Abstract
Address correspondence to Geoff Strange, Pulmonary Hypertension Society ANZ, Inc., PO Box 133, Sans Souci, New South Wales 2219, Australia. E–mail:
A human ex-vivo perfused model of pulmonary arterial hypertension
DC Chambers,1,2 W Hunt,3 R Naidoo,4 D Wall,4 J Choudhary,4 D Enever,1 L Sampson,1 SJ Yerkovich,1,2 I Smith,3 PM Hopkins,1,2 F Kermeen1,2
1 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia; 2 School of Medicine, University of Queensland, Brisbane, Australia; 3 Department of Anaesthetics, Prince Charles Hospital, Brisbane, Australia; 4 Department of Cardiothoracic Surgery, Prince Charles Hospital, Brisbane, Australia
Therapeutic options for pulmonary arterial hypertension (PAH) remain limited because animal models are poorly representative of human PAH, and human in vitro tissue and cell-based assays lack the architectural complexity of the intact organ. We hypothesized that it would be possible to develop a human model of PAH using ex vivo lung perfusion (EVLP) technology and that such a model would serve to both enhance the safety of and expedite early-phase clinical studies for novel PAH therapies. After nationwide consultation, an Australian-first process for the retrieval of human lungs for research was developed. Based on studies in whole animals, a protocol for the establishment of PAH in ex vivo perfused and ventilated lungs using a thromboxane analogue (U-46619, Cayman Chemical) was developed. A 60-year-old female suffered a hypoxic cerebral injury following cardiac arrest. Resuscitation was initially successful; however, a decision to withdraw life-sustaining treatment was made 48 hours later. The family consented to donation after cardiac death, including research. The warm ischemic time was 17 minutes. Initial PaO2 was 467 mmHg; however, the presence of significant right lung congestion, small pulmonary infarcts, and a pancreatic nodule mandated EVLP. The organs were transported at 4°C to TPCH, rewarmed, and established on EVLP (CO 4 L/min). After 2.5 hours, EVLP pulmonary edema worsened, and the organs were declined for transplantation. Stable PAH (PVR: 800–900 dyn/s/cm5) was rapidly established using 260 μg U-46619 with minimal circuit metabolism, facilitating the successful safety testing of a novel biologic with PAH activity. In conclusion, we have pioneered the development of a human model of PAH which will accelerate the development of novel therapies.
Gravity-dependent redistribution of pulmonary perfusion is lost in patients with pulmonary hypertension: a quantitative SPECT/CT study
EMT Lau,1 DL Bailey,2 PJ Roach,2 EA Bailey,2 PJ Torzillo,1 GP Schembri,2 TJ Corte,1 DS Celermajer1
1 Royal Prince Alfred Hospital, Sydney, Australia; 2 Royal North Shore Hospital, Sydney, Australia
In clinical practice, pulmonary vascular disease (PVD) is detected relatively late in its natural history, when pulmonary hypertension (PHT) occurs. We hypothesized that the normal gravity-dependent redistribution of lung perfusion resulting from postural change is impaired in PHT and may thus have potential for the assessment of PVD. Our aim was to assess the redistribution of pulmonary perfusion between supine and upright positions in patients with precapillary PHT and in controls. Regional pulmonary perfusion in supine and upright positions was obtained by quantitative single-photon emission computed tomography (SPECT) using 99mTc-macroaggregated albumin. A perfusion redistribution index (PRI) was calculated to quantify the perfusion shift along the cranial-caudal axis between different postures. Regional lung perfusion was evaluated in 14 PHT subjects and 11 controls. Controls displayed the expected cranial-caudal gradient in lung perfusion in upright position (left lung, 0.074 ± 0.056 normalized perfusion counts/cm; right lung, 0.070 ± 0.079 normalized perfusion counts/cm), which became abolished on lying flat. In relation to perfusion redistribution, PHT subjects had markedly reduced PRI with postural change compared to controls (0.44 ± 0.26 vs. 3.71 ± 0.66, P = 0.0002). A cut-off PRI value of 1.5 had sensitivity and specificity of 93% and 82% in separating PHT from control group. On multivariate analysis, the presence of PHT was the only significant predictor of PRI. In conclusion, gravity-dependent redistribution of lung perfusion is markedly diminished in subjects with PHT. This simple, inexpensive, and noninvasive technique may have potential utility for the detection of PVD.
