Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism.

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.

Cardiopulmonary exercise test to detect cardiac dysfunction from pulmonary vascular disease.

BACKGROUND: Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. METHODS: We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest. RESULTS: From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest. CONCLUSIONS: CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.

Updates in the diagnosis and management of chronic thromboembolic disease.

PURPOSE OF REVIEW: Chronic thromboembolic disease (CTED) is distinct from chronic thromboembolic pulmonary hypertension (CTEPH) and is defined by dyspnea on exertion after acute pulmonary embolism with the presence of residual perfusion defects and absence of resting pulmonary hypertension. Here, we review clinical features and diagnostic criteria for CTED and summarize treatment options. RECENT FINDINGS: The optimal management for CTED is unclear as the long-term outcomes of conservative vs. invasive treatment for this disease have not been reported. There are a few studies evaluating outcomes of pulmonary thromboendarterectomy and balloon pulmonary angioplasty (BPA) in CTED, concluding that these procedures are safe and effective in select patients. However, these trials are small nonrandomized observational studies, reporting outcomes only up to 1 year after the intervention. Conservative management of CTED with observation, pulmonary hypertension-targeted therapy, or cardiopulmonary rehabilitation has not been studied. It is unknown whether these treatments are as effective or superior to pulmonary thromboendarterectomy or BPA in CTED. SUMMARY: The management of CTED is individualized and based on symptoms and exercise limitations. Early referral of patients with CTED to a specialized CTEPH center is recommended to determine if watchful waiting, BPA, or pulmonary thromboendarterectomy is most beneficial.

Multidisciplinary Approach to Chronic Thromboembolic Pulmonary Hypertension: Role of Radiologists.

Management of chronic thromboembolic pulmonary hypertension (CTEPH) should be determined by a multidisciplinary team, ideally at a specialized CTEPH referral center. Radiologists contribute to this multidisciplinary process by helping to confirm the diagnosis of CTEPH and delineating the extent of disease, both of which help determine a treatment decision. Preoperative assessment of CTEPH usually employs multiple imaging modalities, including ventilation-perfusion (V/Q) scanning, echocardiography, CT pulmonary angiography (CTPA), and right heart catheterization with pulmonary angiography. Accurate diagnosis or exclusion of CTEPH at imaging is imperative, as this remains the only form of pulmonary hypertension that is curative with surgery. Unfortunately, CTEPH is often misdiagnosed at CTPA, which can be due to technical factors, patient-related factors, radiologist-related factors, as well as a host of disease mimics including acute pulmonary embolism, in situ thrombus, vasculitis, pulmonary artery sarcoma, and fibrosing mediastinitis. Although V/Q scanning is thought to be substantially more sensitive for CTEPH compared with CTPA, this is likely due to lack of recognition of CTEPH findings rather than a modality limitation. Preoperative evaluation for pulmonary thromboendarterectomy (PTE) includes assessment of technical operability and surgical risk stratification. While the definitive therapy for CTEPH is PTE, other minimally invasive or noninvasive therapies also lead to clinical improvements including greater survival. Complications of PTE that can be identified at postoperative imaging include infection, reperfusion edema or injury, pulmonary hemorrhage, pericardial effusion or hemopericardium, and rethrombosis. ©RSNA, 2022 Online supplemental material is available for this article.

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy.

OBJECTIVES: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN: Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING: Academic medical center in La Jolla, California. PATIENTS: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

Atrial arrhythmias after pulmonary thromboendarterectomy.

BACKGROUND AND OBJECTIVES: Atrial arrhythmias (AAs) are common after cardiac surgeries including pulmonary thromboendarterectomy (PTE). This study was done to identify patients at highest risk of developing post-PTE AA and their length of stay (LOS). METHODS: We reviewed 521 consecutive patients referred to University of California San Diego (UCSD) for PTE and examined their demographics as well as their baseline pulmonary hemodynamics to determine risk factors for AA. RESULTS: Overall, 24.2% of patients developed an AA after PTE. Patients who developed AA had a significantly longer Intensive Care Unit (ICU) LOS (median: 5 vs 3 days, P < 0.001) and postoperative LOS (median: 14 vs 9 days; P < 0.001). Patients who developed AA were more frequently male (63.2% male, P = 0.003), older (mean age 60.8 vs 50.7 years, P < 0.001), had a prior history of atrial fibrillation (80.2% of those who developed AA) and were more likely to have undergone concomitant Coronary Artery Bypass Graft (12.7% vs 6.6%, P = 0.028). Compared to those who did not develop AA, the cardiopulmonary bypass time was longer among those who developed AA (261.6 vs 253.8 minutes, P = 0.027). In a multivariate logistic regression model, the preoperative variables that predicted AA were age (odds ratio [OR], 1.058 per year, 95% confidence interval [CI]: 1.038-1.078), male sex (OR, 1.68, 95% CI: 1.06-2.64), prior AA (OR, 2.52, 95% CI: 1.23-5.15) and baseline right atrial pressure (OR, 1.039 per mm Hg, 95% CI: 1.000-1.079). While mortality rates were similar, patients who developed AA had more bleeding complications and more postoperative delirium. CONCLUSIONS: AA is common after PTE surgery. The strongest risk factors for AA after PTE included the previous history of AA, age and male sex. Development of AA was associated with longer lengths of stay and more postoperative complications.

Management Strategies for Acute Pulmonary Embolism in the ICU.

TOPIC IMPORTANCE: Acute pulmonary embolism (PE) is a common disease encountered by pulmonologists, cardiologists, and critical care physicians throughout the world. For patients with high-risk acute PE (defined by systemic hypotension) and intermediate high-risk acute PE (defined by the absence of systemic hypotension, but the presence of numerous other concerning clinical and imaging features), intensive care often is necessary. Initial management strategies should focus on optimization of right ventricle (RV) function while decisions about advanced interventions are being considered. REVIEW FINDINGS: We reviewed the existing literature of various vasoactive agents, IV fluids and diuretics, and pulmonary vasodilators in both animal models and human trials of acute PE. We also reviewed the potential complications of endotracheal intubation and positive pressure ventilation in acute PE. Finally, we reviewed the data of venoarterial extracorporeal membrane oxygenation (ECMO) use in acute PE. The above interventions are discussed in the context of the underlying pathophysiologic features of acute RV failure in acute PE with corresponding illustrations. SUMMARY: Norepinephrine is a reasonable first choice for hemodynamic support with vasopressin as an adjunct. IV loop diuretics may be useful if evidence of RV dysfunction or volume overload is present. Fluids should be given only if concern exists for hypovolemia and absence of RV dilatation. Supplemental oxygen administration should be considered even without hypoxemia. Positive pressure ventilation should be avoided if possible. venoarterial ECMO cannulation should be implemented early if ongoing deterioration occurs despite these interventions.

NT-pro-BNP is predictive of morbidity and mortality after pulmonary thromboendarterectomy and is independent of preoperative hemodynamics.

Current predictors of clinical outcomes after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are largely limited to preoperative clinical characteristics. N-terminal-pro-brain natriuretic peptide (NT-pro-BNP), a biomarker of right ventricular dysfunction, has not yet been well described as one such predictor. From 2017 to 2021, 816 patients with CTEPH referred to the University of California, San Diego for PTE were reviewed for differences in NT-pro-BNP to predict preoperative characteristics and postoperative outcomes up to 30 days post-PTE. For analysis, NT-pro-BNP was dichotomized to less than/equal to or greater than 1000 pg/mL based on the mean of the study population. Mean NT-pro-BNP was 1095.9 ±1783.4 pg/mL and median was 402.5 pg/mL (interquartile range: 119.5-1410.8). Of the 816 patients included, 250 had NT-pro-BNP > 1000 pg/mL. Those with NT-pro-BNP > 1000 pg/mL were significantly more likely to have worse preoperative functional class (III-IV) and worse preoperative hemodynamics. Patients with NT-pro-BNP > 1000 pg/mL also tended to have more postoperative complications including reperfusion pulmonary edema (22% vs. 5.1%, p < 0.001), airway hemorrhage (8.4% vs. 4.9%, p = 0.075), residual pulmonary hypertension (11.9% vs. 3.1%, p < 0.001), and 30-day mortality (4.8% vs. 1.1%, p = 0.001). Even after adjusting for confounders, patients with NT-pro-BNP > 1000 pg/mL had a 2.48 times higher odds (95% confidence interval: 1.45-4.00) of reaching a combined endpoint that included the above complications. Preoperative NT-pro-BNP > 1000 pg/mL is a strong predictor of more severe preoperative hemodynamics and identifies patients at higher risk for postoperative complications.

