Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study.

BACKGROUND: Acute pulmonary embolism (PE) induces ventilation-perfusion mismatch and hypoxia and increases pulmonary pressure and right ventricular (RV) afterload, entailing potentially fatal RV failure within a short timeframe. Cardiopulmonary factors may respond differently to increased clot burden. We aimed to elucidate immediate cardiopulmonary responses during successive PE episodes in a porcine model. METHODS: This was a randomized, controlled, blinded study of repeated measurements. Twelve pigs were randomly assigned to receive sham procedures or consecutive PEs every 15 min until doubling of mean pulmonary pressure. Cardiopulmonary assessments were conducted at 1, 2, 5, and 13 min after each PE using pressure-volume loops, invasive pressures, and arterial and mixed venous blood gas analyses. ANOVA and mixed-model statistical analyses were applied. RESULTS: Pulmonary pressures increased after the initial PE administration (p < 0.0001), with a higher pulmonary pressure change compared to pressure change observed after the following PEs. Conversely, RV arterial elastance and pulmonary vascular resistance was not increased after the first PE, but after three PEs an increase was observed (p = 0.0103 and p = 0.0015, respectively). RV dilatation occurred following initial PEs, while RV ejection fraction declined after the third PE (p = 0.004). RV coupling exhibited a decreasing trend from the first PE (p = 0.095), despite increased mechanical work (p = 0.003). Ventilatory variables displayed more incremental changes with successive PEs. CONCLUSION: In an experimental model of consecutive PE, RV afterload elevation and dysfunction manifested after the third PE, in contrast to pulmonary pressure that increased after the first PE. Ventilatory variables exhibited a more direct association with clot burden.

Predicting factors for pulmonary embolism response team activation in a general pulmonary embolism population.

Pulmonary embolism response teams (PERT) aim to improve treatment of acute pulmonary embolism (PE). PERT focus on intermediate- and high-risk PE patients, but recent multicenter studies show that low-risk PE patients compose one in five of all PERT cases. Conversely, not all intermediate- and high-risk PE patients elicit a PERT activation. The factors leading to PERT activations remain unknown. This study aims to describe the patient characteristics associated with PERT activation for low-risk PE patients and characteristics precluding PERT activation for intermediate/high-risk PE patients. We analysed data from all patients with confirmed PE diagnosed in the Massachusetts General Hospital Emergency Department from August 2013 to February 2017 and cross-referred these data with patients who received a PERT activation and patients who did not. Patients were stratified into low-risk or intermediate/high-risk PE. Univariate analyses were performed within each risk group comparing patients with a PERT activation and patients without. Fifteen percent (56/374) of low-risk PE patients triggered a PERT activation. Patient characteristics associated with PERT activation were: (1) vascular disease, (2) pulmonary diseases, (3) thrombophilia, (4) current use of anticoagulants, (5) central PE and (6) concurrent DVT. Thirty-five percent (110/283) of intermediate/high-risk PE patients did not elicit a PERT activation. Patient characteristics precluding a PERT activation were: (1) vascular disease, (2) malignancies and (3) asymptomatic presentation. Low-risk PE patients with PERT activations had more extensive clot burden, complex comorbidities, or had failed anticoagulation treatment. Intermediate/high-risk PE patients without PERT activations tended to have malignancies or vascular disease.

Closed Chest Biventricular Pressure-Volume Loop Recordings with Admittance Catheters in a Porcine Model.

Pressure-volume (PV) loop recording enables the state-of-the-art investigation of load-independent variables of ventricular performance. Uni-ventricular evaluation is often performed in preclinical research. However, the right and left ventricles exert functional interdependence due to their parallel and serial connections, encouraging simultaneous evaluation of both ventricles. Furthermore, various pharmacological interventions may affect the ventricles and their preloads and afterloads differently. We describe our closed chest approach to admittance-based bi-ventricular PV loop recordings in a porcine model of acute right ventricular (RV) overload. We utilize minimally invasive techniques with all vascular accesses guided by ultrasound. PV catheters are positioned, under fluoroscopic guidance, to avoid thoracotomy in animals, as the closed chest approach maintains the relevant cardiopulmonary physiology. The admittance technology provides real-time PV loop recordings without the need for post-hoc processing. Furthermore, we explain some essential troubleshooting steps during critical timepoints of the presented procedure. The presented protocol is a reproducible and physiologically relevant approach to obtain a bi-ventricular cardiac PV loop recording in a large animal model. This can be applied to a large variety of cardiovascular animal research.

Oxygen Therapy Lowers Right Ventricular Afterload in Experimental Acute Pulmonary Embolism.

OBJECTIVES: To investigate if oxygen could unload the right ventricle and improve right ventricle function in a porcine model mimicking intermediate-high risk acute pulmonary embolism. DESIGN: Controlled, blinded, animal study. SETTING: Tertiary university hospital, animal research laboratory. SUBJECTS: Female, Danish pigs (n = 16, approximately 60 kg). INTERVENTIONS: Acute autologous pulmonary embolism was induced until doubling of baseline mean pulmonary arterial pressure. Group 1 animals (n = 8) received increasing Fio2 (40%, 60%, and 100%) for time intervals of 15 minutes returning to atmospheric air between each level of Fio2. In group 2 (n = 8), the effects of Fio2 40% maintained over 75 minutes were studied. In both groups, pulmonary vasodilatation from inhaled nitric oxide (40 parts per million) was used as a positive control. MEASUREMENTS AND MAIN RESULTS: Effects were evaluated by biventricular pressure-volume loop recordings, right heart catheterization, and arterial and mixed venous blood gasses. Pulmonary embolism increased mean pulmonary arterial pressure from 15 ± 4 to 33 ± 6 mm Hg (p = 0.0002) and caused right ventricle dysfunction (p < 0.05) with troponin release (p < 0.0001). In group 1, increasing Fio2 lowered mean pulmonary arterial pressure (p < 0.0001) and pulmonary vascular resistance (p = 0.0056) and decreased right ventricle volumes (p = 0.0018) and right ventricle mechanical work (p = 0.034). Oxygenation was improved and pulmonary shunt was lowered (p < 0.0001). Maximal hemodynamic effects were seen at Fio2 40% with no additional benefit from higher fractions of oxygen. In group 2, the effects of Fio2 40% were persistent over 75 minutes. Supplemental oxygen showed the same pulmonary vasodilator efficacy as inhaled nitric oxide (40 parts per million). No adverse effects were observed. CONCLUSIONS: In a porcine model mimicking intermediate-high risk pulmonary embolism, oxygen therapy reduced right ventricle afterload and lowered right ventricle mechanical work. The effects were immediately present and persistent and were similar to inhaled nitric oxide. The intervention is easy and safe. The study motivates extended clinical evaluation of supplemental oxygen in acute pulmonary embolism.

Patient and operational factors that influence the decision to place an inferior vena cava filter in a pulmonary embolism response team.

OBJECTIVE: The use of inferior vena cava (IVC) filters is controversial. However, the procedure is widely performed for secondary prophylaxis in patients with severe pulmonary embolism (PE), including those treated by a PE response team (PERT). In this study, we analyzed patient factors associated with the clinical decision to place an IVC filter in PERT patients. METHODS: Data were collected on all Massachusetts General Hospital patients who had a PERT activation from October 1, 2012, to January 29, 2019. Data describing demographics, medical history, PE characteristics and treatment were collected at the time of PERT activation and prospectively for one year after PERT activation. Univariate and multivariable regression analyses were performed to determine factors associated with IVC filter placement. RESULTS: We identified 834 patients, of whom 91 (10.9%) had an IVC filter placed in the first 7 days after PERT activation. The majority of patients receiving an IVC filter were male (55/91 [60.4%]; P =.096) with a mean age of 65 ± 15.0 years. Patients who received an IVC filter were less likely to have had a PERT referral from the Emergency Department (ED) (41/544 [7.5%]; P < .001) and more likely to have been referred from the intensive care unit (24/107 [22.43%]; P ≤ .001) compared with a floor referral. Patients who presented with syncope (15/86 [17.4%]; P = .040), a history of recent trauma (12/41 [29.3%]; P < .001), intracranial hemorrhage (11/39 [28.2%]; P = .002), a recent surgery or invasive procedure (30/188 [16.0%]; P = .012), a recent surgery (29/160 [18.1%]; P = .001) and a recent hospitalization (38/250 [15.2%]; P = .009) were more likely to have an IVC filter placed. Patients receiving an IVC filter were also more likely to have evidence of right heart dysfunction on a computed tomography pulmonary angiogram (61/359 [17.0%]; P < .001) and an echocardiogram (26/144 [18.1%]; P = .003). Compared with patients without an IVC filter, the 30-day venous thromboembolism recurrence rate was higher (4.7% vs 11.0%) in patients with IVC filters (10/45 [22.2%]; P = .023). CONCLUSIONS: Factors associated with venous thromboembolism severity (eg, PERT referral from intensive care unit and right ventricular dysfunction) and an increased bleeding risk (eg, recent surgery or trauma) were associated with IVC filter placement among PERT patients.

