Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH).
BACKGROUND
Although surgery is the treatment of choice for CTEPH, it is not appropriate for patients with surgically inaccessible distal disease. These patients are traditionally managed supportively, but may benefit from newer, more specific vasoactive therapies. This study examines the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in this patient population.


METHODS
Nine patients with de novo distal CTEPH and nine with persistent pulmonary hypertension post-pulmonary endarterectomy (PEA) were enrolled. At right heart catheterisation, following baseline haemodynamic measurements, iNO was administered at 20 ppm for 10 min. Following repeat measurements, iNO was discontinued with a subsequent washout period of 10 min. Sildenafil was then administered intravenously at two doses, to achieve plasma levels equivalent to 25 mg and 50 mg orally, with further measurements obtained at the end of each infusion.


RESULTS
Significant reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were demonstrated following both iNO (-4.3 mm Hg or -10.3% p=0.001 and -101 dyn/s/cm(5) or -15.6% p<0.001) and sildenafil (-7.4 mm Hg or -16.9% p<0.001 and -188.8 dyn/s/cm(5) or -25.1% p<0.001). Individual mPAP and cardiac output (CO) responses to iNO and sildenafil correlated well, but haemodynamic changes following sildenafil were consistently more marked. There was, however, no difference in effect between the two doses of sildenafil. Although sildenafil caused significant reductions in systemic vascular resistance, the net haemodynamic effect of sildenafil remained pulmonary selective. Subgroup analysis suggested that post-PEA patients were more responsive to both iNO and sildenafil than de novo patients.


CONCLUSIONS
Although all but one patient failed to fulfil the formal haemodynamic response criteria typically used in idiopathic pulmonary arterial hypertension (IPAH), subjects displayed significant acute responses to both iNO and sildenafil suggesting that increased vascular tone forms an important component of distal CTEPH. It is possible that these acute haemodynamic responses may translate to improved clinical outcomes, and thus further long term trials of sildenafil in distal CTEPH are warranted.
Suntharalingam
J
J
Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridgeshire, CB3 8RE, UK.
Hughes
R J
RJ
Goldsmith
K
K
Doughty
N
N
George
P
P
Toshner
M
M
Sheares
K K
KK
Pepke-Zaba
J
J
D000280:Administration, Inhalation; D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage* / Q000627:therapeutic use; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage* / Q000627:therapeutic use; D013923:Thromboembolism / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000627:therapeutic use
D000959:Antihypertensive Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate