Skoro-Sajer et al PAH patients may have to be revisited with the complete range of clinical and hemodynamic endpoints usually applied in PAH trials (Simmoneau et al 2002). Any continuous drug administration through an implanted central venous catheter carries a risk of line infec- tion and sepsis. While the overall incidence of this severe complication is very low, there has been a recent concern about an increased number of gram-negative bloodstream infections in patients treated with intravenous treprostinil compared with intravenous epoprostenol (CDC 2007). This problem appears to be related to differences in prepara- tion and storage, and should be overcome by tightening of sterility precautions. An inhaled formulation of treprostinil is currently being evaluated with encouraging preliminary results (Channick et al 2006). The preliminary results of a randomized con- trolled trial of inhaled treprostinil on top of bosentan or sildenaﬁl therapies have been reported as a press release, with a signiﬁcance on the primary endpoint, the 6-min walk distance. A more detailed report on these results will be hopefully presented soon at a scientiﬁc meeting. Randomized controlled trials of an oral formulation of treprostinil are ongoing. Treprostinil for CTEPH As already mentioned, subcutaneous treprostinil has been occasionally used to treat patients with inoperable CTEPH (Lang et al 2006). The rationale is that pulmonary hyper- tension in these patients may be essentially accounted for by distal vasculopathy, which is actually hispathologically similar to PAH (Hoeper et al 2006). The effects of subcutane- ous treprostinil have been recently reported in 25 inoperable CTEPH patients included in an open-label uncontrolled study (Skoro-Sajer et al 2007). All patients were in NYHA functional classes III or IV, had a 6-min walk distance of less than 380 m, and had undergone at least 1 previous hospitalization for right heart failure within the previous 6 months. The patients were compared to matched historical inoperable CTEPH controls. The patients were followed for 19 ± 6 months. Treprostinil treatment improved survival, increased the 6-min walk distance, improved NYHA func- tional class, decreased B-type natriuretic peptide, increased cardiac output and decreased PVR. Treprostinil plasma levels correlated with drug dose over time, indicating persistently stable absorption, in spite of local reactions in 86% of cases. Thus, subcutaneous treprostinil shows as an interesting therapeutic option for patients with inoperable CTEPH. Subcutaneous treprostinil offers perspective for the treatment 512 of persistent postoperative pulmonary hypertension, or for the preoperative conditioning of patients for surgery in case of excessively high PVR, known to be a poor operative risk. However, these possible indications will have to be conﬁrmed in properly designed randomized controlled trials. Indications and usage Chronic subcutaneous treprostinil has a place in the treatment algorithm of patients with PAH in functional classes II, III, and IV (Galie et al 2004; Badesch et al 2007). The recommendation is to start treprostinil at the dose of 1.25 ng/kg/min, which is increased by 1.25 ng/kg/min per week during the ﬁrst 4 weeks, then by 2.5 ng/kg/min per week until the maximum clinical improvement with no excessive prostacyclin-type side effects. However, in practice most centers now start at 2.5 ng/kg/min and increase in a few days to reach 10 ng/kg/min after a week and 15–20 ng/kg/min after 2 weeks according to tolerance. Weekly adaptations are applied afterwards, aiming at optimal clinical efﬁcacy with minimal side effects. This strategy appears to be safe, allows for more rapid and effective relief in severely ill patients, and outruns the local infusion site pain, which is of course better tolerated in the context of decreased dyspnea and fatigue. Local infusion site pain will occur in around 80% of patients, and may be intolerable in 6%–15% of them. It var- ies markedly from one patient to another, from one infusion site to another, is primarily related to initiation of infusion, and often, but not always, improves after several months. It is usually worse during the ﬁrst days following a change of infusion site, and may sometimes impair the ability of a patient to perform a 6-min walk test. It has been our experi- ence that the administration of more concentrated solutions, starting with 2.5 mg/mL to progress as soon as possible to the use of 5 mg/mL or 10 mg/mL vials, decreases the local pain by decreasing the amount of volume infused for the same dose. The pain is otherwise generally manageable by relocation of infusion site, cold or hot compresses, a variety of local ointments, and paracetamol. Sometimes, a short course of high dose corticosteroids, such as prednisolone 2 mg/kg/day during several days, may help the patient through, and narcotic drugs have been used in some centers. These more aggressive interventions may appear necessary when patients present with severe pain that reduces quality of life. In these cases, especially if on high dose treprostinil, transitioning to intravenous epoprostenol may fail because of major prostacyclin-type side effects of equivalent dose intravenous epoprostenol, and carries the risk of clinical destabilization. It is therefore preferable to switch from Vascular Health and Risk Management 2008:4(3)