Inhaled nitric oxide has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute pulmonary embolism.

BACKGROUND: Inhaled nitric oxide (iNO) effectively reduces right ventricular afterload when administered in the immediate phase of acute pulmonary embolism (PE) in preclinical animal models. In a porcine model of intermediate-risk PE, we aimed to investigate whether iNO has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute PE. METHODS: Anesthetized pigs (n = 18) were randomized into three subgroups. An acute PE iNO-group (n = 6) received iNO at 40 ppm at one, three, six, nine and 12 hours after onset of PE. Vehicle animals (n = 6) received PE, but no active treatment. A third group of sham animals (n = 6) received neither PE nor treatment. Animals were evaluated using intravascular pressures, respiratory parameters, biochemistry and intracardiac pressure-volume measurements. RESULTS: The administration of PE increased mean pulmonary artery pressure (mPAP) (vehicle vs sham; 33.3 vs 17.7 mmHg, p < 0.0001), pulmonary vascular resistance (vehicle vs sham; 847.5 vs 82.0 dynes, p < 0.0001) and right ventricular arterial elastance (vehicle vs sham; 1.2 vs 0.2 mmHg/ml, p < 0.0001). Significant mPAP reduction by iNO was preserved at 12 hours after the onset of acute PE (vehicle vs iNO; 0.5 vs -3.5 mmHg, p < 0.0001). However, this response was attenuated over time (p = 0.0313). iNO did not affect the systemic circulation. CONCLUSIONS: iNO is a safe and effective pulmonary vasodilator both in the immediate and prolonged phase of acute PE in an in-vivo porcine model of intermediate-risk PE.

Right ventricular adaptation in the critical phase after acute intermediate-risk pulmonary embolism.

BACKGROUND: The haemodynamic response following acute, intermediate-risk pulmonary embolism is not well described. We aimed to describe the cardiovascular changes in the initial, critical phase 0-12 hours after acute pulmonary embolism in an in-vivo porcine model. METHODS: Pigs were randomly allocated to pulmonary embolism (n = 6) or sham (n = 6). Pulmonary embolism was administered as autologous blood clots (20 × 1 cm) until doubling of mean pulmonary arterial pressure or mean pulmonary arterial pressure was greater than 34 mmHg. Sham animals received saline. Cardiopulmonary changes were evaluated for 12 hours after intervention by biventricular pressure-volume loop recordings, invasive pressure measurements, arterial and central venous blood gas analyses. RESULTS: Mean pulmonary arterial pressure increased (P < 0.0001) and stayed elevated for 12 hours in the pulmonary embolism group compared to sham. Pulmonary vascular resistance and right ventricular arterial elastance (right ventricular afterload) were increased in the first 11 and 6 hours, respectively, after pulmonary embolism (P < 0.01 for both) compared to sham. Right ventricular ejection fraction was reduced (P < 0.01) for 8 hours, whereas a near-significant reduction in right ventricular stroke volume was observed (P = 0.06) for 4 hours in the pulmonary embolism group compared to sham. Right ventricular ventriculo-arterial coupling was reduced (P < 0.05) for 6 hours following acute pulmonary embolism despite increased right ventricular mechanical work in the pulmonary embolism group (P < 0.01) suggesting right ventricular failure. CONCLUSIONS: In a porcine model of intermediate-risk pulmonary embolism, the increased right ventricular afterload caused initial right ventricular ventriculo-arterial uncoupling and dysfunction. After approximately 6 hours, the right ventricular afterload returned to pre-pulmonary embolism values and right ventricular function improved despite a sustained high pulmonary arterial pressure. These results suggest an initial critical and vulnerable phase of acute pulmonary embolism before haemodynamic adaptation.

