Right ventricle-specific therapies in acute respiratory distress syndrome: a scoping review.

OBJECTIVE: To summarize knowledge and identify gaps in evidence regarding treatment of right ventricular dysfunction (RVD) in acute respiratory distress syndrome (ARDS). DATA SOURCES: We conducted a comprehensive search of MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials. STUDY SELECTION: Studies were included if they reported effects of treatments on right ventricular function, whether or not the intent was to modify right ventricular function. DATA EXTRACTION: Data extraction was performed independently and in duplicate by two authors. Data items included the study design, patient population, type of intervention, comparison group, and RV-specific outcomes. DATA SYNTHESIS: Of 1,430 studies screened, 51 studies reporting on 1,526 patients were included. By frequency, the included studies examined the following interventions: ventilator settings (29.4%), inhaled medications (33.3%), extracorporeal life support (13.7%), intravenous or oral medications (13.7%), and prone positioning (9.8%). The majority of the studies were non-randomized experimental studies (53%), with the next most common being case reports (16%). Only 5.9% of studies were RCTs. In total, 27% of studies were conducted with the goal of modifying RV function. CONCLUSIONS: Given the prevalence of RVD in ARDS and its association with mortality, the dearth of research on this topic is concerning. This review highlights the need for prospective trials aimed at treating RV dysfunction in ARDS.

Disease-specific platelet signaling defects in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with several treatment options. Long-term mortality remains high with great heterogeneity in treatment response. Even though most of the pathology of IPAH is observed in the lung, there is systemic involvement. Platelets from patients with IPAH have characteristic metabolic shifts and defects in activation; therefore, we investigated whether they could be used to identify other disease-specific abnormalities. We used proteomics to investigate protein expression changes in platelets from patients with IPAH compared with healthy controls. Key abnormalities of nitric oxide pathway were tested in platelets from a larger cohort of unique patients with IPAH. Platelets showed abnormalities in the prostacyclin and nitric oxide pathways, which are dysregulated in IPAH and hence targets of therapy. We detected reduced expression of G protein αs and increased expression of the regulatory subunits of the cAMP-dependent protein kinase (PKA) type II isoforms, supporting an overall decrease in the activation of the prostacyclin pathway. We noted reduced levels of the soluble guanylate cyclase (sGC) subunits and increased expression of the phosphodiesterase type 5 A (PDE5A), conditions that affect the response to nitric oxide. Ensuing analysis of 38 unique patients with IPAH demonstrated considerable variation in the levels and specific activity of sGC, a finding with novel implications for personalized therapy. Platelets have some of the characteristic vasoactive signal abnormalities seen in IPAH and may provide comprehensive ex vivo mechanistic information to direct therapeutic decisions.

Cutaneous iontophoresis of vasoactive medications in patients with scleroderma-associated pulmonary arterial hypertension.

BACKGROUND: It remains unknown whether the cutaneous microvascular responses are different between patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and SSc without pulmonary hypertension (PH). METHODS: We included 59 patients with SSc between March 2013 and September 2019. We divided patients into 4 groups: (a) no PH by right heart catheterization (RHC) (n = 8), (b) no PH by noninvasive screening tests (n = 16), (c) treatment naïve PAH (n = 16), and (d) PAH under treatment (n = 19). Microvascular studies using laser Doppler flowmetry (LDF) were done immediately after RHC or at the time of an outpatient clinic visit (group b). RESULTS: The median (IQR) age was 59 (54-68) years, and 90% were females. The responses to local thermal stimulation and postocclusive reactive hyperemia, acetylcholine, and sodium nitroprusside iontophoresis were similar among groups. The microvascular response to treprostinil was more pronounced in SSc patients without PH by screening tests (% change: 340 (214-781)) compared with SSc-PAH (naïve + treatment) (Perfusion Units (PU) % change: 153 (94-255) % [p = .01]). The response to A-350619 (a soluble guanylate cyclase (sGC) activator) was significantly higher in patients with SSc without PH by screening tests (PU % change: 168 (46-1,296)) than those with SSc-PAH (PU % change: 22 (15-57) % [p = .006]). The % change in PU with A350619 was directly associated with cardiac index and stroke volume index (R: 0.36, p = .03 and 0.39, p = .02, respectively). CONCLUSIONS: Patients with SSc-PAH have a lower cutaneous microvascular response to a prostacyclin analog treprostinil and the sGC activator A-350619 when compared with patients with SSc and no evidence of PH on screening tests, presumably due to a peripheral reduction in prostacyclin receptor expression and nitric oxide bioavailability.

