Up to 50% of patients develop post-thrombotic venous outflow obstruction (PTVO) after iliocaval deep venous thrombosis. Chronic venous hypertension can lead to severe limb pain, swelling and venous claudication, limiting exercise tolerance and daily activities. Patients presenting with exertional dyspnea and exercise intolerance may be investigated in the first instance for chronic thromboembolic pulmonary hypertension; however, these symptoms could also be due to insufficient venous return to heart, leading to an impairment in stroke volume and limitation in cardiac output. This study aimed to quantify cardiac function during exercise in patients with PTVO and evaluate changes after endovascular recanalization. Patients with PTVO without chronic thromboembolic pulmonary hypertension, and age and gender matched healthy controls underwent cardiopulmonary exercise testing (CPET) and exercise cardiac magnetic resonance imaging (ExCMR) using an MR-compatible supine cycle-ergometer. A real-time image acquisition and post-processing framework was used to obtain an electrocardiogram and respiratory gated two-dimensional flow and cine images at rest and during exercise, allowing measurement of flow in the aorta and vena cava and quantification of cardiac volumes. These measurements were used to calculate stroke volume and cardiac output. Patient-specific workloads for supine cycle exercise inside the scanner were determined from CPET performance (watts at anaerobic threshold +10%). Patients undergoing stenting repeated the tests 6 to 8 weeks after intervention. Twenty-seven patients (19 males and 8 females; aged 44.2 ± 13.7 years) and 10 controls (7 males and 3 females; aged 44 ± 13.5 years) completed CPET and exCMR. Participants were matched for body mass index (30 ± 5.4 vs 27.6 ± 4.3; P = .33) and physical activity levels (General Practice Physical Activity Questionnaire Score 3.14 ± 0.86 for patients, 3.4 ± 0.5 for controls; P = .4). Peak maximum oxygen uptake (VO2) was impaired in patients (median, 17.9 mL/min/kg; 66% of predicted) and lower than controls (30.65 mL/mL/kg; 100% of predicted; P < .0001) despite maximal tests being achieved. Anaerobic threshold, workload and VO2/heart rate ratio were also lower than controls (P < .0002; P < .05; P < .0007). Ten patients repeated testing after iliocaval stenting. Peak VO2 improved by 28% (P < .002), anaerobic threshold by 24% (P < .002), workload by 10% (P < .001), and VO2/heart rate ratio by 14% (P < .001). The increase in stroke volume and cardiac index during ExCMR was significantly lower in prestent patients vs controls (0.8% vs 16.5% P < .01; and 5.5 L/min/m2 vs 8.6 L/min/m2; P < .05, respectively) despite similar heart rates (approximately 135 bpm). On postoperative testing, patients were able to increase stroke volume significantly from rest to exercise (15% increase; P < .01), leading to improvement in cardiac index (5.5 L/min/m2 prestent to 7.1 L/min/m2 post-stent; P < .05). PTVO can limit peak VO2, stroke volume and cardiac output during exercise. Significant functional improvements are observed after stenting.

Editor—Patients with COVID-19 acute respiratory distress syndrome (C-ARDS) present with severe hypoxaemia that may be disproportionate to the loss in aerated lung.1Chiumello D. Busana M. Coppola S. et al.Physiological and quantitative CT-scan characterization of COVID-19 and typical ARDS: a matched cohort study.Intensive Care Med. 2020; 46: 2187-2196Crossref PubMed Scopus (140) Google Scholar The main mechanism of hypoxaemia has been attributed to a dysregulated pulmonary perfusion, and therefore, inhaled pulmonary vasodilators have been used to improve gas exchange in these patients.2The Faculty of Intensive Care Medicine (FICM) and The Intensive Care Society (ICS). Clinical guide for the management and care of critically ill adults with COVID-19 during the coronavirus pandemic. Available from: https://static1.squarespace.com/static/5e6613a1dc75b87df82b78e1/t/60800b8100361404e3e37493/1619004290257/Clinical+guide_FINAL_MG_16-4-21.pdf (accessed 1 May 2021).Google Scholar However, during the COVID-19 pandemic, the significant increase in C-ARDS resulted in national supply chain shortages of inhaled vasodilators, such as iloprost, epoprostenol, and nitric oxide. Besides the limited availability, these drugs are costly: nitric oxide (£665 per day), iloprost (£60–120 per day), and epoprostenol (£45–75 per day). Milrinone, a phosphodiesterase 3 inhibitor that has shown benefit to improve oxygenation in patients with pulmonary hypertension, is a widely available and less costly alternative (£13 per day), but data in ARDS are scarce.3Haraldsson S.A. Kieler-Jensen N. Ricksten S.E. The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.Anesth Analg. 2001; 93: 1439-1445Crossref PubMed Scopus (142) Google Scholar, 4Theodoraki K. Thanopoulos A. Rellia P. et al.A retrospective comparison of inhaled milrinone and iloprost in post-bypass pulmonary hypertension.Heart Vessels. 2017; 32: 1488-1497Crossref PubMed Scopus (13) Google Scholar, 5Albert M. Corsilli D. Williamson D.R. et al.Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome.World J Crit Care Med. 2017; 6: 74-78Crossref PubMed Google Scholar, 6Nguyen A.Q. Denault A.Y. Théoret Y. Perrault L.P. Varin F. Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization.Sci Rep. 2020; 10: 2069Crossref PubMed Scopus (14) Google Scholar During the pandemic, we hypothesised that in mechanically ventilated patients with C-ARDS with a Pao2/FiO2 ratio <20 kPa, inhaled milrinone would improve oxygenation and reduce physiological dead-space fraction, and we therefore used inhaled milrinone as an alternative vasodilator during the drug shortages. We describe the first 14 patients who received inhaled milrinone (2.5–5 mg every 6 h) for ≥12 h. Milrinone was administered via mesh nebulisation in accordance with departmental guidance, but at the discretion of the clinical team. We retrieved data on ventilation and blood gas analyses from electronic records, and calculated oxygenation index (OI), Pao2/FiO2, and three indices of dead-space ventilation (end-tidal CO2/Paco2, ventilatory ratio, and corrected minute ventilation).7Gajic O. Afessa B. Thompson B.T. et al.Prediction of death and prolonged mechanical ventilation in acute lung injury.Crit Care. 2007; 11: R53Crossref PubMed Scopus (61) Google Scholar, 8Sinha P. Calfee C.S. Beitler J.R. et al.Physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome.Am J Respir Crit Care Med. 2019; 199: 333-341Crossref PubMed Scopus (150) Google Scholar, 9Vasques F. Sanderson B. Formenti F. Shankar-Hari M. Camporota L. Physiological dead space ventilation, disease severity and outcome in ventilated patients with hypoxaemic respiratory failure due to coronavirus disease 2019.Intensive Care Med. 2020; 46: 2092-2093Crossref PubMed Scopus (15) Google Scholar Values were recorded before first milrinone dose, 1–2 h after, and subsequently at 6 and 12 h. The closest temporally associated transthoracic echocardiograms obtained before and after initiation were reviewed by a consultant cardiologist for indices of right ventricle (RV) and left ventricle (LV) size and function.10Zaidi A. Knight D.S. Augustine D.X. et al.Echocardiographic assessment of the right heart in adults: a practical guideline from the British Society of Echocardiography.Echo Res Pract. 2020; 7: G19-G41Crossref PubMed Scopus (93) Google Scholar Records were reviewed for potentially related adverse events, including haemodynamic instability, deterioration in gas exchange, dose adjustments, or early termination of therapy. Continuous data were tested for normal distribution (Shapiro–Wilk test). Normally distributed data are presented as mean (standard deviation [sd]), not normally distributed data as median (inter-quartile range [IQR]), and nominal data as number (%). One-way repeated-measures analysis of variance was used to compare means across different time points. Observed differences to baseline are provided as means and 95% confidence interval (95% CI). Post hoc Bonferroni correction was applied to account for multiple comparisons when comparing individual pairs of groups. For comparison of means, t-test was used for parametric data. A local guidance document for the use of inhaled milrinone was approved by the trust Drug and Therapeutics Committee. Institutional approval was gained from the local audit committee (project reference 11146). The need for individual informed consent was waived for this retrospective analysis of data collected prospectively for routine care, without breach of privacy