Outcomes of systemic sclerosis patients with exercise-induced pulmonary arterial hypertension treated with advanced therapies
J Treleaven, R Fowler, E Gabbay
Royal Perth Hospital, Perth, Australia
Patients with systemic sclerosis (SSc) are at high risk of developing pulmonary arterial hypertension (PAH), which carries a high mortality rate. Although the significance of exercise-induced pulmonary arterial hypertension (EIPAH) is uncertain, it may be a precursor to PAH in SSc patients. The advent of PAH-specific therapies has vastly improved outcomes in SSc patients with PAH. There are no data evaluating the use of these therapies in SSc with EIPAH. From October 2006 to July 2008, 17 patients with SSc were investigated with exercise right heart catheter for exertional dyspnea and borderline PASP on echocardiogram. Of these, 5 had resting PAH, defined as mPAP > 25 mmHg and PAWP15 mmHg, and 12 had EIPAH, defined as mPAP > 30 mmHg and PAWP20 mmHg on exercise. All PAH patients were commenced on bosentan. Of the EIPAH group, 10 were treated with bosentan, 1 with iloprost, and 1 with no treatment. Patients were reassessed at 4 years for survival, functional class (FC), and 6MWT distance. FC was stable or improved in 91.7% of the EIPAH, compared to 40% of the PAH group (P = 0.05). The 6MWT distance increased by a mean of 47 m and decreased by a mean of 45 m in the EIPAH and PAH groups, respectively (P = 0.07). There was a trend toward improved survival (100% vs. 60%) in the EIPAH group (P = 0.07). No EIPAH patients developed resting PAH, defined as PASP > 50 mmHg on echocardiogram. Outcomes in the EIPAH group compared favorably to those in the PAH group. EIPAH in SSc did not progress when treated with PAH-specific therapies. This contrasts to previously published data suggesting SSc patients with EIPAH experienced significant mortality and high rate of progression to resting PAH.
Increased pulmonary arterial perfusion measured by technetium-99m is associated with increased pulmonary arterial remodeling in COPD
J Wrobel,1,2 CA McLean,1,3 BR Thompson,1,2 CR Stuart-Andrews,2 E Paul,1,4 GI Snell,1,2 TJ Williams1,2
1 Department of Medicine, Monash University, Melbourne, Australia; 2 Department of Allergy, Immunology, and Respiratory Medicine, Alfred Hospital, Melbourne, Australia; 3 Anatomical Pathology Unit, Alfred Hospital, Melbourne, Australia; 4 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
Increased pulmonary arterial remodeling has recently been described in the upper lobes, compared with the lower lobes, of patients with severe COPD. However, the relationship between pulmonary arterial remodeling and pulmonary perfusion in patients with COPD has not been established. Histological morphology of muscular pulmonary arteries was performed on COPD explants, using digital image analysis. Pulmonary arterial remodeling was measured as the percentage of wall thickness to vessel diameter (%WT). The lobar perfusion index (LPI) was calculated as the ratio of lobar perfusion to total pulmonary perfusion from technetium-99m ventilation-perfusion (V/Q) scintigraphy. Repeated-measures weighted effects of LPI were calculated for %WT after adjusting for lobar origin and pulmonary arterial size. Five hundred ninety vessels were analyzed from 17 COPD lung transplant patients, with an average (±SEM) %WT of 29.4% (±1.8%). There was no difference in LPI between the upper and lower lobes. However, the LPI was significantly positively associated with %WT (weighted effect ± SEM: 1.69 ± 0.7, P < 0.05), so that for every 10% increase in LPI, the %WT was estimated to increase by an absolute amount of 1.69%. In conclusion, increased lobar perfusion on V/Q scintigraphy is associated with increased pulmonary arterial remodeling in severe COPD. This positive relationship suggests that increased regional blood flow likely contributes to increased regional pulmonary arterial remodeling in patients with severe COPD.
