Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings.

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p < 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145-0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation.

Validation of epistaxis severity score for hereditary hemorrhagic telangiectasia in Japan.

OBJECTIVE: This study aimed to assess the health-related QoL (HR-QoL) of patients with hereditary hemorrhagic telangiectasia (HHT), with emphasis on the role/social aspects, and validate the Japanese version of the epistaxis severity score (ESS) in these patients. METHODS: The Japanese version of the ESS was created through forward and reverse translation, and consultation with the original author. A validation analysis was performed by comparing ESS severity with the invasiveness of previous treatments for epistaxis and assessing the correlation between the ESS and HR-QoL. Medical history forms, ESS questionnaires, and the Medical Outcomes Study Short Form 36 (SF-36) were distributed to participants with HHT in August 2020. The relation between the ESS and summary scores of SF-36 was assessed by performing analysis of variance and Spearman's correlation. RESULTS: In total, 73 participants were included in this study. The average ESS was 5.02; there were mild (32.9%), moderate (45.2%), and severe (21.9%) epistaxis groups. Patients with higher ESS received a significantly more invasive treatment (Fisher's exact test, p < 0.05). The ESS was also negatively correlated with the physical component score (PCS) (r = -0.489, p < 0.001). Comorbid liver and gastrointestinal arteriovenous malformations significantly reduced the PCS (p < 0.05). Multiple regression analysis revealed that the ESS was a significant variable (p < 0.01). The role/social component score was significantly lower in the severe ESS group than in the mild or moderate group. CONCLUSION: The Japanese version of the ESS was considered valid and may be useful as an outcome measure of future HHT-associated epistaxis trials in Japan.

Closure of a bronchopleural fistula complicating cryoprobe biopsy of the lung.

Cryoprobe biopsies are routinely performed by the interventional pulmonologist. Diagnostic yields are larger, with complication rates that are equal to or lower than that of traditional forceps biopsies. We will specifically evaluate one instance where a cryoprobe biopsy led to an alveolo-pleural fistula that did not resolve with simple tube thoracostomy. An endobronchial valve was placed and successfully resolved the pneumothorax and persistent air leak.

Cystic Fibrosis Foundation Pulmonary Guidelines. Use of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy in Patients with Cystic Fibrosis.

RATIONALE: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications. OBJECTIVE: Develop evidence-based guidelines for CFTR modulator therapy in patients with CF. METHODS: A multidisciplinary committee of CF caregivers and patient representatives was assembled. A methodologist, an epidemiologist, a medical librarian, and a biostatistician were recruited to assist with the literature search, evidence grading, and generation of recommendations. The committee developed clinical questions using the Patient-Intervention-Comparison-Outcome format. A systematic review was conducted to find relevant publications. The evidence was then evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, and recommendations were made based on this analysis. RESULTS: For adults and children aged 6 years and older with CF due to gating mutations other than G551D or R117H, the guideline panel made a conditional recommendation for treatment with IVA. For those with the R117H mutation, the guideline panel made a conditional recommendation for treatment with IVA for 1) adults aged 18 years or older, and 2) children aged 6-17 years with a forced expiratory volume in 1 second (FEV1) less than 90% predicted. For those with the R117H mutation, the guideline panel made a conditional recommendation against treatment with IVA for 1) children aged 12-17 years with an FEV1 greater than 90% predicted, and 2) children less than 6 years of age. Among those with two copies of F508del, the guideline panel made a strong recommendation for treatment with IVA/LUM for adults and children aged 12 years and older with an FEV1 less than 90% predicted; and made a conditional recommendation for treatment with IVA/LUM for 1) adults and children aged 12 years or older with an FEV1 greater than 90% predicted, and 2) children aged 6-11 years. CONCLUSIONS: Using the GRADE approach, we have made recommendations for the use of CFTR modulators in patients with CF. These recommendations will be of help to CF clinicians, patients, and their families in guiding decisions regarding use of these medications.

Nosebleeds in hereditary hemorrhagic telangiectasia: Development of a patient-completed daily eDiary.

OBJECTIVE: A prospective, qualitative study was conducted to develop a patient-reported outcome measure (PROM) for daily administration via electronic diary (eDiary) to assess the severity of nosebleeds in patients with hereditary hemorrhagic telangiectasia (HHT), in accordance with Food and Drug Administration (FDA) PROM guidance criteria. METHODS: Three expert clinicians who treat patients with HHT provided input during instrument development, which comprised: 1) Peer-reviewed literature and instrument review; 2) Development of draft Nosebleed Diary items; 3a) Three rounds of qualitative interviews (two with a paper-based diary, one with an eDiary) with patients with documented severe epistaxis related to HHT, for concept elicitation and cognitive debriefing; 3b) Face validity and translatability assessment; 3c) Patient evaluation of the usability and acceptability of the eDiary device; and 4) Preparation of the final Nosebleed eDiary and conceptual framework. RESULTS: No existing instruments were identified that evaluate HHT-related nosebleed severity daily and meet FDA PROM guidance criteria. Frequency, duration, and/or speed of flow (i.e., intensity) were reported by most participants with HHT when asked to describe their nosebleed severity. The Nosebleed eDiary was refined based on 17 patient interviews, clinical expert input and the face validity and translatability assessment. The final four-item eDiary was acceptable to patients with HHT. CONCLUSION: The Nosebleed eDiary is "fit for purpose" to assess the severity of HHT-related nosebleeds, and has established face and content validity. Further adaptation may be required for use in mild or moderate HHT populations. Psychometric testing to evaluate construct validity and reliability are recommended next steps. LEVEL OF EVIDENCE: 2c "Outcomes research".

Daily spirometry in an acute exacerbation of adult cystic fibrosis patients.

To help answer the question of length of intravenous antibiotics during an acute exacerbation of cystic fibrosis (CF), we had subjects to follow daily home spirometry while on intravenous antibiotics. CF patients, 18 and older, with an acute exacerbation requiring intravenous antibiotics had a daily FEV1. The average time to a 10% increase over their initial sick FEV1 was calculated, as well as the time to a new baseline. A total of 25 subjects completed the study. Ten of the 25 subjects did not have a sustainable 10% increase in FEV1. Of the 15 subjects with a sustainable 10% increase in FEV1, it took 5.2 days (±4.5) after day 1, while a new baseline was achieved on average at 6.6 days (±4.8) after day 1. Given the wide range of time to a 10% improvement and new baseline, it is recommended there should be flexibility in length of intravenous antibiotics in CF, not by a preset number.

Retrospective analysis of the influence of 25-hydroxyvitamin D on disease progression and survival in pancreatic cancer.

BACKGROUND: Vitamin D deficiency is implicated in neoplastic processes in multiple organs, including the pancreas. While animal and human data have established a relationship between serum vitamin D (25(OH)D) and the development of pancreatic cancer, few studies have examined the effects of 25(OH)D on time to progression (TTP) and overall survival (OS) in this patient population. We hypothesize that lower baseline serum concentrations (BSC) of 25(OH)D will be associated with decreased TTP and OS. METHODS: This retrospective analysis of 1222 patients with pancreatic cancer aims to identify potential relationships between 25(OH)D and both TTP and OS, while controlling for the effects of ethnicity and body mass index (BMI). Baseline 25(OH)D was divided into quartiles defined as deficient (<20 ng/mL), insufficient (20-39 ng/mL), sufficient (40-59 ng/mL), and optimal (≥60 ng/ml). Statistical significance was declared if the two-sided p-value was ≤ 0.05. RESULTS: For the 627 subjects included for analysis, the median 25(OH)D was 27 ng/mL (range 4 to 114), 30.0 % were 25(OH)D deficient (<20 ng/mL), and 47.2 % were insufficient (20-39 ng/mL). Ethnicity (p < 0.0001) and BMI (p = 0.05) were significantly associated with (BSC)of 25(OH)D, while TTP (p = 0.39) and OS (p = 0.37) were not associated. CONCLUSION: Suboptimal vitamin D levels (<60 ng/mL) occurred in 96 % of patients analyzed. Both ethnicity and BMI were statistically significantly associated with vitamin D deficiency and insufficiency. Similar to results previously reported in the literature, this analysis did not identify a significant association between BSC of 25(OH)D and OS or TTP in patients with pancreatic cancer.

The minimal important difference of the epistaxis severity score in hereditary hemorrhagic telangiectasia.

OBJECTIVES/HYPOTHESIS: Hereditary hemorrhagic telangiectasia (HHT) is a disease of abnormal angiogenesis, causing epistaxis in over 96% of patients. The Epistaxis Severity Score (ESS) was developed as a standardized measurement of nasal symptoms among HHT patients. The minimal important difference (MID) of a disease index estimates the smallest change that a patient and clinician would identify as important. This study aims to establish the MID of the ESS in a diverse population of HHT patients. STUDY DESIGN: Retrospective cross-sectional study in patients with a diagnosis of HHT using Curacao criteria or genetic testing. METHODS: The ESS questionnaire and Medical Outcomes Study 36-Item Short Form (SF-36) were administered to participants recruited through the HHT Foundation Web site. Demographics and relevant medical histories were collected from all participants. An anchor-based method using a change of 5 in the Physical Component Summary (PCS) of the SF-36 and a distributional method were used to estimate the MID. RESULTS: A total of 604 subjects were recruited between April and August 2008. All participants reported epistaxis. An increasing ESS in the study cohort showed a significant negative correlation to the PCS (r = -0.43, P < 0.001). The MID was determined to be 0.41 via the anchor-based approach and 1.01 via the distribution-based approach, giving a mean MID of 0.71. CONCLUSION: Using both the anchor-based and distribution-based approaches, the estimated MID for the ESS in HHT is 0.71. Further implications include key metrics to help guide treatment responses in clinical care and essential information to calculate power and sample size for future clinical trials. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1029-1032, 2016.

Protocols and Hospital Mortality in Critically Ill Patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study.

OBJECTIVE: Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized ICUs have superior patient outcomes compared with less highly protocolized ICUs. DESIGN: Observational study in which participating ICUs completed a general assessment and enrolled new patients 1 day each week. PATIENTS: A total of 6,179 critically ill patients. SETTING: Fifty-nine ICUs in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was the number of ICU protocols; the primary outcome was hospital mortality. A total of 5,809 participants were followed prospectively, and 5,454 patients in 57 ICUs had complete outcome data. The median number of protocols per ICU was 19 (interquartile range, 15-21.5). In single-variable analyses, there were no differences in ICU and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in ICUs with a high versus low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p = 0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between ICUs with high versus low numbers of protocols for lung protective ventilation in acute respiratory distress syndrome (47% vs 52%; p = 0.28) and for spontaneous breathing trials (55% vs 51%; p = 0.27). CONCLUSIONS: Clinical protocols are highly prevalent in U.S. ICUs. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality.

The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease mainly characterized by epistaxis in more than 96% of patients. Recently, a validated questionnaire known as the HHT Epistaxis Severity Score (ESS) was developed. However, little is known about the relationship between epistaxis and quality of life. We hypothesize that epistaxis severity is a major factor predicting health-related quality of life (HR-QoL) in HHT patients. METHODS: This is a cross-sectional study. The ESS questionnaire and Medical Outcomes Study 36-item short form (SF-36) were administered to subjects through an Internet survey. All participants had a definitive diagnosis of HHT through Curaçao criteria or genetic testing. Demographic information, genetics, and extensive histories were also collected. Descriptive analyses were performed with calculations of means and standard deviations (SDs) for continuous variables and proportions for categorical variables. Linear regressions were then performed to assess the association between HR-QoL and ESS. RESULTS: A total of 604 subjects participated between April and August 2008. All patients reported epistaxis, 285 (47.2%) had telangiectasias, and 545 (90.2%) had a family history of HHT; 167 (27.6%) patients had mild epistaxis (ESS <4), 285 (47.2%) reported moderate epistaxis (≥4 ESS <7), and 152 (25.2%) reported severe epistaxis (ESS ≥7). Patients with severe epistaxis had lower scores for both the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of HR-QoL when compared to those with mild epistaxis (p < 0.001, p < 0.001). CONCLUSION: The ESS is a major determinant of HR-QoL and should be considered as a measurement of treatment efficacy in HHT-related epistaxis.