Evaluation of Dyspnea and Exercise Intolerance After Acute Pulmonary Embolism.

Long-term dyspnea and exercise intolerance are common clinical problems after acute pulmonary embolism. Unfortunately, no single test can distinguish among the range of potential pathologic outcomes after pulmonary embolism. We illustrate a stepwise approach to post-pulmonary embolism evaluation that uses a hierarchic series of clinically validated diagnostic tests. The algorithm is represented by the acronym SEARCH, which stands for Symptom screening, Exercise testing, Arterial perfusion, Resting echocardiography, Confirmatory chest imaging, and Hemodynamics measured by right heart catheterization. We illustrate the algorithm with a patient whom we saw in our pulmonary embolism follow-up clinic. Patients are asked at least 6 months after pulmonary embolism whether they have returned to their baseline level of respiratory comfort and exercise tolerance. Patients with dyspnea and exercise intolerance undergo noninvasive cardiopulmonary exercise testing to identify elevated ventilatory dead space ratios, decreased stroke volume augmentation with exercise, and other physiologic abnormalities during exertion. Ventilation-perfusion scanning is performed on those patients with exercise-related physiologic findings to confirm the presence of residual pulmonary arterial obstruction or to suggest alternative diagnoses. Resting echocardiography may provide evidence of pulmonary hypertension; confirmatory imaging with pulmonary angiography or CT angiography may disclose findings characteristic of chronic pulmonary artery obstruction. Finally, right heart catheterization is performed to confirm chronic thromboembolic pulmonary hypertension; if resting pulmonary hemodynamics are normal, then invasive cardiopulmonary exercise testing may disclose exercise-induced defects.

Observational cohort study to validate SEARCH, a novel hierarchical algorithm to define long-term outcomes after pulmonary embolism.

BACKGROUND: Chronic dyspnoea and exercise impairment are common after acute pulmonary embolism (PE) but are not defined and quantified sufficiently to serve as outcomes in clinical trials. The planned project will clinically validate a novel method to determine discrete, clinically meaningful diagnoses after acute PE. The method uses an algorithm entitled SEARCH, for symptom screen, exercise testing, arterial perfusion, resting echocardiography, confirmatory imaging and haemodynamic measurements. SEARCH is a stepwise algorithm that sorts patients by a hierarchical series of dichotomous tests into discreet categories of long-term outcomes after PE: asymptomatic, post-PE deconditioning, symptoms from other causes, chronic thromboembolism with ventilatory inefficiency, chronic thromboembolism with small stroke volume augmentation, chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension. METHODS: The project will test the inter-rater reliability of the SEARCH algorithm by determining whether it will yield concordant post-PE diagnoses when six independent reviewers review the same diagnostic data on 150 patients evaluated at two time points after PE. The project will also determine whether the post-PE diagnoses are stable, according to the SEARCH algorithm, between the first evaluation and the subsequent one 6 months later. IMPLICATIONS: Validation of the SEARCH algorithm would offer clinicians a straightforward method to diagnose post-PE conditions that are rarely distinguished clinically. Their categorisation and definition will allow post-PE conditions to be used as endpoints in clinical trials of acute PE treatment. TRIAL REGISTRATION NUMBER: NCT05568927.

Airway Hemorrhage Complicating Pulmonary Thromboendarterectomy: Risk Factors and Outcomes.