Breathing efficiency measured during six-minute walk test predicts disease severity in pulmonary arterial hypertension
NR Morris,1,2 H Seale,2 J Harris,2 K Hall,2 F Kermeen2
1 School of Rehabilitation Sciences, Griffith University, Gold Coast Campus, Southport, Australia; 2 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia
The six-minute walk distance (6MWD) is a validated measure of mortality and morbidity in pulmonary arterial hypertension (PAH). However, the addition of cardiopulmonary measures to a 6MWT may provide further indices of disease severity in PAH, in particular an estimate of oxygen uptake (VO2) and breathing efficiency (BE: VE/VCO2). The purpose of this study was to examine the relationship between disease severity and cardiopulmonary measures during a 6MWT. Prospectively, 42 patients (27 F, 49 ± 18 years) from tertiary PH center completed a 6MWT while gas exchange was simultaneously measured using a portable metabolic cart. Pre- and end-exercise measurements of VO2, carbon dioxide production (VCO2), and ventilation (VE) were determined from 30-second averages. Heart rate (HR), oxygen saturation, and rating of exertion (RPE) were recorded every minute. All patients underwent echocardiography, and standard measurements of right ventricular function were measured. Mean 6MWD was 503 ± 102 m, with mean WHO-FC 2.0 ± 0.34. During the 6MWT there was a significant increase in VO2 (pre: 6.0 ± 1.3 mL kg−1 min−1; end: 14.1 ± 1.6 mL kg−1 min−1), VE (pre: 17.0 ± 5.2 L min−1; end: 48.4 ± 5.0 L min−1), BE (pre: 41.2 ± 7.6, end: 43.2 ± 7.6), HR (pre: 83 ± 14 beats min−1; end: 133 ± 18 beats min−1), and RPE (pre: 0.3 ± 0.7; end: 4.0 ± 1.4). RVSP was significantly correlated with end-exercise BE (r = 0.49, P < 0.01) and 6MWD (r = −0.34, P < 0.05). This study demonstrates that the addition of cardiopulmonary measures to a 6MWT provides additional information regarding disease severity in PAH and therefore may be a useful tool to assess response to therapies.
An echocardiographic snapshot of right ventricular dysfunction
D Seaton,1 B Shearer,1 K Aldridge,1 F Kermeen2
1 Queensland Nuclear Imaging, Prince Charles Campus, Brisbane, Australia; 2 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia
Right ventricular function is an important predictor of mortality and morbidity in pulmonary hypertension (PH). Identifying accurate and reliable echocardiographic parameters for the functional assessment of the right ventricle (RV) still remains a challenge. Our aim was to assess the efficacy of echocardiographic parameters in the assessment of right ventricular dysfunction in patients with advanced PHT as directed by current guidelines. Eighty-two patients (68% F) from a tertiary PAH center—21 IPAH, 3 FPAH, 20 PAH-CHD, 17 PAH-CTD, 7 CTEPH, 4 portopulmonary, and 10 out of proportion PHT—underwent echocardiography with an RVSP > 50 mmHg over a 3-month period by a blinded operator. Mean age of patients was 54.3 ± 17.7 years, mWHO was FC 2.7 ± 0.6, and m6MWT was 404 ± 150.3 m, with 45% prescribed one, 29% two, and 17% triple PAH therapies. Echocardiography confirmed severe PHT with mean RVSP 90.6 ± 24 mmHg, mRA size 25.4 ± 7.6 cm2, and 18% trivial, 6% mild, and 2% moderate pericardial effusion and RVD present in 84% of this group. However, the mean TAPSE 18 ± 4.7 mm and mean S' of 10.8 were preserved within normal limits. Our data support RVSP, RA size, and the presence of pericardial effusion as important predictors but challenge current pulmonary hypertension guidelines in the utility of TAPSE and S' in the prognosis and monitoring of patients prescribed advanced PH therapies. Further analysis of RV strain patterns and fractional area change within this group is warranted.