Platelet glycolytic metabolism correlates with hemodynamic severity in pulmonary arterial hypertension.

Group 1 pulmonary hypertension (PH), i.e., pulmonary arterial hypertension (PAH), is associated with a metabolic shift favoring glycolysis in cells comprising the lung vasculature as well as skeletal muscle and right heart. We sought to determine whether this metabolic switch is also detectable in circulating platelets from PAH patients. We used Seahorse Extracellular Flux to measure bioenergetics in platelets isolated from group 1 PH (PAH), group 2 PH, patients with dyspnea and normal pulmonary artery pressures, and healthy controls. We show that platelets from group 1 PH patients exhibit enhanced basal glycolysis and lower glycolytic reserve compared with platelets from healthy controls but do not differ from platelets of group 2 PH or dyspnea patients without PH. Although we were unable to identify a glycolytic phenotype unique to platelets from PAH patients, we found that platelet glycolytic metabolism correlated with hemodynamic severity only in group 1 PH patients, supporting the known link between PAH pathology and altered glycolytic metabolism and extending this association to ex vivo platelets. Pulmonary artery pressure and pulmonary vascular resistance in patients with group 1 PH were directly associated with basal platelet glycolysis and inversely associated with maximal and reserve glycolysis, suggesting that PAH progression reduces the capacity for glycolysis even while demanding an increase in glycolytic metabolism. Therefore, platelets may provide an easy-to-harvest, real-time window into the metabolic shift occurring in the lung vasculature and represent a useful surrogate for interrogating the glycolytic shift central to PAH pathology.

Treatment Barriers in Portopulmonary Hypertension.

Portopulmonary hypertension (PoPH) is a form of pulmonary arterial hypertension (PAH) that can develop as a complication of portal hypertension. Treatment of PoPH includes PAH-specific therapies, and in certain cases, such therapies are necessary to facilitate a successful liver transplantation. A significant number of barriers may limit the adequate treatment of patients with PoPH and explain the poorer survival of these patients when compared to patients with other types of PAH. Until recently, only one randomized controlled trial has included PoPH patients, and the majority of treatment data have been derived from relatively small observational studies. In the present article, we review some of the barriers in the treatment of patients with PoPH and implications for liver transplantation.

Inpatient Initiation of Oral Treprostinil in an Academic Medical System.

PURPOSE: Clinicians may transition patients on parenteral or inhaled prostacyclins to oral treprostinil for ease of use or to avoid adverse effects related to parenteral therapy. However, few data are available to guide these transitions in inpatients. The purpose of this analysis is to describe the inpatient initiation of oral treprostinil at an academic medical system. METHODS: This is a retrospective cohort analysis of patients newly initiated on oral treprostinil at Cleveland Clinic Heath System from 2015 to 2017. Demographic information regarding pulmonary arterial hypertension (PAH) history and previous PAH therapies were recorded. Outcomes evaluated included doses of oral treprostinil utilized, adverse effects related to therapy, and measures of clinical and functional status before and after the initiation of oral treprostinil. RESULTS: Overall, 29 patients were prescribed oral treprostinil, of which 15 patients were included in the analysis. Common reasons for initiation of oral treprostinil included disease progression (6, 40%) and patient desire (4, 25%). The median duration of transition/initiation of oral treprostinil was 4 days (range, 3-11 days). Median daily dose of oral treprostinil on day 1 of initiation was 2 mg (0.25-4 mg). By day 7, median daily dose was 15 mg (0.75-27.75 mg). Common adverse effects related to therapy were gastrointestinal (7, 47%) and headache (4, 27%). No patients required discontinuation of oral treprostinil due to adverse effects within 90 days of initiation. CONCLUSION: Inpatient initiation/transition to oral treprostinil was relatively well tolerated. Future studies should evaluate clinical outcomes surrounding the transitioning to oral treprostinil.