BACKGROUND: Airway hemorrhage is a known complication of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension. Predisposing factors for postoperative airway hemorrhage have not been well described. The aims of this study were to determine the incidence and outcomes of airway hemorrhage after PTE and to identify potential risk factors. METHODS: This was a retrospective chart review of subjects undergoing PTE between 2015 and 2019. Postoperative airway hemorrhage was defined as significant endobronchial bleeding requiring withholding anticoagulation, bronchial blocker placement, and/or extracorporeal membrane oxygenation (ECMO). RESULTS: Of 877 subjects who underwent PTE, 58 subjects (6.6%) developed postoperative airway hemorrhage. Subjects with hemorrhage were more likely to be women (60% vs 45%, P = .03), to be older (57.8 vs 54.0 years, P = .04), and to have a higher incidence of preoperative hemoptysis (19.0% vs 7.6%, P = .006) compared with control subjects (subjects without airway hemorrhage). Those with hemorrhage had significantly higher preoperative right atrial pressure (P = .002) and pulmonary vascular resistance (P < .001) and a higher incidence of residual pulmonary hypertension (P = .005). Airway hemorrhage management included ECMO with bronchial blocker (n = 2), bronchial blocker without ECMO (n = 26), or withholding anticoagulation alone until bleeding subsided (n = 30). Mortality was significantly higher in those with airway hemorrhage compared with control subjects (13.8% vs 1.2%, P < .001). CONCLUSIONS: The incidence of postoperative airway hemorrhage is low but associated with significant mortality. Older age, female sex, preoperative hemoptysis, and worse preoperative pulmonary hypertension were associated with an increased risk of developing postoperative airway hemorrhage.

Repeat pulmonary thromboendarterectomy outcomes: A 15-year single-center retrospective review.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension is potentially curable via pulmonary thromboendarterectomy. A minority of patients experience recurrence of their symptoms and are eligible for repeat pulmonary thromboendarterectomy. However, little data exist regarding risk factors and outcomes for this patient population. METHODS: We performed a retrospective review of the University of California San Diego chronic thromboembolic pulmonary hypertension quality improvement database, including all patients who underwent pulmonary thromboendarterectomy from December 2005 to December 2020. Of the 2019 cases performed during this period, 46 were repeat pulmonary thromboendarterectomy procedures. Demographics, preoperative and postoperative hemodynamics, and surgical complications were compared between the repeat pulmonary thromboendarterectomy group and 1008 first pulmonary thromboendarterectomy group. RESULTS: Repeat pulmonary thromboendarterectomy recipients were more likely to be younger, to have an identified hypercoagulable state, and to have higher preoperative right atrial pressure. Etiologies of recurrent disease include incomplete initial endarterectomy, discontinuation of anticoagulation (noncompliance or for medical reasons), and anticoagulation treatment failure. Patients who received repeat pulmonary thromboendarterectomy had significant hemodynamic improvement, but less pronounced compared with patients who received first pulmonary thromboendarterectomy. Repeat pulmonary thromboendarterectomy was associated with an increased risk of postoperative bleeding, reperfusion lung injury, residual pulmonary hypertension, and increased ventilator, intensive care unit, and hospital days. However, hospital mortality was similar between the groups (2.2% vs 1.9%). CONCLUSIONS: This is the largest reported series of repeat pulmonary thromboendarterectomy surgery. Despite an increase in postoperative complications, this study demonstrates that repeat pulmonary thromboendarterectomy surgery can result in significant hemodynamic improvement with acceptable surgical mortality in an experienced center.

Distal vessel pulmonary thromboendarterectomy: Results from a single institution.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is primarily managed by pulmonary thromboendarterectomy (PTE). As advanced surgical techniques permit resection at the segmental and subsegmental level, PTE can now be curative for CTEPH mostly involving the distal pulmonary arteries. METHODS: Between January 2017 and June 2021, consecutive patients undergoing PTE were categorized according to the most proximal level of chronic thrombus resection: Level I (main pulmonary artery), Level II (lobar), Level III (segmental) and Level IV (subsegmental). Proximal disease patients (any Level I or II) were compared to distal disease (Level III or IV bilaterally) patients. Demographics, medical history, preoperative pulmonary hemodynamics, and immediate postoperative outcomes were obtained for each group. RESULTS: During the study period, 794 patients underwent PTE, 563 with proximal disease and 231 with distal disease. Patients with distal disease more frequently had a history of an indwelling intravenous device, splenectomy, upper extremity thrombosis or use thyroid replacement and less often had prior lower extremity thrombosis or hypercoagulable state. Despite more use of PAH-targeted medications in the distal disease group (63.2% vs 50.1%, p < 0.001), preoperative hemodynamics were similar. Both patient groups exhibited significant improvements in pulmonary hemodynamics postoperatively with comparable in-hospital mortality rates. Compared to proximal disease, a lower percentage of patients with distal disease showed residual pulmonary hypertension (3.1% vs 6.9%, p = 0.039) and airway hemorrhage (3.0% vs 6.6%, p = 0.047) postoperatively. CONCLUSIONS: Thromboendarterectomy for distal (segmental and subsegmental) CTEPH is technically feasible and may result in favorable pulmonary hemodynamic outcomes, without increased mortality or morbidity.