The addition of cardiopulmonary measurements to a six-minute walk test differentiates pulmonary arterial hypertension patients on mono versus dual versus triple therapy
NR Morris,1,2 H Seale,2 J Harris,2 K Hall,2 F Kermeen2
1 School of Rehabilitation Sciences, Griffith University, Gold Coast Campus, Southport, Australia; 2 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia
Compared to patients on mono or dual therapies, patients on triple therapy would be expected to have more severe pulmonary arterial hypertension (PAH) and poorer prognosis. The six-minute distance (6MWD) is well correlated with disease severity and prognosis. The purpose of this study was to determine if exercise gas exchange during a six-minute walk test (6MWT) could be used to differentiate between patients on different levels of therapy. Nineteen PAH patients on mono therapy (57 ± 16 yr, 11 F), 11 on dual therapy (45 ± 17 yr, 8 F), and 11 on triple therapy (39 ± 18 yr, 6 F) participated in the study. Each subject completed a 6MWT while gas exchange was measured simultaneously with a portable metabolic cart (Cortex). Standard echocardiographic measurements of right ventricular function were measured on the same day. There was significant (P < 0.03) progressive increase in right ventricular systolic pressure between the groups (mono: 66 ± 25 mmHg; dual: 79 ± 16 mmHg; triple: 95 ± 34 mmHg). There was no significant difference between groups in the 6MWD (mono: 503 ± 95 m; dual: 502 ± 127 m; triple: 509 ± 110 m) or end-exercise oxygen uptake (mono: 14.3 ± 4.2 mL kg−1 min−1; dual: 15.0 ± 6.6 mL kg−1 min−1; triple: 13.2 ± 2.4 mL kg−1 min−1). Both end-exercise breathing efficiency (VE/VCO2; mono: 40.1 ± 8.3; dual: 40.9 ± 8.0; triple: 51.8 ± 10.7) and end-tidal carbon dioxide production (PETCO2; mono: 30.5 ± 6.4; dual: 26.7 ± 5.2; triple: 21.8 ± 3.9) were significantly (P < 0.01) different for the triple therapy versus the other therapy groups. Despite groups having a similar exercise capacity on 6MWT, PAH patients on triple therapy have a greater ventilatory response to exercise. These data demonstrate that the addition of cardiopulmonary measures to a 6MWT can differentiate between different severities of PAH and response to PAH therapies.
Predicting clinical deterioration in patients with idiopathic pulmonary arterial hypertension (iPAH)
A-M Harrison,1 E Gabbay,1,2 T Hannon,3 D Playord1,4
1 University of Notre Dame, Fremantle, Australia; 2 Advanced Lung Diseases Unit, Royal Perth Hospital, Perth, Australia; 3 Respiratory West, Wembley, Australia; 4 University of Western Australia, Crawley, Australia
Patients with iPAH receiving disease-specific therapy are assessed regularly, but noninvasive measures predicting deterioration are needed. We investigated whether clinical deterioration of patients with iPAH could be predicted by echo characteristics. Thirty-five stable patients (7 M, 28 F; age 70 ± 10 [SD] years) with iPAH confirmed on right heart catheter (21 with resting iPAH and 14 with iPAH on exercise [eiPAH]) were followed as outpatients in a community-based specialist practice for a mean of 4.1 ± 1.8 years. All echo parameters, including standard 2D echo measurements, estimated PASP (ePASP) atrial volumes, RV Tei index, and calculated pulmonary vascular resistance (cPVR), were collected prospectively, the present study being a retrospective review of this cohort. Patient deterioration was defined as death; worsening of 6-minute walk test (6MWT) distance, NYHA class, or Borg dyspnea score; or increased drug treatment. Sixteen patients improved clinically, 12 were unchanged, and 7 deteriorated, including 2 patients who died. Two patients were current smokers, and neither deteriorated clinically during follow-up. Patients who deteriorated were older (78 ± 10 vs. 68 ± 10 years, P = 0.04) with more severe PAH at baseline (mPAP: 37 ± 9 vs. 27 ± 11 mmHg, P = 0.025; cPVR. 2.9 ± 1.0 vs. 2.0 ± 0.8 WU, P = 0.04). During follow-up, increasing cPVR was the only echo parameter predicting deterioration (change: 1.4 ± 2.3 vs. 0.0 ± 0.4, P = 0.03). Patients with eiPAH were younger than those with iPAH (65 ± 2 vs. 73 ± 2 years), with less severe PAH at baseline (mPAP: 17 ± 1 vs. 37 ± 2 mmHg, P < 0.001; cPVR: 1.6 vs. 2.7 ± 0.3 WU, P = 0.004). During follow-up, no patient with eiPAH clinically deteriorated, and when compared with iPAH patients, the echo-derived PASP and 6MWT improved (–2.6 ± 0.7 vs. 12.7 ± 4.4 mmHg, P = 0.005, and 120 ± 17 vs. 64 ± 20 m, P = 0.04, respectively). One-fourth of patients with treated iPAH at rest deteriorated clinically, whereas treated eiPAH patients remained stable. Deterioration was predicted at baseline by age and PAH severity, but during follow-up only cPVR predicted worsening. The cPVR appears to be a robust measure during follow-up of patients with PAH.