or anonymity. The study qualified as a service evaluation as defined by the UK NHS Health Research Authority, and therefore did not require review by a research ethics committee. The 14 patients had a mean (sd) age of 62.6 (6.9) yr. Admission Acute Physiology and Chronic Health Evaluation II was 17 (IQR: 13.8–18.5), 10 were male (71.4%) and had a BMI 29.0 (6.6) kg m−2. Patients had been ventilated for 20.6 (15.5) days before initiation of milrinone. At baseline (pre-milrinone), patients had a Sequential Organ Failure Assessment score of 7.5 (IQR: 5–12.5), received tidal volume of 5.8 (1.9) ml kg−1 predicted body weight, PEEP 8 (IQR: 6–10) cm H2O, peak pressure 30 (3) cm H2O, and had a dynamic compliance of 20 (IQR: 15–22) ml cm H2O−1. Mean Pao2/FiO2 at baseline was 11.6 (1.6) kPa, and 6/14 (42.9%) were proned. At baseline, 2/12 (16%) had impaired longitudinal RV function (tricuspid annular plane systolic excursion [TAPSE] <17 mm), 3/12 (25%) a dilated RV (RV end-diastolic basal diameter >43 mm [female] or >47 mm [male]), and 3/12 (25%) RV/LV ratio >1; none of the patients had impaired LV function (LV ejection fraction <50%). Another pulmonary vasodilator had been used in 5/14 (35.7%) patients before starting milrinone. There was a significant main effect of inhaled milrinone on Pao2/FiO2 (P<0.01) and OI (P<0.001), in the first 12 h (Fig. 1). This improvement was statistically significant (after correction for multiple comparisons) for Pao2/FiO2 post-6 h dose (mean difference to baseline +2.7 kPa; 95% CI: 0.3–5.0; P<0.05) and post-12 h dose (+3.1 kPa; 95% CI: 0.8–5.4; P<0.01), and for OI post-6 h dose (–3.2; –0.12 to –6.2; P<0.01) and 12 h dose (–4.0; 95% CI: –0.5 to –7.6; P<0.01 [lower OI reflects improved Pao2, or similar Pao2 for lower applied mean airway pressure or FiO2]). During this observation time, no additional patient received prone positioning. For patients in whom milrinone was continued for ≥48 h (n=7), the improvement in Pao2/FiO2 was maintained, and this was higher by +3.9 kPa (95% CI: 0.6–7.2; P<0.05) and OI was lower by –5.1 (95% CI: –0.5 to –9.7; P<0.05) post-48 h dose compared with baseline, respectively. There was a greater improvement in Pao2/FiO2 compared with baseline post-6 h dose in the group with a shorter duration of mechanical ventilation (<20 days; n=7), compared with those who had been ventilated longer (>20 days; n=7) before receiving the first dose (mean difference +26.3%; 95% CI: 0.8–51.9%; P<0.05). These patients had high indices of dead space with end-tidal CO2/Paco2 0.67 (0.12), ventilatory ratio 2.37 (1.17), and corrected minute volume 14.13 (6.1) L min−1. However, there was no change in dead space after milrinone (end-tidal CO2/Paco2 0.70 [0.12], ventilatory ratio 2.62 [1.12], and corrected minute ventilation 15.5 [7.4] L min−1 at 12 h). For patients in whom comparable studies were available, there was no significant difference in TAPSE (n=9; 19 [6] and 19 [5] mm), RV diameter (n=9; 3.8 [1.1] and 3.6 [0.8]), or RV/LV ratio (n=7; 0.88 [0.2] and 0.87 [0.1]) before and after milrinone, respectively. No adverse events were observed during the patients' ICU admission. A transient deterioration in oxygenation (<6 h) was noted in one patient, but coincided with the development of a new ventilator-associated pneumonia. These results show that milrinone might be a useful alternative to inhaled nitric oxide, epoprostenol, or iloprost for improving oxygenation even late in the course of C-ARDS, and at this late stage milrinone did not affect dead-space ventilation. It is likely that given the duration of the disease and the low compliance, the predominant mechanism of hypoxaemia in these patients was venous admixture secondary to consolidation or fibrosis, and may explain why the physiological dead space was unmodified. These results are based on observational data from a case series and need to be interpreted in this context. The effects of milrinone on dead space could be tested earlier in the disease, where functional vasoconstriction of ventilated areas can affect physiological dead space. We conclude that in mechanically ventilated patients with severe COVID-19, inhaled milrinone was associated with improved oxygenation for up to 48 h of administration. The authors declare that they have no conflicts of interest.

