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Importance - Endotracheal intubation and mechanical ventilation are life-saving treatments for acute respiratory failure but are complicated by significant rates of dyspnea and dysphonia after extubation. Unilateral vocal fold immobility (UVFI) after extubation can alter respiration and phonation, but its incidence, risk factors, and pathophysiology remain unclear.
Objectives - To determine the incidence of UVFI after prolonged (>12 hours) mechanical ventilation in a medical intensive care unit and investigate associated clinical risk factors for UVFI after prolonged mechanical ventilation.
Design, Setting, and Participants - This subgroup analysis of a prospective cohort study was conducted in a single-center medical intensive care unit from August 17, 2017, through May 31, 2018, among 100 consecutive adult patients who were intubated for more than 12 hours. Patients were identified within 36 hours of extubation and recruited for study enrollment. Those with an established tracheostomy prior to mechanical ventilation, known laryngeal or tracheal pathologic characteristics, or a history of head and neck radiotherapy were excluded.
Exposure - Invasive mechanical ventilation via an endotracheal tube.
Main Outcomes and Measures - The incidence of UVFI as determined by flexible nasolaryngoscopy.
Results - One hundred patients (62 men [62%]; median age, 58.5 years [range, 19.0-87.0 years]) underwent endoscopic evaluation after extubation. Seven patients had UVFI, of which 6 cases (86%) were left sided. Patients with hypotension while intubated (odds ratio [OR], 10.8; 95% CI, 1.6 to ∞), patients requiring vasopressors while intubated (OR, 16.7; 95% CI, 2.4 to ∞), and patients with a preadmission diagnosis of peripheral vascular disease (OR, 6.2; 95% CI, 1.2-31.9) or coronary artery disease (OR, 5.1; 95% CI, 1.0-25.5) were more likely to develop UVFI.
Conclusions and Relevance - Unilateral vocal fold immobility occurred in 7 of 100 patients in the medical intensive care unit who were intubated for more than 12 hours. Unilateral vocal fold immobility was associated with inpatient hypotension and preadmission vascular disease, suggesting that ischemia of the recurrent laryngeal nerve may play a role in disease pathogenesis.

Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial HO in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg·day), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial HO in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases.

BACKGROUND - Orthostatic hypotension causes ≈80 000 hospitalizations per year in the United States. Treatments for orthostatic hypotension include fludrocortisone, a mineralocorticoid analog that promotes sodium reabsorption; and midodrine, an α-1 adrenergic agonist that is a direct vasoconstrictor. Although both medications are used to treat orthostatic hypotension, few studies have compared their relative safety.
METHODS AND RESULTS - We compared incidence rates of hospitalizations for all causes, and for congestive heart failure between users of fludrocortisone and users of midodrine in a retrospective cohort study of Tennessee Medicaid adult enrollees (1995-2009). Adjusted incidence rate ratios were calculated using negative binomial regression models. Subgroup analyses based on history of congestive heart failure were conducted. We studied 1324 patients initiating fludrocortisone and 797 patients initiating midodrine. Compared with fludrocortisone users, midodrine users had higher prevalence of cardiovascular conditions. Incidence rates of all-cause hospitalizations for fludrocortisone and midodrine users were 1489 and 1330 per 1000 person-years, respectively (adjusted incidence-rate ratio 1.20, 95% confidence interval, 1.02-1.40). The respective rates of heart failure-related hospitalization were 76 and 84 per 1000 person-years (adjusted incidence-rate ratio: 1.33, 95% confidence interval, 0.79-2.56). Among patients with a history of congestive heart failure, the rates of all-cause hospitalization for fludrocortisone and midodrine were 2448 and 1820 per 1000 person-years (adjusted incidence-rate ratio: 1.42, 95% confidence interval, 1.07-1.90), and the respective rates of heart failure exacerbation-related hospitalizations were 297 and 263 per 1000 person-years (adjusted incidence-rate ratio: 1.48, 95% confidence interval, 0.69-3.16).
CONCLUSIONS - Compared with users of midodrine, users of fludrocortisone had higher rates of all-cause hospitalizations, especially among patients with congestive heart failure.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

OBJECTIVES - Catatonia, a condition characterized by motor, behavioral, and emotional changes, can occur during critical illness and appear as clinically similar to delirium, yet its management differs from delirium. Traditional criteria for medical catatonia preclude its diagnosis in delirium. Our objective in this investigation was to understand the overlap and relationship between delirium and catatonia in ICU patients and determine diagnostic thresholds for catatonia.
DESIGN - Convenience cohort, nested within two ongoing randomized trials.
SETTING - Single academic medical center in Nashville, TN.
PATIENTS - We enrolled 136 critically ill patients on mechanical ventilation and/or vasopressors, randomized to two usual care sedation regimens.
MEASUREMENTS AND MAIN RESULTS - Patients were assessed for delirium and catatonia by independent and masked personnel using Confusion Assessment Method for the ICU and the Bush Francis Catatonia Rating Scale mapped to Diagnostic Statistical Manual 5 criterion A for catatonia. Of 136 patients, 58 patients (43%) had only delirium, four (3%) had only catatonia, 42 (31%) had both, and 32 (24%) had neither. In a logistic regression model, more catatonia signs were associated with greater odds of having delirium. For example, patient assessments with greater than or equal to three Diagnostic Statistical Manual 5 symptoms (75th percentile) had, on average, 27.8 times the odds (interquartile range, 12.7-60.6) of having delirium compared with patient assessments with zero Diagnostic Statistical Manual 5 criteria (25th percentile) present (p < 0.001). A cut-off of greater than or equal to 4 Bush Francis Catatonia Screening Instrument items was both sensitive (91%; 95% CI, 82.9-95.3) and specific (91%; 95% CI, 87.6-92.9) for Diagnostic Statistical Manual 5 catatonia.
CONCLUSIONS - Given that about one in three patients had both catatonia and delirium, these data prompt reconsideration of Diagnostic Statistical Manual 5 criteria for "Catatonic Disorder Due to Another Medical Condition" that preclude diagnosing catatonia in the presence of delirium.