A call for IV therapy for pulmonary artery hypertension (PAH) in New Zealand
T McWilliams, K Whyte, A Coverdale, C Stewart, C Wasywich
Auckland Regional PAH and New Zealand Heart and Lung Transplant Service, Auckland City Hospital, Auckland, New Zealand
Treatment for PAH in New Zealand is tightly restricted for economic reasons, and IV therapy has never been available to patients other than for brief in-hospital use. The only drug registered for IV use is iloprost, and this is funded only in its nebulized form, Ventavis. Dual oral/nebulized combination therapy is funded; however, when this fails, switching drugs and lung transplant (LT), if appropriate, are the only options available to patients. The Auckland Regional PAH Clinic sees around half of all patients in New Zealand on therapy and all patients with PAH being assessed for LT. We wanted to investigate the need for IV therapy in this group by first assessing the severity of patients already on combination therapy (CT) and then developing a criteria for initiating IV therapy. We present the demographics and the 6MW results and hemodynamics of our patients at the start of monotherapy (MT) and CT and the numbers on CT who would be suitable for IV therapy and/or LT. In total, 147 patients with Class I, IV, and V PH (all of whom are eligible for therapy in New Zealand if they have WHO III or IV symptoms) have been under the care of the Auckland Regional service. One hundred eight are female, and mean age at diagnosis is 49 years (SD = 17 years). Mean time to diagnosis was 102 weeks. 52 (35%) had IPAH, 43 (29%) CTD, and 27 (18.2%) had CTEPH. In total, 121 patients have received PH-specific therapy: 72 on MT, 49 on CT, and a further 6 on CCB (calcium channel blocker) therapy. Mean time to combination therapy was 76 weeks. A recent review of this clinic reported a 91% 1-year and 67% 5-year survival. To assess the number of patients eligible for IV therapy if available, we identified 32 of the 49 patients on CT still alive as of January 9, 2012; 13 have died, and 4 have had LT. For these 32 patients (of whom only 12 are LT candidates), the proposed criteria for IV therapy would be persistence of WHO IV, 6MW < 300 m (unless limited by other factors, e.g., gout, obesity, immobility), rising RA, and worsening RHC hemodynamics on combination therapy for 6 months. Clearly, our patients have severe disease at initiation of therapy, and there is a need for IV therapy in New Zealand.
Pharmaceutical Benefits Scheme (PBS)–funded epoprostenol in Australia: are we making optimal use of this therapy?
