Sprague-Dawley (SD) rats, and they were compared with Lewis and Fischer rats, with and without exposure to CH (10% O2 for 3 wk). Remarkably, a unique colony of SD rats from Charles River Laboratories, termed the SD-hyperresponsive type, exhibited severe pulmonary arterial hypertension (PAH) with SU alone, characterized by increased right ventricular systolic pressure, right ventricular/left ventricular plus septal weight ratio, and arteriolar occlusive lesions at 7-8 weeks (all P < 0.0001 versus vehicle). In contrast, the other SD substrain from Harlan Laboratories, termed SD-typical type, as well as Fischer rats, developed severe PAH only when exposed to SU and CH, whereas Lewis rats showed only a minimal response. All SD-typical type rats survived for up to 13 weeks after SU/CH, whereas SD-hyperresponsive type rats exhibited mortality after SU and SU/CH (35% and 50%, respectively) at 8 weeks. Fischer rats exposed to SU/CH exhibited the greatest mortality at 8 weeks (78%), beginning as early as 4 weeks after SU and preceded by right ventricle enlargement. Of note, a partial recovery of PAH after 8 weeks was observed in the SD-typical type substrain only. In conclusion, variation in strain, even between colonies of the same strain, has a remarkable influence on the nature and severity of the response to SU, consistent with an important role for genetic modifiers of the PAH phenotype.

Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response.

AIMS: It is thought that clopidogrel bioactivation and antiplatelet response are related to cytochrome P450 2C19 (CYP2C19). However, a recent study challenged this notion by proposing CYP2C19 as wholly irrelevant, while identifying paraoxonase-1 (PON1) and its Q192R polymorphism as the major driver of clopidogrel bioactivation and efficacy. The aim of this study was to systematically elucidate the mechanism and relative contribution of PON1 in comparison to CYP2C19 to clopidogrel bioactivation and antiplatelet response. METHODS AND RESULTS: First, the influence of CYP2C19 and PON1 polymorphisms and plasma paraoxonase activity on clopidogrel active metabolite (H4) levels and antiplatelet response was assessed in a cohort of healthy subjects (n = 21) after administration of a single 75 mg dose of clopidogrel. There was a remarkably good correlation between H4 AUC (0-8 h) and antiplatelet response (r2 = 0.78). Furthermore, CYP2C19 but not PON1 genotype was predictive of H4 levels and antiplatelet response. There was no correlation between plasma paraoxonase activity and H4 levels. Secondly, metabolic profiling of clopidogrel in vitro confirmed the role of CYP2C19 in bioactivating clopidogrel to H4. However, heterologous expression of PON1 in cell-based systems revealed that PON1 cannot generate H4, but mediates the formation of another thiol metabolite, termed Endo. Importantly, Endo plasma levels in humans are nearly 20-fold lower than H4 and was not associated with any antiplatelet response. CONCLUSION: Our results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response.

Preoperative oximetry-derived hypoxemia predicts postoperative cardiovascular events in surgical patients with unrecognized obstructive sleep apnea.

STUDY OBJECTIVE: Obstructive sleep apnea (OSA) is known to be associated with postoperative cardiovascular events in patients undergoing major non-cardiac surgery. The objective of the study is to determine whether preoperative oximetry-derived hypoxemia predicts postoperative cardiovascular events in surgical patients with unrecognized obstructive sleep apnea. DESIGN AND SETTING: The study was a planned post hoc analyses of a multicenter prospective cohort study. PATIENTS: The inclusion criteria were patients ≥45 years old undergoing major non-cardiac surgery with cardiovascular risk factors. INTERVENTIONS AND MEASUREMENTS: All patients underwent pre-operative pulse oximetry (PULSOX-300i, Konica-Minolta Sensing, Inc). The severity of OSA was classified based on oxygen desaturation index (ODI) (mild: ≥5 to <15, moderate: ≥15 to <30, and severe OSA: ≥30 events/h). The 30 days cardiovascular events were a composite of myocardial injury, cardiac death, congestive heart failure, thromboembolism, atrial fibrillation, and stroke. MAIN RESULTS: For 1218 patients with mild, moderate, or severe OSA (mean age: 67.2 ± 9.3 years; body mass index: 27.0 ± 5.3 kg/m2), the rate of postoperative cardiovascular events was 16.4%, 25.2%, and 29.8% respectively. The multivariable analysis showed that preoperative oxygen desaturation index (ODI) ≥30 events per hour {adjusted hazard ratio (aHR) 1.63 [95% confidence interval (CI): 1.05-2.53]}, and cumulative time spent during sleep with oxygen saturation below 80% (CT80) ≥10 min {aHR 1.79 [95% CI: 1.28-2.50]} were independent predictors of 30-day postoperative cardiovascular events. CONCLUSIONS: Preoperative ODI ≥30 events per hour and CT80 ≥ 10 min are associated with increased risk of postoperative cardiovascular events. Preoperative screening using oximetry helps in risk stratification for unrecognized sleep apnea. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01494181.

Characteristics of Patients with Unrecognized Sleep Apnea Requiring Postoperative Oxygen Therapy.

Surgical patients with obstructive sleep apnea (OSA) have increased risk of perioperative complications. The primary objective is to determine the characteristics of surgical patients with unrecognized OSA requiring oxygen therapy for postoperative hypoxemia. The secondary objective is to investigate the characteristics of patients who were responsive to oxygen therapy. This was a post-hoc multicenter study involving patients with cardiovascular risk factors undergoing major non-cardiac surgery. Patients ≥45 years old underwent Type 3 sleep apnea testing and nocturnal oximetry preoperatively. Responders to oxygen therapy were defined as individuals with ≥50% reduction in oxygen desaturation index (ODI) on postoperative night 1 versus preoperative ODI. In total, 624 out of 823 patients with unrecognized OSA required oxygen therapy. These were mostly males, had larger neck circumferences, higher Revised Cardiac Risk Indices, higher STOP-Bang scores, and higher ASA physical status, undergoing intraperitoneal or vascular surgery. Multivariable regression analysis showed that the preoperative longer cumulative time SpO2 < 90% or CT90% (adjusted p = 0.03), and lower average overnight SpO2 (adjusted p < 0.001), were independently associated with patients requiring oxygen therapy. Seventy percent of patients were responders to oxygen therapy with ≥50% ODI reduction. Preoperative ODI (19.0 ± 12.9 vs. 14.1 ± 11.4 events/h, p < 0.001), CT90% (42.3 ± 66.2 vs. 31.1 ± 57.0 min, p = 0.038), and CT80% (7.1 ± 22.6 vs. 3.6 ± 8.7 min, p = 0.007) were significantly higher in the responder than the non-responder. Patients with unrecognized OSA requiring postoperative oxygen therapy were males with larger neck circumferences and higher STOP-Bang scores. Those responding to oxygen therapy were likely to have severe OSA and worse preoperative nocturnal hypoxemia. Preoperative overnight oximetry parameters may help in stratifying patients.

Postoperative outcomes in older surgical patients with preoperative cognitive impairment: A systematic review and meta-analysis.

STUDY OBJECTIVE: To determine the effect of cognitive impairment (CI) and dementia on adverse outcomes in older surgical patients. DESIGN: A systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs). Various databases were searched from their inception dates to March 8, 2021. SETTING: Preoperative assessment. PATIENTS: Older patients (≥ 60 years) undergoing non-cardiac surgery. MEASUREMENTS: Outcomes included postoperative delirium, mortality, discharge to assisted care, 30-day readmissions, postoperative complications, and length of hospital stay. Effect sizes were calculated as Odds Ratio (OR) and Mean Difference (MD) based on random effect model analysis. The quality of included studies was assessed using the Cochrane Risk Bias Tool for RCTs and Newcastle-Ottawa Scale for observational cohort studies. RESULTS: Fifty-three studies (196,491 patients) were included. Preoperative CI was associated with a significant risk of delirium in older patients after non-cardiac surgery (25.1% vs. 10.3%; OR: 3.84; 95%CI: 2.35, 6.26; I2: 76%; p < 0.00001). Cognitive impairment (26.2% vs. 13.2%; OR: 2.28; 95%CI: 1.39, 3.74; I2: 73%; p = 0.001) and dementia (41.6% vs. 25.5%; OR: 1.96; 95%CI: 1.34, 2.88; I2: 99%; p = 0.0006) significantly increased risk for 1-year mortality. In patients with CI, there was an increased risk of discharge to assisted care (44.7% vs. 38.3%; OR 1.74; 95%CI: 1.05, 2.89, p = 0.03), 30-day readmissions (14.3% vs. 10.8%; OR: 1.36; 95%CI: 1.00, 1.84, p = 0.05), and postoperative complications (40.7% vs. 18.8%; OR: 1.85; 95%CI: 1.37, 2.49; p < 0.0001). CONCLUSIONS: Preoperative CI in older surgical patients significantly increases risk of delirium, 1-year mortality, discharge to assisted care, 30-day readmission, and postoperative complications. Dementia increases the risk of 1-year mortality. Cognitive screening in the preoperative assessment for older surgical patients may be helpful for risk stratification so that appropriate management can be implemented to mitigate adverse postoperative outcomes.

