Magnitude and implications of spontaneous hemodynamic variability in primary pulmonary hypertension

The pulmonary artery (PA) pressure and pulmonary resistance at rest have been noted to vary spontaneously in patients with primary pulmonary hypertension. To evaluate this variation, in 12 patients (8 women, 4 men, aged 43 +/- 13 years), hourly measurements were made for 6 consecutive hours of heart rate, systemic and PA pressures, cardiac output, systemic and pulmonary resistance. After these baseline measurements the patients were tested with hydralazine and nifedipine therapy. Spontaneous variability in pulmonary pressures and resistances occurred in each patient, with the amount of variation (coefficient of variation) in PA pressure averaging 8% and in total pulmonary resistance 13% over the 6 hours. The patients with the most variability in mean PA pressure also had the most variability in cardiac output (r = 0.69, P = 0.02). Variability also correlated with the severity of the disease, as the patients with the highest total pulmonary resistances also had the most variation for that factor (r = 0.91, p < 0.01). The amount of variability did not correlate, however, with the acute response to either hydralazine or nifedipine administration. Based on the average coefficients of variation in these 12 patients, estimates were obtained of the percent change needed for an observed change to be attributed to a drug effect with 95% confidence. From these estimates, it was projected that for a single patient, a mean change in pulmonary resistance of 36% or a mean change in PA pressure of 22% would be required in order to attribute the changes to a drug effect. Thus, spontaneous hemodynamic variability is a common phenomenon in patients with primary pulmonary hypertension and may account for substantial changes in PA pressure and pulmonary resistance at rest.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25855/1/0000418.pd

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Unexpected pulmonary mechanics during positive pressure mechanical ventilation in fibrotic lung disease with concomitant flail chest

Understanding of pulmonary mechanics is essential to understanding mechanical ventilation. Typically, clinicians are mindful of peak and plateau pressures displayed on the ventilator and lung compliance, which is decreased in lung disease such as idiopathic pulmonary fibrosis (IPF). Decreased lung compliance leads to elevated peak and plateau pressures. We present a patient with IPF undergoing mechanical ventilation after cardiac arrest. Despite low lung compliance, he had normal peak and plateau pressures due to the presence of flail chest and increased chest wall compliance. This case highlights the role chest wall compliance plays in total respiratory system compliance and pulmonary mechanics

Utility of the ROX Index in Predicting Intubation for Patients With COVID-19–Related Hypoxemic Respiratory Failure Receiving High-Flow Nasal Therapy: Retrospective Cohort Study

BackgroundThe use of high-flow nasal therapy (HFNT) to treat COVID-19 pneumonia has been greatly debated around the world due to concerns about increased health care worker transmission and delays in invasive mechanical ventilation (IMV). Herein, we analyzed the utility of the noninvasive ROX (ratio of oxygen saturation) index to predict the need for and timing of IMV. ObjectiveThis study aimed to assess whether the ROX index can be a useful score to predict intubation and IMV in patients receiving HFNT as treatment for COVID-19–related hypoxemic respiratory failure. MethodsThis is a retrospective cohort analysis of 129 consecutive patients with COVID-19 admitted to Temple University Hospital in Philadelphia, PA, from March 10, 2020, to May 17, 2020. This is a single-center study conducted in designated COVID-19 units (intensive care unit and other wards) at Temple University Hospital. Patients with moderate and severe hypoxemic respiratory failure treated with HFNT were included in the study. HFNT patients were divided into two groups: HFNT only and intubation (ie, patients who progressed from HFNT to IMV). The primary outcome was the value of the ROX index in predicting the need for IMV. Secondary outcomes were mortality, rate of intubation, length of stay, and rate of nosocomial infections in a cohort treated initially with HFNT. ResultsOf the 837 patients with COVID-19, 129 met the inclusion criteria. The mean age was 60.8 (SD 13.6) years, mean BMI was 32.6 (SD 8) kg/m², 58 (45%) were female, 72 (55.8%) were African American, 40 (31%) were Hispanic, and 48 (37.2%) were nonsmokers. The mean time to intubation was 2.5 (SD 3.3) days. An ROX index value of less than 5 at HFNT initiation was suggestive of progression to IMV (odds ratio [OR] 2.137, P=.052). Any further decrease in ROX index value after HFNT initiation was predictive of intubation (OR 14.67, P<.001). Mortality was 11.2% (n=10) in the HFNT-only group versus 47.5% (n=19) in the intubation group (P<.001). Mortality and need for pulmonary vasodilators were higher in the intubation group. ConclusionsThe ROX index helps decide which patients need IMV and may limit eventual morbidity and mortality associated with the progression to IMV