Objectives: Changes in right ventricular size and function are frequently observed in patients with severe acute respiratory distress syndrome. The majority of patients who receive venovenous extracorporeal membrane oxygenation undergo chest CT and transthoracic echocardiography. The aims of this study were to compare the use of CT and transthoracic echocardiography to evaluate the right ventricular function and to determine the prevalence of acute cor pulmonale in this patient population. Design: Observational, retrospective, single-center, cohort study. Setting: Severe respiratory failure and extracorporeal membrane oxygenation center. Patients: About 107 patients with severe acute respiratory distress syndrome managed with venovenous extracorporeal membrane oxygenation. Interventions: Chest CT to evaluate right ventricular size and transthoracic echocardiography to evaluate right ventricular size and function. Measurements and Main Results: All 107 patients had a qualitative assessment of right ventricular size and function on transthoracic echocardiography. Quantitative measurements were available in 54 patients (50%) who underwent transthoracic echocardiography and in 107 of patients (100%) who received CT. Right ventricular dilatation was defined as a right ventricle end-diastolic diameter greater than left ventricular end-diastolic diameter upon visual assessment or an right ventricle end-diastolic diameter/left ventricular end-diastolic diameter and/or right ventricle cavity area/left ventricular cavity area of greater than 0.9. Right ventricle systolic function was visually estimated as being normal or impaired (visual right ventricular systolic impairment). The right ventricle was found to be dilated in 38/107 patients (36%) and in 58/107 patients (54%), using transthoracic echocardiography or CT right ventricle end-diastolic diameter/left ventricular end-diastolic diameter, respectively. When the CT right ventricle cavity/left ventricular cavity area criterion was used, the right ventricle was dilated in 19/107 patients (18%). About 33/107 patients (31%) exhibited visual right ventricular systolic impairment. Transthoracic echocardiography right ventricle end-diastolic diameter/left ventricular end-diastolic diameter showed good agreement with CT right ventricle cavity/left ventricular cavity area (R 2 = 0.57; p < 0.01). A CT right ventricle cavity/left ventricular cavity area greater than 0.9 provided the optimal cutoff for acute cor pulmonale on transthoracic echocardiography with an AUC of 0.78. Acute cor pulmonale was defined by the presence of a right ventricle “D-shape” and quantitative right ventricle dilatation on transthoracic echocardiography or a right ventricle cavity/left ventricular cavity area greater than 0.9 on CT. A diagnosis of acute cor pulmonale was made in 9/54 (14% patients) on transthoracic echocardiography and in 19/107 (18%) on CT. Conclusions: Changes in right ventricular size and function are common in patients with severe acute respiratory distress syndrome requiring venovenous extracorporeal membrane oxygenation with up to 18% showing imaging evidence of acute cor pulmonale. A CT right ventricular cavity /left ventricular cavity area greater than 0.9 is indicative of impaired right ventricular systolic function.

BACKGROUND:The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death.METHODS:A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research.RESULTS:Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning.CONCLUSIONS:With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

Background: The risk of complications, including death, is markedly increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures. We performed a systematic literature review of available studies in patients with PAH or chronic thromboembolic PH (CTEPH) undergoing non-cardiac, non-obstetric surgery, finding a mortality ranging between 2-18% in elective and 15-50% in emergency surgery. Methods/Results: We devised relevant clinical questions based on expert consensus opinion in order to provide recommendations of best practice, using a Delphi scoring method. Based on findings from our literature review and expert opinion, we provide 10 recommendations for best clinical practice involving (1) preoperative planning and the use of a perioperative MDT, (2) management of procedural sedation, (3) decision making where surgery is performed, (4) patient-related risk assessment, (5) procedure-related risk assessment, (6) perioperative optimization of PH therapies, (7) perioperative parenteral PAH therapy, (8) perioperative monitoring and anaesthetic management, (9) postoperative management, and (1) management of perioperative pulmonary hypertensive crises, including consideration of ECMO and lung transplantation. Areas for future research are also suggested. Conclusion: This was a collaborative project by UK PH services. We provide 10 recommendations for good clinical practice in this common clinical scenario, where risk assessment is crucial, as mortality remains high.

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Patients with diffuse interstitial lung disease (DILD) admitted to the intensive care unit (ICU) often present with difficult diagnostic and management challenges to the intensivist and hence it is essential that a multidisciplinary approach is employed. Clinically, the difficulty lies in differentiating between progression of an exist-ing DILD and the potential need for a new or increased immunosuppression, and other causes of respiratory deterioration which may require individual therapy and a potential reduction in immunosuppression. In this chapter we review the importance of the clinical history, radiological imaging and the role of additional invasive diagnostic techniques including bronchscopy, bronchoalveolar lavage and transbronchial versus open surgical biopsy, in complex patients. We review both disease-specific and general critical care management for such patients including the limited role of lung transplantation. In the absence of a reversible disease, the prognosis for patients with DILD requiring mechanical ventilation is extremely poor, and the importance of effective palliation and end-of-life-care management is discussed.