Prevalence of preoperative cognitive impairment in older surgical patients.: A systematic review and meta-analysis.

STUDY OBJECTIVE: Older surgical patients with cognitive impairment are at an increased risk for adverse perioperative outcomes, however the prevalence of preoperative cognitive impairment is not well-established within this population. The purpose of this review is to determine the pooled prevalence of preoperative cognitive impairment in older surgical patients. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE (Ovid), PubMed (non-MEDLINE records only), Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, and EMCare Nursing for relevant articles from 1946 to April 2021. PATIENTS: Patients aged ≥60 years old undergoing surgery, and preoperative cognitive impairment assessed by validated cognitive assessment tools. INTERVENTIONS: Preoperative assessment. MEASUREMENTS: Primary outcomes were the pooled prevalence of preoperative cognitive impairment in older patients undergoing either elective (cardiac or non-cardiac) or emergency surgery. MAIN RESULTS: Forty-eight studies (n = 42,498) were included. In elective non-cardiac surgeries, the pooled prevalence of unrecognized cognitive impairment was 37.0% (95% confidence interval [CI]: 30.0%, 45.0%) among 27,845 patients and diagnosed cognitive impairment was 18.0% (95% CI: 9.0%, 33.0%) among 11,676 patients. Within the elective non-cardiac surgery category, elective orthopedic surgery was analyzed. In this subcategory, the pooled prevalence of unrecognized cognitive impairment was 37.0% (95% CI: 26.0%, 49.0%) among 1117 patients, and diagnosed cognitive impairment was 17.0% (95% CI: 3.0%, 60.0%) among 6871 patients. In cardiac surgeries, the unrecognized cognitive impairment prevalence across 588 patients was 26.0% (95% CI: 15.0%, 42.0%). In emergency surgeries, the unrecognized cognitive impairment prevalence was 50.0% (95% CI: 35.0%, 65.0%) among 2389 patients. CONCLUSIONS: A substantial number of surgical patients had unrecognized cognitive impairment. In elective non-cardiac and emergency surgeries, the pooled prevalence of unrecognized cognitive impairment was 37.0% and 50.0%. Preoperative cognitive screening warrants more attention for risk assessment and stratification.

Prevalence of Undiagnosed Obstructive Sleep Apnea Among Patients Hospitalized for Cardiovascular Disease and Associated In-Hospital Outcomes: A Scoping Review.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with long-term cardiovascular morbidity and is highly prevalent in patients with cardiovascular disease (CVD). The objectives of this scoping review were to determine the prevalence of OSA inpatients hospitalized for CVD and to map the range of in-hospital outcomes associated with OSA. METHODS: We searched MEDLINE(R), Embase, and Cochrane Databases for articles published from 1946-2018. We included studies involving non-surgical adults with OSA or at high risk of OSA who were hospitalized for CVD. The outcomes were considered as in-hospital if they were collected from admission up to 30 days post-discharge from hospital. RESULTS: After the screening of 4642 articles, 26 studies were included for qualitative synthesis. Eligible studies included patients presenting with acute coronary syndromes (n = 19), congestive heart failure (n = 6), or any cardiovascular disease (n = 1). The pooled prevalence of OSA in cardiac inpatients was 48% (95% CI: 42-53). The in-hospital outcomes reported were mortality (n = 4), length of stay (n = 8), left ventricular ejection fraction (n = 8), peak troponin (n = 7), peak B-type natriuretic peptide (n = 4), and composite cardiovascular complications (n = 2). CONCLUSIONS: OSA is highly prevalent in the cardiac inpatient population. The outcomes reported included mortality, cardiac function, cardiac biomarkers, and resource utilization. There are significant knowledge gaps regarding the effect of treatment and OSA severity on these outcomes. The findings from this review serve to inform further areas of research on the management of OSA among patients with CVD.