UNLABELLED - Splanchnic venous pooling is a major hemodynamic determinant of orthostatic hypotension, but is not specifically targeted by pressor agents, the mainstay of treatment. We developed an automated inflatable abdominal binder that provides sustained servo-controlled venous compression (40 mm Hg) and can be activated only on standing. We tested the efficacy of this device against placebo and compared it to midodrine in 19 autonomic failure patients randomized to receive either placebo, midodrine (2.5-10 mg), or placebo combined with binder on separate days in a single-blind, crossover study. Systolic blood pressure (SBP) was measured seated and standing before and 1-hour post medication; the binder was inflated immediately before standing. Only midodrine increased seated SBP (31±5 versus 9±4 placebo and 7±5 binder, P=0.003), whereas orthostatic tolerance (defined as area under the curve of upright SBP [AUCSBP]) improved similarly with binder and midodrine (AUCSBP, 195±35 and 197±41 versus 19±38 mm Hg×minute for placebo; P=0.003). Orthostatic symptom burden decreased with the binder (from 21.9±3.6 to 16.3±3.1, P=0.032) and midodrine (from 25.6±3.4 to 14.2±3.3, P<0.001), but not with placebo (from 19.6±3.5 to 20.1±3.3, P=0.756). We also compared the combination of midodrine and binder with midodrine alone. The combination produced a greater increase in orthostatic tolerance (AUCSBP, 326±65 versus 140±53 mm Hg×minute for midodrine alone; P=0.028, n=21) and decreased orthostatic symptoms (from 21.8±3.2 to 12.9±2.9, P<0.001). In conclusion, servo-controlled abdominal venous compression with an automated inflatable binder is as effective as midodrine, the standard of care, in the management of orthostatic hypotension. Combining both therapies produces greater improvement in orthostatic tolerance.
CLINICAL TRIAL REGISTRATION - URL: https://www.clinicaltrials.gov. Unique identifier: NCT00223691.
© 2016 American Heart Association, Inc.

Traditional methods of intraoperative human saphenous vein preparation for use as bypass grafts can be deleterious to the conduit. The purpose of this study was to characterize acute graft preparation injury, and to mitigate this harm via an improved preparation technique. Porcine saphenous veins were surgically harvested (unprepared controls, UnP) and prepared using traditional (TraP) and improved preparations (ImP). The TraP used unregulated radial distension, marking with a surgical skin marker and preservation in heparinized normal saline. ImP used pressure-regulated distension, brilliant blue FCF-based pen marking and preservation in heparinized Plasma-Lyte A. Rings from each preparation were suspended in a muscle bath for characterization of physiologic responses to vasoactive agents and viscoelasticity. Cellular viability was assessed using the methyl thiazolyl tetrazolium (MTT) assay and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay for apoptosis. Contractile responses to potassium chloride (110 mM) and phenylephrine (10 µM), and endothelial-dependent and independent vasodilatory responses to carbachol (0.5 µM) and sodium nitroprusside (1 µM), respectively, were decreased in TraP tissues compared to both UnP and ImP tissues (p ⩽ 0.05). TraP tissues demonstrated diminished viscoelasticity relative to UnP and ImP tissues (p ⩽ 0.05), and reduced cellular viability relative to UnP control (p ⩽ 0.01) by the MTT assay. On the TUNEL assay, TraP tissues demonstrated a greater degree of apoptosis relative to UnP and ImP tissues (p ⩽ 0.01). In conclusion, an improved preparation technique prevents vascular graft smooth muscle and endothelial injury observed in tissues prepared using a traditional approach.
© The Author(s) 2016.

BACKGROUND - Predicting the need for intensive care among adults with community-acquired pneumonia (CAP) remains challenging.
METHODS - Using a multicenter prospective cohort study of adults hospitalized with CAP, we evaluated the association of serum procalcitonin (PCT) concentration at hospital presentation with the need for invasive respiratory or vasopressor support (IRVS), or both, within 72 h. Logistic regression was used to model this association, with results reported as the estimated risk of IRVS for a given PCT concentration. We also assessed whether the addition of PCT changed the performance of established pneumonia severity scores, including the pneumonia severity index and the American Thoracic Society minor criteria, for prediction of IRVS.
RESULTS - Of 1,770 enrolled patients, 115 required IRVS (6.5%). Using the logistic regression model, PCT concentration had a strong association with IRVS risk. Undetectable PCT (< 0.05 ng/mL) was associated with a 4% (95% CI, 3.1%-5.1%) risk of IRVS. For concentrations < 10 ng/mL, PCT had an approximate linear association with IRVS risk: for each 1 ng/mL increase in PCT, there was a 1% to 2% absolute increase in the risk of IRVS. With a PCT concentration of 10 ng/mL, the risk of IRVS was 22.4% (95% CI, 16.3%-30.1%) and remained relatively constant for all concentrations > 10 ng/mL. When added to each pneumonia severity score, PCT contributed significant additional risk information for the prediction of IRVS.
CONCLUSIONS - Serum PCT concentration was strongly associated with the risk of requiring IRVS among adults hospitalized with CAP and is potentially useful for guiding decisions about ICU admission.
Copyright © 2016 American College of Chest Physicians. All rights reserved.

BACKGROUND - We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).
METHODS - Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.
RESULTS - Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05).
CONCLUSION - The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

RATIONALE - Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.
OBJECTIVE - Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.
METHODS AND RESULTS - Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.
CONCLUSIONS - Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.