Right ventricular adaptation in the critical phase after acute intermediate-risk pulmonary embolism.

BACKGROUND: The haemodynamic response following acute, intermediate-risk pulmonary embolism is not well described. We aimed to describe the cardiovascular changes in the initial, critical phase 0-12 hours after acute pulmonary embolism in an in-vivo porcine model. METHODS: Pigs were randomly allocated to pulmonary embolism (n = 6) or sham (n = 6). Pulmonary embolism was administered as autologous blood clots (20 × 1 cm) until doubling of mean pulmonary arterial pressure or mean pulmonary arterial pressure was greater than 34 mmHg. Sham animals received saline. Cardiopulmonary changes were evaluated for 12 hours after intervention by biventricular pressure-volume loop recordings, invasive pressure measurements, arterial and central venous blood gas analyses. RESULTS: Mean pulmonary arterial pressure increased (P < 0.0001) and stayed elevated for 12 hours in the pulmonary embolism group compared to sham. Pulmonary vascular resistance and right ventricular arterial elastance (right ventricular afterload) were increased in the first 11 and 6 hours, respectively, after pulmonary embolism (P < 0.01 for both) compared to sham. Right ventricular ejection fraction was reduced (P < 0.01) for 8 hours, whereas a near-significant reduction in right ventricular stroke volume was observed (P = 0.06) for 4 hours in the pulmonary embolism group compared to sham. Right ventricular ventriculo-arterial coupling was reduced (P < 0.05) for 6 hours following acute pulmonary embolism despite increased right ventricular mechanical work in the pulmonary embolism group (P < 0.01) suggesting right ventricular failure. CONCLUSIONS: In a porcine model of intermediate-risk pulmonary embolism, the increased right ventricular afterload caused initial right ventricular ventriculo-arterial uncoupling and dysfunction. After approximately 6 hours, the right ventricular afterload returned to pre-pulmonary embolism values and right ventricular function improved despite a sustained high pulmonary arterial pressure. These results suggest an initial critical and vulnerable phase of acute pulmonary embolism before haemodynamic adaptation.

Inhaled nitric oxide has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute pulmonary embolism.

BACKGROUND: Inhaled nitric oxide (iNO) effectively reduces right ventricular afterload when administered in the immediate phase of acute pulmonary embolism (PE) in preclinical animal models. In a porcine model of intermediate-risk PE, we aimed to investigate whether iNO has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute PE. METHODS: Anesthetized pigs (n = 18) were randomized into three subgroups. An acute PE iNO-group (n = 6) received iNO at 40 ppm at one, three, six, nine and 12 hours after onset of PE. Vehicle animals (n = 6) received PE, but no active treatment. A third group of sham animals (n = 6) received neither PE nor treatment. Animals were evaluated using intravascular pressures, respiratory parameters, biochemistry and intracardiac pressure-volume measurements. RESULTS: The administration of PE increased mean pulmonary artery pressure (mPAP) (vehicle vs sham; 33.3 vs 17.7 mmHg, p < 0.0001), pulmonary vascular resistance (vehicle vs sham; 847.5 vs 82.0 dynes, p < 0.0001) and right ventricular arterial elastance (vehicle vs sham; 1.2 vs 0.2 mmHg/ml, p < 0.0001). Significant mPAP reduction by iNO was preserved at 12 hours after the onset of acute PE (vehicle vs iNO; 0.5 vs -3.5 mmHg, p < 0.0001). However, this response was attenuated over time (p = 0.0313). iNO did not affect the systemic circulation. CONCLUSIONS: iNO is a safe and effective pulmonary vasodilator both in the immediate and prolonged phase of acute PE in an in-vivo porcine model of intermediate-risk PE.