Iron deficiency and pulmonary arterial hypertension.

The purpose of this review article is to provide a comprehensive review of iron deficiency in the setting of pulmonary arterial hypertension (PAH) and to evaluate the utility of iron supplementation in PAH. Iron deficiency is present in 33%-46% of patients with PAH and has been associated with reduced exercise capacity, compromised oxygen handling, deterioration of right ventricular function, and even mortality. Iron homeostasis and the pathophysiology of PAH are highly intertwined, which has inspired the use of iron supplementation in patients with iron deficiency and PAH. A literature search was performed to identify all available evidence on iron supplementation for PAH. Limited evidence has suggested poor oral bioavailability of oral iron dosed three times a day, but newer formulations such as ferrous maltol may provide better absorption and clinical benefit, especially when dosed less frequently, such as every other day. Intravenous (IV) iron has been shown in observational studies to improve outcomes, but the single randomized control trial in patients without anemia has failed to show benefits in any measure of exercise tolerance. Larger randomized control studies on oral iron with good bioavailability or IV iron in patients with anemia are warranted to explore the potential utility of iron supplementation in patients with PAH.

Direct oral anticoagulants in patients with chronic thromboembolic pulmonary hypertension and the presence of recent thrombus during pulmonary endarterectomy.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong anticoagulant therapy. The safety and efficacy of direct oral anticoagulant (DOAC) in the chronic and transitional management of CTEPH has not been investigated. We performed a retrospective analysis of 405 consecutive pulmonary endarterectomy (PEA) cases at the University of California, San Diego, from July 2015 through July 2017. PEA specimen was reviewed for the presence of acute or subacute thrombotic material distinct from the expected chronic disease removed at the time of PEA by two investigators blinded to the patient information. Of 405 PEA cases, 166 patients (41.0%) were anticoagulated with one of three available DOACs; 239 (59.0%) presented on either oral vitamin-K antagonist or chronic injectable therapy. There were no significant differences in baseline characteristics between DOAC and non-DOAC groups. Evidence of recent thrombus was observed in 22 (13.3%) in the DOAC group versus 16 (6.7%) within the non-DOAC group. The odds ratio of DOACs usage and evidence of recent thrombus was 2.34 (95% confidence interval: 1.1-5.0, p = 0.03) after adjusting for age, gender, race, body mass index, and history of antiphospholipid antibody syndrome. CTEPH patients referred for PEA while on DOAC therapy were twice as likely to have associated acute or subacute thrombi present at the time of surgery compared with those on more traditional, non-DOAC anticoagulant therapies. This raises questions of the safety and efficacy of DOACs in the chronic management of CTEPH.

Outcomes of cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.

Over the past 20 years, despite significant advancements in pulmonary arterial hypertension (PAH) medical therapy, many patients require admission to the hospital and are at risk for in-hospital cardiac arrest (IHCA). Prior data found poor survival in PAH patients after cardiac arrest. The purpose of this study was to explore post-IHCA outcomes in PAH patients receiving advanced medical therapies. This is a single-center retrospective study of PAH patients who underwent cardiopulmonary resuscitation for IHCA between July 2005 and May 2021. Patients were identified through an internal cardiac arrest database. Twenty six patients were included. Half of the cohort had idiopathic PAH, with 54% of patients on combination therapy, 27% on monotherapy, and 19% of patients on no therapy. Mean right atrial pressure, mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 13 ± 6 mmHg, 57 ± 13 mmHg, 2.0 ± 0.7 L/min/m2, and 14.5 ± 7.6 Wood units, respectively. Most common etiology of cardiac arrest was circulatory collapse. Initial arrest rhythm in all but one patient was pulseless electrical activity. Six patients (23%) achieved return of spontaneous circulation (ROSC) and one patient (4%) survived to hospital discharge. Rates of ROSC and survival to discharge after IHCA are poor in patients with PAH. Even patients with mild hemodynamics had low likelihood of survival. In patients who are lung transplant candidates, there should be early consideration of extracorporeal support before cardiac arrest.

Drug-Drug Interactions in the Management of Patients With Pulmonary Arterial Hypertension.

The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors.