Safety and efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension in the Netherlands.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an emerging treatment in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTED). We describe the first safety and efficacy results of BPA in the Netherlands. METHODS: We selected all consecutive patients with inoperable CTEPH and CTED accepted for BPA treatment who had a six-month follow-up in the St. Antonius Hospital in Nieuwegein and the Amsterdam University Medical Center (UMC) in Amsterdam. Functional class (FC), N­terminal pro-brain natriuretic peptide (NT-proBNP), 6­minute walking test distance (6MWD) and right-sided heart catheterisation were performed at baseline and six months after last BPA. Complications for each BPA procedure were noted. RESULTS: A hundred and seventy-two BPA procedures were performed in 38 patients (61% female, mean age 65 ± 15 years). Significant improvements six months after BPA treatment were observed for functional class (63% FC I/II to 90% FC I/II, p = 0.014), mean pulmonary artery pressure (-8.9 mm Hg, p = 0.0001), pulmonary vascular resistance (-2.8 Woods Units (WU), p = 0.0001), right atrial pressure (-2.0 mm Hg, p = 0.006), stroke volume index (+5.7 ml/m2, p = 0.009) and 6MWD (+48m, p = 0.007). Non-severe complications occurred in 20 (12%) procedures. CONCLUSIONS: BPA performed in a CTEPH expert centre is an effective and safe treatment in patients with inoperable CTEPH.

Healthcare utilization in chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.

Essentials Diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) is long. We explored healthcare utilisation of patients diagnosed with CTEPH after pulmonary embolism. A large number of physicians were consulted and test results were not always interpreted correctly. Better education and higher awareness of CTEPH may lead to faster diagnosis. SUMMARY: Background The median diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) is 14 months, which may affect prognosis. We aimed to explore the healthcare utilization of patients diagnosed with CTEPH after acute pulmonary embolism (PE), and to identify the causes of diagnostic delay. Methods We collected all data on patient symptoms, medical specialist referrals and ordered diagnostic tests to reconstruct the clinical pathways of 40 patients referred to the VU University Medical Center Amsterdam (VUMC, the Netherlands) for CTEPH treatment. Diagnostic delay was defined as the time between first symptom onset and referral to the VUMC. Correlations of patient-specific characteristics and diagnostic delay were evaluated. Results Patients consulted four (median) different physicians for a median of 13 (interquartile range [IQR] 10-18) consultations before the correct diagnosis was made. The median diagnostic delay was 21 months (IQR 12-49 months). Echocardiographic results suggestive of CTEPH were not always followed by an adequate work-up; most patients were not subjected to ventilation/perfusion scanning. Prior cardiopulmonary comorbidity and recurrent venous thromboembolism were predictors of a longer delay. Conclusion Healthcare utilization in patients before their final CTEPH diagnosis was far from optimal, contributing to a considerable diagnostic delay. Better education and higher awareness of CTEPH among PE caretakers may lead to faster diagnosis.

Using patient data to optimize an expert-based guideline on convalescence recommendations after gynecological surgery: a prospective cohort study.

BACKGROUND: Convalescence advice is often based on tradition and anecdote from health care providers, rather than being based on experiences from patients themselves. The aim of this study was to analyse recovery in terms of resumption of various daily activities including work, following different laparoscopic and abdominal surgery in order to optimize an expert-based guideline on convalescence recommendations. METHODS: This is a prospective cohort study conducted in nine general and one university hospital in the Netherlands. Women aged 18-65 years and scheduled for a hysterectomy (laparoscopic, vaginal, abdominal) and/or laparoscopic adnexal surgery (n = 304) were eligible to participate. Preoperatively, participants were provided with tailored expert-based convalescence recommendations on the graded resumption of several daily activities including sitting, standing, walking, climbing stairs, bending, lifting, driving, cycling, household chores, sport activities and return to work (RTW). Postoperatively, time until the resumption of these activities was tracked. Convalescence recommendations were considered correct when at least 25% and less than 50% of the women were able to resume an activity before or at the recommended recovery time. RESULTS: There was a wide variation in the duration until the resumption of daily activities within and between groups of patients undergoing different types of surgery. Recovery times lengthened with increasing levels of physical burden as well as with increasing levels of invasiveness of the surgery. For the majority of activities actual recovery times exceeded the recovery time recommended by the expert panel. CONCLUSIONS: This study provided insight in the resumption of daily activities after gynecological surgery and the adequacy of an expert-based convalescence guideline in clinical practice. Patient data was used to optimize the convalescence recommendations. TRIAL REGISTRATION: Dutch trial registry, NTR2087 (August 2009) and NTR2933 (June 2011).

Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

Platypnoea-orthodeoxia syndrome, an underdiagnosed cause of hypoxaemia: four cases and the possible underlying mechanisms.

Cardiac platypnoea-orthodeoxia syndrome (POS) is a position-dependent condition of dyspnoea and hypoxaemia due to right-to-left shunting. It often remains unrecognised in clinical practice, possibly because of its complex underlying pathophysiology. We present four consecutive patients with POS and patent foramen ovale (PFO) who underwent a successful percutaneous PFO closure, describe the mechanism of their POS and provide a review of the literature.

Granulomatous lung disease in a patient with a family history of hematological disorders.

BACKGROUND: A 29-year old patient presented with granulomatous lung disease and a family history of myelodysplastic syndrome/acute myeloid leukemia. She appeared to be a carrier of a mutation in the transcription factor GATA2. The case adds to the recent described heterogeneous clinical manifestations and syndromes in which, against a background of hematologic disorders, GATA2 mutations have been demonstrated, such as the Monomac and Emberger syndromes. In patients with a granulomatous disease and a history of (familial) hematologic disorders, the occurence of GATA2 mutations should be considered, as to gain further insight in the occurrence of granulomatous disease in a possible distinct phenotype among GATA2 mutation carriers.

A personalised eHealth programme reduces the duration until return to work after gynaecological surgery: results of a multicentre randomised trial.

OBJECTIVE: To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery. DESIGN: Randomised multicentre trial that ran from March 2010 until September 2011. SETTING: Secondary care in seven general and university hospitals in The Netherlands. POPULATION: A cohort of 215 women (aged 18-65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication. METHODS: The women were randomly assigned to the intervention group (n = 110) or the control group (n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre- and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website. MAIN OUTCOME MEASURES: The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity. RESULTS: In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003-2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20-67 days) in the intervention group and 48 days (interquartile range 21-69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04-3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4-57; P = 0.024) in the intervention group, compared with the control group. CONCLUSIONS: The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain.

Pressure-overload-induced right heart failure.

Although pulmonary arterial hypertension originates in the lung and is caused by progressive remodeling of the small pulmonary arterioles, patients die from the consequences of pressure-overload-induced right heart failure. Prognosis is poor, and currently there are no selective treatments targeting the failing right ventricle. Therefore, it is of utmost importance to obtain more insights into the mechanisms of right ventricular adaptation and the transition toward right heart failure. In this review, we propose that the same adaptive mechanisms, which initially preserve right ventricular systolic function and maintain cardiac output, eventually initiate the transition toward right heart failure.

Prediction of time to return to work after gynaecological surgery: a prospective cohort study in the Netherlands.

OBJECTIVE: To measure the impact of the level of invasiveness of gynaecological procedures on time to full Return to Work (RTW) and to identify the most important preoperative sociodemographic, medical and work-related factors that predict the risk of prolonged sick leave. DESIGN: Prospective cohort study. SETTING: Dutch university hospital. POPULATION: A total of 148 women aged 18-65 years scheduled for gynaecological surgery for benign indications. METHODS: A questionnaire regarding the surgical procedure as well as perioperative and postoperative complications was completed by the attending resident at baseline and 6 weeks after surgery. All other outcome measures were assessed using self-reported patient questionnaires at baseline and 12 weeks post-surgery. The follow-up period was extended up to 1 year after surgery in women failing to return to work. Surgical procedures were categorised into diagnostic, minor, intermediate and major surgery. MAIN OUTCOME MEASURES: Time to RTW and important predictors for prolonged sick leave after surgery. RESULTS: Median time to RTW was 7 days (interquartile range [IQR] 5-14) for diagnostic surgery, 14 days (IQR 9-28) for minor surgery, 60 days (IQR 28-101) for intermediate surgery and 69 days (IQR 56-135) for major surgery. Multivariable analysis showed a strongest predictive value of RTW 1 year after surgery for level of invasiveness of surgery (minor surgery hazard ratio [HR] 0.51, 95% CI 0.32-0.81; intermediate surgery HR 0.20, 95% CI 0.12-0.34; major surgery HR 0.09, 95% CI 0.06-0.16), RTW expectations before surgery (HR 0.55, 95% CI 0.36-0.84), and preoperative functional status (HR 1.09, 95% CI 1.04-1.13). A prediction model regarding the probability of prolonged sick leave at 6 weeks was developed, with a sensitivity of 89% and a specificity of 86%. CONCLUSIONS: RTW often takes a long time, especially after intermediate and major surgery. This study reveals important predictors for prolonged sick leave and provides a prediction model for the risk of sick leave extending 6 weeks after benign gynaecological surgery in the Netherlands.