Is There Value in Repeating Inhaled Nitric Oxide Vasoreactivity Tests in Patients with Pulmonary Arterial Hypertension?

BACKGROUND: In patients with pulmonary arterial hypertension (PAH), it remains unknown if the response to the acute pulmonary vasoreactivity test changes over time and determines prognosis. METHODS: We included PAH patients who underwent two right heart catheterizations (RHC) with acute vasoreactivity challenge using inhaled nitric oxide (NO). The hemodynamic response was assessed by absolute or percentage change in mean pulmonary artery pressure (mPAP) or pulmonary vascular resistance (PVR). RESULTS: We included 54 patients, age 51 ± 17 years, and 44 (82%) female. The median (IQR) time between the two RHC was 24.5 months (14.8-42 months). The percentage drop in mPAP was less pronounced in the second RHC (- 8.6 ± 8.1 versus - 12.3 ± 13.8 mmHg, p = 0.02). A total of 8 (14%) patients met criteria for a positive vasodilatory test during the first RHC but only 1 during the second. Patients with increased vasoreactivity at second RHC were more likely to receive (a) treatment with phosphodiesterase-5 inhibitors (PDE5-inh) at first RHC (56% versus 27%, p = 0.04) and (b) more PAH-specific medications by second RHC (2.3 ± 0.8 versus 1.8 ± 0.9, p = 0.03). Cox survival analysis showed that change in mPAP or PVR during vasodilatory challenge at or between the first and second RHC had no impact on survival. CONCLUSIONS: Pulmonary vascular reactivity to inhaled NO might decrease over time; however, there is great variability among patients. The use of PDE5-inh at first RHC and number of PAH-specific treatments by the second RHC were associated with an improvement in pulmonary vasoreactivity over time.

Microvascular involvement in systemic sclerosis and systemic lupus erythematosus.

Microvascular changes play central roles in the pathophysiology of SSc and SLE, and represent major causes of morbidity and mortality in these patients. Therefore, clinical tools that can assess the microvasculature are of great importance both at the time of diagnosis and follow-up of these cases. These tools include capillaroscopy, laser imaging techniques, infrared thermography, and iontophoresis. In this review, we examined the clinical manifestations and pathobiology of microvascular involvement in SSc and SLE as well as the methodologies used to evaluate the microvasculature.

Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension.

INTRODUCTION: Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival. METHODS: During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences. RESULTS: We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2-5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCO2 than PA blood. In group 1 PAH (age 58 ± 15 years, 72% females), methemoglobin in the PAW was lower than in the PA blood (0.83% ± 0.43 vs 0.95% ± 0.50, p = 0.03) and was directly associated with the degree of change in pulmonary vascular resistance (R = 0.35, p = 0.02) during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82-0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84-0.98), p = 0.003) blood was associated with adjusted survival in PAH. CONCLUSIONS: Marked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH.

Changes in main pulmonary artery diameter during follow-up have prognostic implications in pulmonary arterial hypertension.

BACKGROUND AND OBJECTIVE: A dilated pulmonary artery (PA) is a common finding in patients with pulmonary arterial hypertension (PAH). Little is known on the variations in PA size over time and whether these changes track with disease severity and/or predict long-term survival. METHODS: We included patients with PAH who had at least two computed tomography (CT) scans of the chest done on different visits. Both scans matched the use of i.v. contrast. RESULTS: Pairs of CT scans were compared in 113 PAH patients. During a median (interquartile range (IQR)) time difference between scans of 8 (IQR: 3.5-20.0) months, we noted an increase in main PA diameter of 0.5 ± 1.8 mm (mean ± SD) (P = 0.008). When CT scans were performed >12 months apart (n = 47), the main PA diameter increased or decreased by >1 mm in 40% and 13% of the patients, respectively. An increase in main PA diameter was associated with lower PA compliance, higher right ventricular (RV) systolic pressure, worse RV function and a decline in 6-min walk distance. During a median (IQR) follow-up of 33 (IQR: 4.5-47) months, 53 (46.9%) patients died. The change in PA diameter was a significant predictor of mortality (hazard ratio (HR) per mm increase: 1.33 (95% CI: 1.11-1.61), P = 0.002) when adjusted for difference in time and slice thickness between CT scans, age, gender, PAH aetiology and pulmonary vascular resistance. CONCLUSION: In PAH patients, an increase in CT-derived main PA diameter over time is associated with progression in pulmonary pressures, RV dysfunction, a decline in functional capacity and higher mortality.

Assessing the kinetics of microbubble appearance in cirrhotic patients using transthoracic saline contrast-enhanced echocardiography.

BACKGROUND: The number of cardiac cycles that need to be reviewed by echocardiography before a significant intrapulmonary shunt can be excluded remains unclear. METHODS: We retrospectively identified patients with cirrhosis who underwent technetium-99 m-labeled macroaggregated albumin scanning. The kinetics of bubble appearance after the injection of agitated saline during transthoracic echocardiograms were assessed in these patients. RESULTS: For the 64 eligible patients, the mean ± SD age was 56 ± 9 years. The median (IQR) shunt fraction by radionuclide scanning was 7.7% (2.8%-19.9%). Microbubbles were seen in the left atrium (LA) and left ventricle (LV) at a median (IQR) of 4 (2-5) and 4 (2-5) beats, respectively. The number of heart cycles before microbubbles appeared in the LA or LV was inversely associated with the nuclear scanning shunt fraction (R = -0.42, P = .001, R = -0.46, P < .001, respectively). If no microbubbles were detected by heart cycle 7, the shunt fraction was uniformly less than 3%. Patients with arterial oxygen <60 mm Hg, compared to ≥60 mm Hg, had earlier appearance of microbubbles in the left heart chambers (2.6 ± 1.9 vs 4.0 ± 2.3 beats, P = .046). CONCLUSIONS: In patients with advanced cirrhosis suspected of having hepatopulmonary syndrome, a greater shunt fraction during nuclear scanning was associated with more pronounced hypoxemia and a prompt and more intense appearance of microbubbles in the left-sided heart chambers. Patients with a shunt fraction above 3% have microbubbles in the LA or LV at some point during the first seven heart cycles.

Are transcutaneous oxygen and carbon dioxide determinations of value in pulmonary arterial hypertension?

BACKGROUND: We hypothesized that transcutaneous gas determinations of O2 and CO2 (TcPO2 and TcPCO2 ) are associated with the severity of PAH. METHODS: In this cross-sectional study, we included consecutive patients with PAH (group 1 PH; n = 34). Transcutaneous gas determinations were compared to those of age- and gender-matched healthy controls (n = 14), nongroup 1 PH (n = 19) or patients with high estimated RVSP on echocardiography but without hemodynamic evidence of PH (n = 12). RESULTS: In patients with PAH, TcPO2 , and TcPCO2 were significantly associated with PaO2 (R = 0.44, p = 0.03) and PaCO2 (R = 0.77, p < 0.001), respectively. TcPO2 /FiO2 (mean difference: -65.0 [95% CI: -121.3, -8.7]) and TcPCO2 (mean difference: -7.4 [95% CI: -11.6, -3.1]) were significantly lower in patients with PAH than healthy controls. TcPCO2 was useful in discriminating PAH patients from other individuals (AUC: 0.74 [95% CI: 0.62, 0.83]). TcPO2 /FiO2 ratio was significantly associated with mean PAP, TPG, PVR, CI, SVI, DLCO, six-minute walk distance and components of the CAMPHOR questionnaire. CONCLUSIONS: Transcutaneous pressure of CO2 was lower in patients with PAH. Transcutaneous pressure of O2 over inspired fraction of O2 ratio was inversely associated with severity of disease in patients with PAH.

