Disease Progression
As PH progresses the PVR rises and cardiac output falls. Initially dyspnoea may occur with exertion and subsequently at rest. Chest pain, palpitations, pre syncope, syncope or haemoptysis may be reported and ultimately the signs and symptoms of right heart failure develop. A median survival of 2.8 years has been reported for untreated patients in NYHA class 3 or 4.3,5,6 PH crises are acute elevations in PVR and are potentially life threatening as a consequence of acute reduction in left heart filling with profound systemic hypotension. This can occur during general anaesthetic induction (e.g. when the systolic vascular resistance falls) and is one of the reasons that patients with PAH need careful preoperative evaluation prior to surgical intervention.
Surgical Intervention
Pre-operative close communication between the PH team, surgeons and anaesthetists is essential when patients with PH require surgical intervention. The patient may require deployment of a PA flotation catheter perioperatively, advice may be required on fluid replacement, optimal haemoglobin values inotropic and vasoactive support and how baseline therapy will be given if patients are intolerant of oral drugs post op. It is important that the patient is managed in an appropriate environment e.g. for some patients post-operative management in intensive care may be appropriate and that appropriate work up and treatment strategies are defined. A joint discussion regarding the most appropriate approach to surgical intervention e.g. open versus laproscopic should take place. For example, laparoscopic abdominal surgery may require intra-abdominal gas inflation and this may compromise venous return, which in turn may be poorly tolerated. Additionally, pre-operative close communication and assessment will ensure that if a pulmonary hypertensive crisis develops, appropriate information will have been given to staff who will have management strategies in place. Whenever possible, patients with congenital heart disease should be managed in a congenital heart disease centre. Pregnant women with PAH should always be supervised closely by a PH centre and delivery should ideally be made at a specialist centre or have a PH specialist as part of the multi-disciplinary team in attendance.32
Depending on the underlying cause of PH and the kind of surgery proposed, mortality rates between 7 % and 24 % have been reported especially in cases of emergency interventions.32–35 It is clear that PH must be diagnosed, classified and treated pre-operatively and that there is pre-operative multi-disciplinary input. The necessity for surgery must be scrutinised bearing in mind the potential risks attendant on the proposed procedure for the patient and their median-term outcome on the basis of their PH alone independent of intervention. Pre-operative optimisation includes identifying and addressing conditions contributing to PH and assessing whether peri- and post- operative pulmonary vaso dilators are necessary. It is important that PH specialists are involved in the pre-operative treatment strategy.
Treatment
If patients have PH occurring in association with other disease processes their primary disorder should be optimised in the first instance. Strategies for the treatment of PAH vary around the world and typically advanced pulmonary vasodilator therapy is given to those patients who are in groups 1 and 4 and those who are in renal failure on dialysis. It is customary for advanced pulmonary vaso dilator therapy to be prescribed if the mPAP exceeds 25 mmHg at rest and the mean pulmonary capillary wedge pressure is less than 15 mmHg. Usually patients who receive specific targeted therapy are in World Health Organization (WHO) functional class 2, 3 or 4.1,2,4,36
There is insufficient evidence to justify the use of specific targeted therapy to treat patients whose PH occurs in association with lung disease. Furthermore, there is concern that should patients have PH in association with cardiac disease with left atrial filling pressure above 15 mmHg, specific targeted therapy may lead to increased venous return that, in turn, can exacerbate or produce acute left heart failure. Patients with obstructive sleep apnoea should have appropriate treatment e.g. lifestyle advice, nocturnal nasal continuous positive airway pressure in the first instance and only have consideration given to advanced pulmonary vasodilator therapy should PH persist after standard therapies for sleep-disordered breathing have been prescribed.1,4
For the majority of patients who develop PAH there is no effective cure, but the use of specific targeted therapeutic agents have been shown to improve exercise capacity, WHO functional class, haemodynamic parameters and time-to-clinical worsening. Recent evidence suggests that one of the newer endothilin receptor antagonists (ERA), macitentan, may be associated with improved survival, although further studies are required to support this.37 Usually ERAs are prescribed as second-line therapy after patients have been started on either a calcium channel blocker or much more commonly a phosphodiesterase type 5 inhibitor. ERAs are contraindicated in pregnancy because of concerns relating to teratogenicity.
A small number of PAH patients may respond to calcium channel blockers; however, calcium channel blockers are not effective for the vast majority of patients with PAH. They should only be prescribed either by or in conjunction with PH specialists and should not be given as an alternative to recommended therapies.
Sildenafil and tadalifil are phosphodiesterase type V inhibitors acting on the nitric oxide pathway promoting vaso dilatation. Sildenafil may also possess anti-proliferative effects on vascular smooth muscle.37–39 Soluble guanylate cyclise stimulators (e.g. riociguat) reduce intracellular calcium in a nitric oxide dependent and independent fashion and have been used to treat patients with PAH and those whose PH is associated with CTEPH.40
Usually patients are started on a phosphodiesterase V inhibitor and then either an ERA is added or replaces the initial agent. There are different ERAs available that can block either the endothelin A or A and B receptors and these antagonise vaso contriction and vascular remodelling promoted by the excessive endothelin release known to occur in patients with PAH.1,2,4,6,36–39
As a consequence of other endothelial factors that are absent or deficient in patients with PAH some patients, usually those in WHO class 3 who are unresponsive to combination therapy or in class 4 can be given intravenous continuous prostacyclin therapy, although this agent can also be prescribed by regular inhalation of subcutaneous injection.4 A newer oral formulation is expected to be available for clinical use within the next 2 years. However, the precise role of combination therapies for patients with PAH is receiving constant evaluation. There are a variety of other agents being studied, which include anti-inflammatory drugs, monoclonal antibodies, anti-platelet agents and lipid-lowering compounds.4,36
For some patients in class 4 disease, atrial septostomy is available to offload the right ventricle as a bridge to transplantation.40
Pulmonary thromboendarterctomy is available for selected patients with CTEPH although this is a major operation with a complication rate approximating 50 %. It should be performed in specialised centres.4,36 Lung transplantation (single or more usually bilateral) is an option for carefully selected patients, but limited donor organ availability and the complication of obliterative bronchiolitis remain major problems to be addressed.