Prevalence of sleep-disordered breathing in opioid users with chronic pain: a systematic review and meta-analysis.

STUDY OBJECTIVES: Opioids have been reported to increase the risk for sleep-disordered breathing (SDB) in patients with noncancer chronic pain on opioid therapy. This study aims to determine the pooled prevalence of SDB in opioid users with chronic pain and compare it with patients with pain:no opioids and no pain:no opioids. METHODS: A literature search of PubMed, Medline, Embase, and Cochrane Central Register of Controlled Trials was conducted. We included all observational studies that reported the prevalence of SDB in patients with chronic pain on long-term opioid therapy (≥3 months). The primary outcome was the pooled prevalence of SDB in opioid users with chronic pain (pain:opioids group) and a comparison with pain:no opioids and no pain:no opioids groups. The meta-analysis was performed using a random-effects model. RESULTS: After screening 1,404 studies, 9 studies with 3,791 patients were included in the meta-analysis (pain:opioids group, n = 3181 [84%]; pain:no opioids group, n = 359 [9.4%]; no pain:no opioids group, n = 251 [6.6%]). The pooled prevalence of SDB in the pain:opioids, pain:no opioids, and no pain:no opioids groups were 91%, 83%, and 72% in sleep clinics and 63%, 10%, and 75% in pain clinics, respectively. Furthermore, in the pain: opioids group, central sleep apnea prevalence in sleep and pain clinics was 33% and 20%, respectively. CONCLUSIONS: The pooled prevalence of SDB in patients with chronic pain on opioid therapy is not significantly different compared with pain:no opioids and no pain:no opioids groups and varies considerably depending on the site of patient recruitment (ie, sleep vs pain clinics). The prevalence of central sleep apnea is high in sleep and pain clinics in the pain:opioids group. Clinical Trial Registration: Registry: PROSPERO: International prospective register of systematic reviews; Name: Prevalence of sleep disordered breathing, hypoxemia and hypercapnia in patients on oral opioid therapy for chronic pain management; URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018103298; Identifier: CRD42018103298.

Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure.

AIMS: The ability of the right ventricle (RV) to adapt to increased afterload is the major determinant of survival in patients with pulmonary hypertension (PH). In this study, we explored the effect of genetic background on RV adaptation and survival in a rat model of severe pulmonary arterial hypertension (PAH). METHODS AND RESULTS: PH was induced by a single injection of SU5416 (SU) in age-matched Sprague Dawley (SD) or Fischer rats, followed by a 3-week exposure to chronic hypoxia (SUHx). SD and Fischer rats exhibited similar elevations in RV systolic pressure, number of occlusive pulmonary vascular lesions, and RV hypertrophy (RV/LV+S) in response to SUHx. However, no Fischer rats survived beyond 7 weeks compared with complete survival for SD rats. This high early mortality of Fischer rats was associated with significantly greater RV dilatation and reduced ejection fraction, cardiac output, and exercise capacity at 4 weeks post-SU. Moreover, microarray analysis revealed that over 300 genes were uniquely regulated in the RV in the severe PAH model in the Fischer compared with SD rats, mainly related to angiogenesis and vascular homoeostasis, fatty acid metabolism, and innate immunity. A focused polymerase chain reaction array confirmed down-regulation of angiogenic genes in the Fischer compared with SD RV. Furthermore, Fischer rats demonstrated significantly lower RV capillary density compared with SD rats in response to SUHx. CONCLUSION: Fischer rats are prone to develop RV failure in response to increased afterload. Moreover, the high mortality in the SUHx model of severe PAH was caused by a failure of RV adaptation associated with lack of adequate microvascular angiogenesis, together with metabolic and immunological responses in the hypertrophied RV.

Sleep Study and Oximetry Parameters for Predicting Postoperative Complications in Patients With OSA.