Cystic fibrosis and pregnancy in the modern era: a case control study.

BACKGROUND: Increasingly, women with cystic fibrosis become pregnant. Outcomes of these women need further study particularly in the setting of improved survival in CF. METHODS: We performed a case-control study of pregnant CF women including 22 matched pairs with an average follow-up of 4.5 years. Nutritional outcomes, changes in lung function, and exacerbation rates were compared. RESULTS: Matched pairs were similar in age, sweat chloride, FEV1 and FVC % predicted, BMI, and diabetes status. Change in BMI, FEV1 and FVC % predicted at the end of pregnancy and at last follow-up were similar between groups. Moreover, rates of exacerbation before, during and after pregnancy were similar. On multivariable analysis pregnancy had no effect on change in lung function over the study period. Significant predictors of decline included higher pre-pregnancy lung function and pancreatic insufficiency. CONCLUSIONS: Pregnancy does not lead to immediate or medium-term adverse effects for CF patients.

The microbiology of postobstructive pneumonia in lung cancer patients.

Recurrent pneumonias often occur in the setting of an airway obstruction and can be the presenting symptom of an undiagnosed malignancy. Little is known regarding the microbiology of these pneumonias making antibiotic therapy difficult to direct; however, the few studies available show these pneumonias to be polymicrobial. Examining the colonization patterns of at-risk populations such as patients with chronic obstructive pulmonary disease and using techniques such as ultrasound and computed tomography-guided biopsies may help in the treatment of these pneumonias. The following review is presented to highlight the current medical knowledge as well as suggest areas for future evaluation.

Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health.

RATIONALE: Cystic fibrosis (CF) is an autosomal recessive disease characterized by abnormal airways secretions, chronic endobronchial infection, and progressive airway obstruction. The use of medications to slow the progression of lung disease has led to significant improvement in survival. An evidence review of chronic medications for CF lung disease was performed in 2007 to provide guidance to clinicians in evaluating and selecting appropriate treatment for individuals with this disease. We have undertaken a new review of the literature to update the recommendations, including consideration of new medications and additional evidence on previously reviewed therapies. A multidisciplinary committee of experts in CF pulmonary care was established to review the evidence for use of chronic medications for CF lung disease and make treatment recommendations. Published evidence for chronic lung therapies was systematically reviewed and resulting treatment recommendations were graded based on the United States Preventive Services Task Force scheme. These guidelines provide up-to-date evidence of safety and efficacy of chronic treatments of CF lung disease, including the use of novel therapies that have not previously been included in CF pulmonary guidelines.

Primary synovial sarcoma of the lung with intra-cardiac extension.

Synovial sarcomas are a distinct clinical entity occurring most often in the lower extremities. They account for 10-14% of all soft tissue sarcomas. Pulmonary synovial sarcomas are quite rare and account for less than 0.5% of all intra-thoracic neoplasms. We present the first reported case of primary pulmonary synovial sarcoma with intra cardiac extension in a 53-year-old male who presented with chronic cough. Imaging revealed a large right upper lobe mass extending through the superior pulmonary veins into the left atrium. The patient underwent a right total pneumonectomy with extraction of the left atrial mass and left atrial reconstruction. Pathology and immunohistochemistry was diagnostic of primary pulmonary synovial sarcoma positive for SYT-SSX1 gene fusion transcription.

A comprehensive review of spontaneous pneumothorax complicating sarcoma.

BACKGROUND: Spontaneous pneumothorax (SPTX) is an uncommon phenomenon in the general population and is most commonly associated with prior bulbous emphysema, cystic parenchymal lung disease, and tuberculous lung disease. A rare cause of SPTX is malignant disease, either in the form of primary lung or pleural cancers, or in metastatic disease to the lungs. The purpose of this investigation was to compile patient characteristics, treatments received, and outcomes of patients with SPTX complicating sarcomatous cancer. METHODS: Case reports and series published in the medical literature were identified through a MEDLINE search and compiled to determine similarities among patient characteristics, treatments received, and outcomes. RESULTS: One hundred fifty-three cases representing 20 different sarcoma cell types were included; 126 (82.3%) had received some form of treatment prior to the development of pneumothorax, and 70 (45.7%) experienced recurrence of pneumothorax at an average of 61 (+/- 112) days. Patients had poor survival, with only seven of 81 subjects remaining alive 2 years after the initial diagnosis of SPTX. CONCLUSIONS: SPTX complicating sarcoma is associated with most cell types and is associated with increased mortality compared with patients without this complication.