Process evaluation of a multidisciplinary care program for patients undergoing gynaecological surgery.

PURPOSE: This study describes the process evaluation of an innovative multidisciplinary care program for patients undergoing benign gynaecologic surgery. This care program aims at improving recovery and preventing delayed return to work and consists of two steps: (1) an interactive e-health intervention for all participants, and (2) integrated clinical and occupational care management for those participants whose sick leave exceeds 10 weeks. METHODS: Eligible for this study were employed women aged between 18-65 years scheduled for a laparoscopic adnexal surgery and/or hysterectomy. Data were collected from patients, their supervisors and their gynaecologists, by means of electronic questionnaires during a 6 month follow-up period and an automatically generated, detailed weblog of the patient web portal ( www.ikherstel.nl ). Investigated process measures included: reach, dose delivered, dose received, and fidelity. In addition, attitudes towards the intervention were explored among all stakeholders. RESULTS: 215 patients enrolled in the study and accounted to a reach of 60.2 % (215/357). All intervention group patients used their account at least once and total time spent on the patient web portal was almost 2 h for each patient (median 118 min, IQR 64-173 min). Most patients visited the website several times (median 11 times, IQR 6-16). Perceived effectiveness among patients was high (74 %). In addition, gynaecologists (76 %) and employers (61 %) were satisfied with the web portal as well. Implementation of the second step of the intervention was suboptimal. Motivating patients to consent to additional guidance and developing an accurate return-to-work-prognosis were two important obstacles. CONCLUSIONS: The results of this study indicate good feasibility for implementation on a broad scale of the e-health intervention for patients undergoing benign gynaecological surgery. To enhance the implementation of the second step of the perioperative care program, adaptations in the integrated care protocol are needed.

The role of the right ventricle in pulmonary arterial hypertension.

Although changes in the pulmonary vasculature are the primary cause of pulmonary arterial hypertension (PAH), severity of symptoms and survival are strongly associated with right ventricular function, and right heart failure is the main cause of death in patients with PAH. Echocardiography and cardiac magnetic resonance imaging allow noninvasive evaluation of right ventricular function and structure, and a number of indices have been shown to have potential prognostic value in PAH. Given the importance of the right ventricle in PAH, preservation and improvement of its function should be important aspects of therapy; however, there are currently few data specifically related to this aspect of treatment response. Simple, reproducible, noninvasive measures of right ventricular function would help to improve the management of patients with PAH, and to provide tools with which to help establish the optimal therapeutic approach to manage not only the effects of the disease on the pulmonary vasculature, but also to support and improve right ventricular function.

Genetic counselling for pulmonary arterial hypertension: a matter of variable variability.

We report three cases which highlight the complex considerations surrounding genetic counselling for pulmonary arterial hypertension (PAH). The first counselee developed PAH symptoms shortly after his daughter's death from PAH and was diagnosed with a delay of 1 year. An early diagnosis of familial PAH was established in the second counselee. Oral therapy was initiated immediately, and her functional status has since remained stable. The third counselee was a healthy woman who struggled to cope with her risk for familial PAH, having lost two siblings from the disease. These cases show that incomplete penetrance and variable expression need particular attention during clinical assessment and genetic counselling of heritable PAH patients and family members.

Multidisciplinary convalescence recommendations after gynaecological surgery: a modified Delphi method among experts.