In the surgical setting, OSA is associated with an increased risk of postoperative complications. At present, risk stratification using OSA-associated parameters derived from polysomnography (PSG) or overnight oximetry to predict postoperative complications has not been established. The objective of this narrative review is to evaluate the literature to determine the association between parameters extracted from in-laboratory PSG, portable PSG, or overnight oximetry and postoperative adverse events. We obtained pertinent articles from Ovid MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, and Embase (2008 to December 2017). The search included studies with adult patients undergoing surgery who had OSA diagnosed with portable PSG, in-laboratory PSG, or overnight oximetry that reported on specific sleep parameters and at least one adverse outcome. The search was restricted to English-language articles. The search yielded 1,810 articles, of which 21 were included in the review. Preoperative apnea-hypopnea index (AHI) and measurements of nocturnal hypoxemia such as oxygen desaturation index (ODI), cumulative sleep time percentage with oxyhemoglobin saturation (Spo2) < 90% (CT90), minimum Spo2, mean Spo2, and longest apnea duration were associated with postoperative complications. OSA is associated with postoperative complications in the population undergoing surgery. Clinically and statistically significant associations between AHI and postoperative adverse events exists. Complications may be more likely to occur in the category of moderate to severe OSA (AHI ≥ 15). Other parameters from PSG or overnight oximetry such as ODI, CT90, mean and minimal Spo2, and longest apnea duration can be associated with postoperative complications and may provide additional value in risk stratification and minimization.

Regenerative cell therapy for pulmonary arterial hypertension in animal models: a systematic review.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary arterial pressures leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. The objective of this systematic review was to compare the efficacy of regenerative cell therapies in preclinical models of PAH. METHODS: A systematic search strategy was developed and executed. We included preclinical animal studies using regenerative cell therapy in experimental models of PAH. Primary outcomes were right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). The secondary outcome was right ventricle/left ventricle + septum weight ratio (RV/LV+S). Pooled effect sizes were undertaken using random effects inverse variance models. Risk of bias and publication bias were assessed. RESULTS: The systematic search yielded 1285 studies, of which 44 met eligibility criteria. Treatment with regenerative cell therapy was associated with decreased RVSP (SMD - 2.10; 95% CI - 2.59 to - 1.60), mPAP (SMD - 2.16; 95% CI - 2.97 to - 1.35), and RV/LV+S (SMD - 1.31, 95% CI - 1.64 to - 0.97). Subgroup analysis demonstrated that cell modification resulted in greater reduction in RVSP. The effects on RVSP and mPAP remained statistically significant even after adjustment for publication bias. The majority of studies had an unclear risk of bias. CONCLUSIONS: Preclinical studies of regenerative cell therapy demonstrated efficacy in animal models of PAH; however, future studies should consider incorporating design elements to reduce the risk of bias. SYSTEMATIC REVIEW REGISTRATION: Suen CM, Zhai A, Lalu MM, Welsh C, Levac BM, Fergusson D, McIntyre L and Stewart DJ. Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol. Syst Rev. 2016;5:89. TRIAL REGISTRATION: CAMARADES-NC3Rs Preclinical Systematic Review & Meta-analysis Facility (SyRF). http://syrf.org.uk/protocols/ . Syst Rev 5:89, 2016.

Efficacy of treprostinil in the SU5416-hypoxia model of severe pulmonary arterial hypertension: haemodynamic benefits are not associated with improvements in arterial remodelling.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor-2 inhibitor)-chronic hypoxia (Hx) model of PAH. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were injected with SU (20 mg·kg-1 , s.c.) followed by 3 weeks of Hx (10% O2 ) to induce severe PAH. Four weeks post-SU injection, baseline right ventricular (RV) systolic pressure (RVSP) was measured, and the rats were randomized to receive vehicle or treprostinil treatment (Trep-100: 100 ng·kg-1 ·min-1 or Trep-810: 810 ng·kg-1 ·min-1 ). Following 3 weeks of treatment, haemodynamic and echocardiographic assessments were performed, and tissue samples were collected for protein expression and histological analysis. KEY RESULTS: At week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep-100; however, Trep-810 significantly reduced RVSP and RV hypertrophy. Trep-810 treatment significantly improved cardiac structure and function. Further, a short-term infusion of treprostinil in rats with established PAH at 4 weeks post-SU produced an acute, dose-dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep-810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs. CONCLUSIONS AND IMPLICATIONS: Treprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.