Subcutaneous to intravenous prostacyclin analog transition in pulmonary hypertension.

INTRODUCTION: Prostacyclin analogs are Food and Drug Administration-approved therapies for the treatment of pulmonary arterial hypertension and can be administered by inhalational, intravenous (IV), or subcutaneous (SQ) routes. Because there are limited data to guide the transition between SQ to IV prostacyclin analogs, we describe our experience. METHODS: We performed a retrospective review of patients with pulmonary hypertension diagnosed by right heart catheterization, who underwent transition from SQ to IV prostacyclin analogs. RESULTS: We included 7 patients with pulmonary arterial hypertension and 2 with chronic thromboembolic pulmonary hypertension in this retrospective study. Median (interquartile range) age was 54 (39-63) years, and 67% were women. The reasons for the SQ to IV switch were site pain (n = 6, 67%), major surgery (n = 2, 22%), and septic shock (n = 1, 11%). SQ treprostinil was converted to IV treprostinil (n = 5, 56%) or IV epoprostenol (n = 4, 44%). When SQ treprostinil was converted to IV treprostinil, the initial mean (range) dose decreased from 84.9 (36.5-167) to 70.8 (24-114) ng·kg⁻¹·min⁻¹. When SQ treprostinil was converted to IV epoprostenol, the dose decreased from 24.5 (17.5-30) to 13.3 (9-20) ng·kg⁻¹·min⁻¹. The patient transitioned from SQ to IV treprostinil in the context of septic shock died a month after hospitalization. No deteriorations were observed in the remaining patients during the first year. CONCLUSIONS: Under careful monitoring, SQ treprostinil was transitioned to IV treprostinil or epoprostenol without complications. Dosing downadjustment was needed in some patients who were switched over from SQ to IV prostacyclin analogs.

Pharmacologic management of perioperative pulmonary hypertension.

Perioperative pulmonary hypertension can originate from an established disease or acutely develop within the surgical setting. Patients with increased pulmonary vascular resistance are consequently at greater risk for complications. Despite the various specific therapies available, the ideal therapeutic approach in this patient population is not currently clear. This article describes the basic principles of perioperative pulmonary hypertension and reviews the different classes of agents used to promote pulmonary vasodilation in the surgical setting.

Beyond the evidence: treating pulmonary hypertension in the intensive care unit.

Most patients with pulmonary arterial hypertension succumb to their disease in the ICU; however, limited evidence-based information exists to guide treatment in those that present with advanced right ventricular failure. Critical care physicians should be aware of the complexities of the treatment of patients with pulmonary arterial hypertension and should develop a strategy for their care. Current management is based on the pathophysiology of the disease and involves a multidisciplinary team supported by institutional polices directed at optimizing patient safety.

Electrocardiography at diagnosis and close to the time of death in pulmonary arterial hypertension.

BACKGROUND: Scarce information exits on the electrocardiographic (ECG) characteristics of pulmonary arterial hypertension (PAH) patients close to their death and whether observed abnormalities progress from the time of PAH diagnosis. METHODS: We analyzed the characteristics of the ECG performed at initial diagnosis, during the course of the disease and close to the time of death on consecutive PAH patients followed at our institution between June 2008 and December 2010. RESULTS: We included 50 patients with PAH (76% women) with mean (SD) age of 58 (14) years. Median heart rate (83 vs 89 bpm, P = 0.001), PR interval (167 vs 176 ms, P = 0.03), QRS duration (88 vs 90 ms, P = 0.02), R/S ratio in lead V1 (1 vs 2, P = 0.01), and QTc duration (431 vs 444 ms, P = 0.02) significantly increased from the initial to the last ECG. In addition, the frontal QRS axis rotated to the right (97 vs 112 degrees, P = 0.003) and we more commonly observed right bundle branch block (5% vs 8%, P = 0.03) and negative T waves in inferior leads (31% vs 60%, P = 0.004). No patient had normal ECG at the time of death. CONCLUSIONS: Significant changes progressively occur in a variety of ECG parameters between the time of the initial PAH diagnosis and close to death.