An epistaxis severity score for hereditary hemorrhagic telangiectasia.

OBJECTIVES/HYPOTHESIS: Hereditary hemorrhagic telangiectasia (HHT)-related epistaxis leads to alterations in social functioning and quality of life. Although more than 95% experience epistaxis, there is considerable variability of severity. Because no standardized method exists to measure epistaxis severity, the purpose of this study was to determine factors associated with patient-reported severity to develop a severity score. STUDY DESIGN: Prospective, survey-based study. METHODS: HHT care providers and a focus group of patients were interviewed to determine epistaxis-associated factors. From this, an electronic survey was developed and administered to patients with HHT. Descriptive analyses were performed with calculations of means and medians for continuous and proportions for categorical variables. Multiple ordinal logistic and linear regression models were developed to determine risk factors for epistaxis severity. RESULTS: Nine hundred respondents from 21 countries were included. Eight hundred fifty-five (95%) subjects reported epistaxis. The mean (standard deviation) age was 52.1 (13.9) years, and 61.4% were female. Independently associated risk factors for self-reported epistaxis severity included epistaxis frequency (odds ratio [OR] 1.57), duration (OR 2.17), intensity (OR 2.45), need for transfusion (OR 2.74), anemia (OR 1.44), and aggressiveness of treatment required (OR 1.53, P < .001 for all). CONCLUSIONS: Risk factors for increasing epistaxis severity in patients with HHT include frequency, duration, and intensity of episodes; invasiveness of prior therapy required to stop epistaxis; anemia; and the need for blood transfusion. From these factors, an epistaxis severity score will be presented.

Practice patterns for maintaining airway stents deployed for malignant central airway obstruction.

Although significant experience exists in placing airway stents, and knowledge of stent-related complications is widespread, information is lacking regarding methods of surveillance and maintaining patency of these stents. The purpose of this investigation was to determine the actual practice patterns used by interventional pulmonologists for airway stent maintenance. We prospectively surveyed members of the American Association of Bronchology and Interventional Pulmonology or attendees at their annual meeting during Chest 2008. Sixty-two respondents returned the completed surveys and were included in the analysis. Practice settings included university (50%), single specialty (27%), community academic (11%), and multispecialty (11%) settings. Annual placement of stents was ≤10 (31%); 11 to 30 (45%); and >30 (24%). Considerable variability existed in both medications used for maintenance and surveillance schedules, and less than 50% protocolized postplacement management. Although stent placement is common among experienced interventional pulmonologists, half have no protocol for surveillance or maintenance. Similarly, there is no discernable consistency or standard practice pattern to monitor for or prevent stent failure. Further study is required to determine the best practices for postdeployment surveillance and maintenance of airway stents.

Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review.

Compounds derived from biologic sources, or biologicals, are increasingly utilized as therapeutic agents in malignancy. Development of anti-cancer targeted therapies from biologics is increasingly being utilized. Cetuximab, a chimeric monoclonal antibody, is one such anti-cancer targeted therapeutic that has shown efficacy in quelling the rate of patient decline in colorectal, head/neck, and non-small cell lung cancer. However, due to the relatively recent addition of biologic compounds to the therapeutic arsenal, information related to adverse reactions is less well known than those seen in traditional chemotherapeutics. Dermatologic reactions have been demonstrated as the most frequent side effect cited during cetuximab therapy for malignancy; however, other effects may lead to greater morbidity. In general, pulmonary complications of therapeutics can lead to significant morbidity and mortality. The purpose of this review is to compile the various pulmonary side effects seen in patients treated with cetuximab for various malignancies, and to compare the incidence of these adverse reactions to standard therapies.