OBJECTIVE: To generate structured detailed uniform convalescence recommendations after gynaecological surgery by a modified Delphi method amongst experts and a representative group of physicians. DESIGN: Modified Delphi study. SETTING: Expert physicians recruited by their respective medical boards and employed at different hospitals, doctor's surgeries and healthcare services. POPULATION: Twelve experts (five gynaecologists, two general practitioners [GPs] and five occupational physicians [OPs]) and a representative sample of 63 medical doctors. METHODS: Multidisciplinary detailed recommendations for graded resumption of relevant activities after uncomplicated hysterectomy (laparoscopic supracervical, total laparoscopic/laparoscopic-assisted, vaginal and abdominal hysterectomies) and laparoscopic adnexal surgery were developed. Recommendations were based on a literature review and a modified Delphi procedure among 12 experts, recruited in collaboration with the participating medical boards of gynaecologists, GPs and OPs. MAIN OUTCOME MEASURES: A multidisciplinary consensus of at least 67% on the relevant detailed convalescence recommendations in relation to hysterectomy and laparoscopic adnexal surgery. RESULTS: Out of initially 65 activities, the expert panel judged 38 activities relevant for convalescence recommendations. Consensus for all activities was achieved after four Delphi rounds and two group discussions. The recommendations were judged as feasible by a representative sample of 26 gynaecologists, 19 GPs and 18 OPs. CONCLUSIONS: Consensus between gynaecologists, GPs and OPs was achieved on all relevant convalescence recommendations regarding hysterectomy (abdominal, vaginal and laparoscopic) and laparoscopic adnexal surgery.

Diaphragm muscle fiber function and structure in humans with hemidiaphragm paralysis.

Recent studies proposed that mechanical inactivity of the human diaphragm during mechanical ventilation rapidly causes diaphragm atrophy and weakness. However, conclusive evidence for the notion that diaphragm weakness is a direct consequence of mechanical inactivity is lacking. To study the effect of hemidiaphragm paralysis on diaphragm muscle fiber function and structure in humans, biopsies were obtained from the paralyzed hemidiaphragm in eight patients with hemidiaphragm paralysis. All patients had unilateral paralysis of known duration, caused by en bloc resection of the phrenic nerve with a tumor. Furthermore, diaphragm biopsies were obtained from three control subjects. The contractile performance of demembranated muscle fibers was determined, as well as fiber ultrastructure and morphology. Finally, expression of E3 ligases and proteasome activity was determined to evaluate activation of the ubiquitin-proteasome pathway. The force-generating capacity, as well as myofibrillar ultrastructure, of diaphragm muscle fibers was preserved up to 8 wk of paralysis. The cross-sectional area of slow fibers was reduced after 2 wk of paralysis; that of fast fibers was preserved up to 8 wk. The expression of the E3 ligases MAFbx and MuRF-1 and proteasome activity was not significantly upregulated in diaphragm fibers following paralysis, not even after 72 and 88 wk of paralysis, at which time marked atrophy of slow and fast diaphragm fibers had occurred. Diaphragm muscle fiber atrophy and weakness following hemidiaphragm paralysis develops slowly and takes months to occur.

Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target.

Iron deficiency is known to be common and detrimental in chronic left heart failure, where parenteral iron treatment has been shown to improve exercise capacity, New York Heart Association functional class and patient wellbeing. There is now increasing interest in the role of iron in the natural history of pulmonary arterial hypertension (PAH). Iron availability influences the pulmonary vasoconstrictor response to hypoxia and accumulating evidence indicates that iron deficiency is prevalent in idiopathic and heritable forms of PAH, iron status being related to exercise capacity, symptoms and poorer survival in patients with idiopathic PAH (IPAH). Potential mechanisms behind iron deficiency in IPAH include inhibition of dietary iron uptake by the master iron regulator hepcidin. High hepcidin levels underlie the anaemia of chronic disease. Possible stimuli of the observed high levels of hepcidin in IPAH include dysfunctional bone morphogenetic protein receptor type II signalling and inflammation. Iron status may influence outcomes through modulation of the pulmonary circulation as well as myocardial and skeletal muscle function. Two parallel studies, from our centre (Hammersmith Hospital, London, UK) and others in the UK and Amsterdam (the Netherlands), investigating the safety and potential benefit of iron supplementation in patients with PAH are currently under way.