H Whitford, T Miller, C Manterfield, D Keating, M Richardson, T Williams
Alfred Hospital, Melbourne, Australia
Epoprostenol has been United States Food and Drug Administration (FDA) approved as first-line therapy in pulmonary arterial hypertension (PAH) since 1996. It remains the only agent to show a survival advantage in short-term trials. It is recommended therapy for World Health Organization (WHO) functional class III and IV in the major guidelines, but in practice it is often reserved for treatment failures. Epoprostenol has been PBS funded for idiopathic and heritable PAH since 2006, and more recently for connective tissue–associated PAH. The current PBS listing requires WHO class III patients to fail an oral therapy prior to accessing funded epoprostenol. The aim of this study was to assess outcomes in patients treated with epoprostenol in Australia since 2006. Retrospective analysis of the outcomes of patients treated at a single center with IV epoprostenol. Endpoints were freedom from death or lung transplantation, change in 6MWD, hemodynamics, echocardiographic parameters, and WHO functional class. Twenty-one patients were commenced on IV epoprostenol during this period, 14 female; 16 were WHO class III and 5 class IV. Results are expressed as median and range. Time to commencement of epoprostenol from time of first therapy was 15 (0–49) months. Duration of therapy was 17 (4–50) months. Peak dose achieved was 19.75 (8.25–38.5) ng/kg/min. During this period, 5 patients died, 5 received lung transplantation, 2 were weaned to oral therapies, and 9 are ongoing on epoprostenol. There was a change in 6MWD from baseline at 6 months: 50 (373–444) m, NS; at 12 months: 82.5 (116–510) m, P = 0.008. RAP decreased from a median of 11 (5–25) to 6 (1–23) mmHg, P = 0.02; mPAP fell from 59 (26–76) to 46 (15–69) mmHg, P = 0.02; CI increased from 1.85 (1.17–3.19) to 2.2 (1.73–2.94) L/min/m2, P = 0.28; and PVR fell from 12.5 (7.8–2.5) to 7.05 (2.2–17.4) WU, P = 0.04. No statistically significant changes were found in echocardiographic parameters after 6 or 12 months of therapy, compared to baseline. No difference was found in WHO functional class at 6 or 12 months. Despite improvements in 6MWD and hemodynamics, freedom from death or transplantation is around 50%. Several factors may influence this: the sample size may be too small, the dose too low, or the drug started too late in the natural history of the disease. Alternatively, this group of patients who have failed oral therapies may be less likely to respond to epoprostenol.
No adverse effect in pulmonary arterial hypertension (PAH) patients switched from sitaxsentan to alternate ERA
S Hayes,1 A Keogh,1 T Williams2
1 St. Vincent's Hospital, Sydney, Australia; 2 Alfred Hospital, Melbourne, Australia
Following the withdrawal from market of the pulmonary arterial hypertension (PAH) drug sitaxsentan in December 2010, patients on sitaxsentan had to be switched to an alternate agent. We assessed the clinical effect of this switch on subsequent six-minute walk distance test (SMWD) and echocardiographic parameters. Pulmonary arterial hypertension patients from St. Vincent's Hospital and the Alfred Hospital who were taking sitaxsentan were retrospectively enrolled in this study (total n = 61). These patients were switched to another endothelin receptor antagonist (ERA), either bosentan or ambrisentan, with some patients combining one of these agents with sildenafil. The inclusion criteria required that patient had been taking the drug for >6 months in order that the regular follow-up SMWD and echocardiogram would be available for assessment (n = 30). Data prior to and after the switch, including pre/post scores based on gender, were analyzed using repeated-measures t tests and repeated-measures ANOVA tests. The pre- and post-6MWD data suggested that over half of the population had experienced some degree of functional decline (16/30), while 12 of 30 patients reported improvement and 2 of 30 remained stable. Furthermore, the mean pre- and postswitch 6MWD scores (388 ± 148 vs. 365 ± 182 m) across the entire population suggested that the switch had resulted in some degree of clinical instability. However, repeated-measures t tests revealed no significant difference between mean SMWD on sitaxsentan and that 6 months after the switch (average decrease of 23 ± 80 m; P = 0.135). Repeated-measures ANOVA showed no significant difference in the pre- and postswitch scores in males (n = 4; 514 ± 194 vs. 534 ± 192 m) versus females (n = 26; 366 ± 133 vs. 335 ± 169 m). With regard to the drug therapy used after the switch, repeated-measures ANOVA determined that there was no significant difference in clinical outcomes (P = 0.472; ambrisentan n = 14, bosentan n = 6, bosentan/sildenafil n = 8). Given the small population for the combination of ambrisentan/sildenafil (n = 1) and sildenafil alone (n = 1), these populations were omitted from statistical analysis. Echocardiogram parameters were assessed on a 0–6 semiquantitative scale. Repeated-measures t tests revealed no significant difference in the population between pre- and postswitch echocardiogram results. The statistical analysis evaluated pre- and postswitch mean left atrial size (39.4 ± 6.5 vs. 39.7 ± 6.1 mm), and assessed pre- and postswitch semiquantitative scores for severity of tricuspid regurgitation (2.64 ± 1.6 vs. 2.64 ± 1.7), right ventricular (3.1 ± 1.8 vs. 3.2 ± 2.3), and right ventricular function (1.75 ± 2.1 vs. 2.07 ± 2.4). The findings suggest that patients remained clinically stable when switching from sitaxsentan to another ERA, with no demonstrable deterioration in SMWD or echocardiographic parameters. This adds to other available evidence that a switch between ERAs can be made without clinical detriment.
Which invasive line to choose in pulmonary arterial hypertension?
M Rogers, K O'Brien, P Ve, P Hopkins, F Kermeen
Queensland Lung Transplant Service, Prince Charles Hospital, Chermside, Australia
Guidelines recommend the insertion of a tunneled central venous catheter (Hickman) for the continual administration of IV epoprostenol (EPO) in patients with severe PAH. The practice at our institution is to administer IV EPO via peripherally inserted central catheter (PICC). We carried out a retrospective audit of the incidence of catheter-related infections (CRI) and technical difficulties between PICC and Hickman catheters in 34 patients at a tertiary PAH center (24 F : 10 M) from 2004 to 2012; mean age: 37 years (range: 16–69 years). Thirty-four patients were commenced on IV EPO via PICC, with a total of 70 PICC insertions and 11,322 treatment-days (mean: 474 days). Thirteen clinical CRI were reported in 10 patients: 11 isolates of Staphylococcus aureus and 2 intermediate MRSA, 5 patients had skin allergies to multiple dressings resulting in infection. Five patients reported 10 upper-limb thrombosis events, and 5 PICC lines dislodged or fractured. Ten of the 34 patients were converted to Hickman, with a total of 3,086 treatment-days (mean: 257 days); 4 Hickman CRI were reported: 3 S. aureus and 1 Micrococcus mitus. Three patients reported recurrent upper-limb thrombosis, and 3 patients required reinsertion due to line fracture or dislodgement. In conclusion, there were no differences in CRI or technical problems when comparing PICC and Hickman catheters, supporting the unit's decision to administer IV EPO via PICC lines.
The cyanotic nonbreathless patient: how low do they go?
H Seale,1 J Harris,1 K Hall,1 N Morris,1,2 F Kermeen1
1 School of Rehabilitation Sciences, Griffith University, Gold Coast Campus, Southport, Australia; 2 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia
The 6-minute walk test (6MWT) is reported a safe assessment of exercise capacity in pulmonary arterial hypertension-associated congenital heart disease (PAH-CHD). However, PAH-CHD patients have a marked decrease in arterial oxygen saturation (SpO2) during exercise, which, based on current guidelines, would result in ceasing the 6MWT. Given the clinical value of the 6-minute walk distance (6MWD), many centers continue to undertake 6MWT in PAH-CHD patients, albeit with a marked reduction in end-exercise SaO2. To date, there has been no description of the cardiopulmonary response to 6MWT in PAH-CHD. We report gas exchange abnormalities during a 6MWT to challenge current literature in PAH-CHD. A 39-year-old patient born with transposition of the great vessels, with ventricular septal defect and irreversible PAH (mPAP 87 mmHg), WHO-FC II, and on PAH therapy completed a 6MWT while the gas exchange was measured simultaneously (portable metabolic cart; Cortex). SpO2 was estimated using the average value from two forehead probes. Oxygen carrying capacity (CaO2) was estimated from the resting Hb (17.8 g/dL) and the SaO2. The 6MWD was 563 m with no rest breaks. Pre-exercise SaO2 and rating of exertion (RPE) were 88% and 0 respectively. At the end of the 6MWT, SaO2 was 42%, RPE was 3, heart rate was 161 bpm, oxygen uptake was 17 mL/kg/min, and breathing efficiency (VE/VCO2) was 43.4. The patient's CaO2 fell from 20 to 13 mL/100 mL. This PAH-CHD patient had a marked reduction in the CaO2 during exercise, characterized by an alarming fall in SpO2. Despite this, the individual was able to complete the 6MWT and remain remarkably nonbreathless. These data highlight the need to develop specific guidelines for 6MWT in this PAH subgroup.
Intravenous sildenafil: new role for a not so new drug?
K Shekar,1 R Buschel,1 F Kermeen2
1 Intensive Care Unit, Prince Charles Hospital, Brisbane, Australia; 2 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia
Pulmonary hypertension (PHT) and right ventricular dysfunction (RVD) are important considerations in the management of cardiothoracic (CTS) patients in the ICU. Management involves optimization of oxygenation, ventilation, acid-base balance, volume status, inotrope support, pulmonary vasodilation, and mechanical RV support. Sildenafil, a PDE-5 inhibitor, has been shown to improve exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic Group I PAH. We report our experience in the effectiveness and safety of IV sildenafil in adult CTS patients. Four patients with RVD/PH were prospectively assigned to IV sildenafil: (1) acute PE; (2) severe PH post-(R) pneumonectomy in lung transplant recipient; (3) RVD post–(L) ventricular device insertion; and (4) RVD post–orthotopic heart transplantation. Patients received standard therapy for RVD: mechanical ventilation, inotropes, and inhaled NO. Hemodynamic and echocardiography parameters were compared pre- and post–sildenafil administration. Median sildenafil dose was 1.6 mg/h (IQR: 0.75–2.5 mg/h). There was a significant reduction in CVP (P = 0.03) on day 2. The reductions in mean arterial pressure (P = 0.07) and heart rate (P = 0.2) were not statistically significant. There were no significant increases in inotrope or vasopressors doses, volume administered, or O2 requirements. 3 patients survived to hospital discharge, and 1 died in the ICU. Inhaled NO was weaned in all patients except patient 2. In conclusion, IV sildenafil can be an effective and safe adjunct in the management of PH/RVD in the adult ICU, resulting in improvements in RV function and enabled successful wean of NO. More research is required in a larger population before consideration as a standard of care in management of patients with RVD/PH.
Rocking right ventricle
D Seaton,1 B Shearer,1 K Aldridge,1 F Kermeen2
1 Queensland Nuclear Imaging, Prince Charles Campus, Brisbane, Australia; 2 Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, Australia
The tricuspid annular plane systolic excursion (TAPSE) and S' are validated echocardiography markers of morbidity and mortality in pulmonary arterial hypertension (PAH). We report the concerning anomaly of normalization of quantitative parameters of annular motion in the setting of severe right heart dysfunction (RVD) characterized by the “rocking right ventricle.” Our aim was to perform a comparative analysis on imaging modalities in patients with RVD and normal TAPSE and S'. Cardiac MRI, echocardiography RV fractional area change (FAC), and visual assessment of right ventricular (RV) function are compared. Fourteen patients (50% F) from a tertiary PAH center—5 IPAH, 2 FPAH, 3 PAH-CHD, 2 CTEPH, and 2 out-of-proportion PHT—underwent one echocardiogram (including FAC, TAPSE, and S') with prior cardiac MRI. Mean age of patients was 52.4 ± 17 years, mNYHA class was 2.6 ± 0.5, and m6MWD was 480 ± 166.2 m, with 36% prescribed one, 27% two, and 27% triple PAH therapies. The mRVSP was 98.2 ± 18.4 mmHg, mTAPSE was 19.9 ± 3.7 mm, and mean S' was 11.8 ± 1.8, with mRA size 27.4 ± 5.5 cm and 21% pericardial effusion. Calculated RV FAC was 18.9% ± 6.6%; normal range was >35%, compared to mRVEDV of 141.7 ± 35 mL (BSA corrected) and RVEF of 32.8% ± 7.3%. In conclusion, the visual assessment of the presence of RVD in PAH has high specificity and correlates with cardiac MRI and FAC change on echocardiography. TAPSE and S' have poor correlation and are frequently normal in patients with advanced PAH and associated RVD. Visual assessment in PAH patients may have a characteristic appearance with “rocking” of the RV during the cardiac cycle and tricuspid annular motion dissociated from overall RV function.