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a Comprehensive Cardiovascular Care Group, Milwaukee, Wisconsin
b Infectious Disease Associates, Milwaukee, Wisconsin
c United Therapeutics Corporation, Research Triangle Park, North Carolina
Accepted for publication November 20, 2007.
* Address correspondence to Dr Zwicke, Comprehensive Cardiovascular Care Group, 2801 W. Kinnickinnic River Pkwy, Ste 777, Milwaukee, WI 53215 (Email: dzwicke1{at}yahoo.com).
| Ms Strootman and Dr Rollins disclose that they have a financial relationship with United Therapeutics Corp.
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Abstract |
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Coronary artery bypass grafting (CABG) surgery is one of the most frequently performed surgical procedures in the United States. The saphenous vein (SV) is the most common conduit for coronary revascularization. Impaired healing of the SV harvest incision has been reported to occur in 1% to 24% of cases and is a potentially limb-threatening complication that contributes substantially to postoperative morbidity and costs [1]. Peripheral arterial disease (PAD) has been identified as a major correlate to the development of a major SV harvest wound complication, with female sex, obesity, diabetes mellitus, and the postoperative use of an intraaortic balloon pump (IABP) as other significant independent predictors [2, 3].
We report the successful treatment of multiple, nonhealing SV harvest incisions with continuous subcutaneous infusion of treprostinil, an analog of prostacyclin. Prostacyclin (prostaglandin I2 or PGI2) and its analogues have potent vasodilatory and platelet antiaggregatory properties and have been studied with some success in critical limb ischemia for more than 10 years [4]. Several small trials of treprostinil sodium have suggested efficacy in relieving ischemic rest pain and facilitating ischemic wound healing [5–8].
This patient is a 70-year-old man with a significant medical history of PAD, coronary artery disease, congestive heart failure, hypertension, and renal insufficiency. He underwent a third aortic valve replacement procedure, with reimplantation of the left main coronary artery and revascularization of the right coronary artery. Endoscopic harvest of the SV from the left lower leg was unsuccessful, and the left lesser SV was harvested using an open harvest technique.
A pericardial tamponade developed postoperatively, and the patient underwent reoperation for the evacuation of a mediastinal hematoma. Owing to persistent right ventricular dysfunction unresponsive to dobutamine and epinephrine, an IABP was inserted in the left femoral artery for ventricular support. He stabilized during the next 2 days and was discharged to home on postoperative day 7. There was no documentation of a preoperative peripheral vascular evaluation.
Five weeks after discharge, the patient was referred to the wound care center for evaluation of the nonhealing SV harvest incisional wounds. The incisions had dehisced soon after discharge and were unresponsive to standard wound care, which consisted of neomycin and polymyxin B dressings as well as prophylactic antibiotics.
The lower leg appearance was noted to be consistent with the stigmata of PAD: dermal atrophy, rubor, and ecchymosis. An arteriogram confirmed inoperable lesions with complete occlusion of the left superficial femoral, popliteal, and tibial arteries. In the opinion of the wound care consultant, hyperbaric treatment and aggressive débridement could lead to more tissue loss in the presence of critical limb ischemia, and a conservative wound care regimen consisting of daily mupirocin dressings was started.
After 2 weeks with no improvement, the patient signed appropriate informed consent and enrolled in an open-label, 12-week study evaluating the safety and efficacy of a continuous subcutaneous infusion of treprostinil on ischemic wound healing. Four measurable lower leg wounds were identified: a superior medial incision wound area measuring 4 cm2, an inferior medial incision area measuring 4.8 cm2 (endoscopic SV harvest sites), and the posterior incision (open SV harvest site), which had dehisced in 2 places—a superior wound area measuring 3.8 cm2 and an inferior wound measuring 1.2 cm2. The wound beds had various stages of eschar formation and no signs of granulation or infection.
The patient was trained in the management of a pager-sized ambulatory infusion pump (MiniMed 407C; Medtronic, Northridge, CA) and subcutaneous catheter. Continuous infusion of treprostinil was initiated as an outpatient therapy at a starting dose of 2 ng/kg/min. The dose was increased by approximately 1 ng/kg/min daily. The patient’s daily wound care regimen of neomycin and polymyxin B dressings continued unchanged.
By week 2, a treprostinil dose of 14.6 ng/kg/min was reached. Adverse events of mild to moderate jaw pain and headache were resolved by decreasing the maximal dose to 11 ng/kg/min for the remainder of the study. The patient also experienced intermittent mild to severe pain at the infusion site, a well-characterized treprostinil side effect that was managed by relocating the catheter site or oxycodone with acetaminophen.
Considerable improvement in the wounds was observed as early as the second week of therapy, with closure of the superior medial incision and the inferior posterior incision. The superior posterior incision closed by the fourth week. The inferior medial incision proved to be the most difficult to heal and measured 1.5 cm2 at week 12, a 78% reduction in area. The patient received 2 additional weeks of treprostinil, and closure of the final wound was noted (Figs 1 and 2).
The patient has had no further wound problems.
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Mohler and colleagues [5] demonstrated a 35% improvement in common femoral artery blood flow (p = 0.018) in 8 patients with severe intermittent claudication receiving intravenous treprostinil. In 2 patients with minimal or no detectable blood flow before infusion, arterial blood flow at the ankle level was observed on ultrasonography. In another pilot study of 7 patients with recalcitrant wounds of greater than 3 months’ duration who had failed to respond to hyperbaric treatment, transcutaneous oxygen pressure and laser Doppler values increased 44% to 175% and 236%, respectively, with subcutaneous treprostinil [6].
Treprostinil is approved for continuous intravenous or subcutaneous use in patients with pulmonary arterial hypertension. Subcutaneous infusion sites may be any area where a subcutaneous injection can be given (thighs, upper arm, and abdomen), but the fatty areas of the abdomen are generally preferred. Therapy is systemic, and there is no relationship between the location of the infusion site and wounds to be treated. Dosing generally is started in the clinic, and patients are observed for several hours, after which treatment and subsequent dose changes may be managed on an outpatient basis. In this patient, dosing was based on our experience in patients with pulmonary arterial hypertension as well as the doses reported in the small peripheral ischemia studies. We titrated the dose based on clinical signs of improved wound healing and tolerability (emergence of prostacyclin side effects such as headache, jaw pain, nausea). In the previous studies in PAD, improved blood flow, wound healing, and ischemic pain relief were observed with doses of 15 to 20 ng/kg/min, [5–8], comparable with the effective dose in this case.
Patients at risk for vein graft harvest complications may be identified by a preoperative assessment for risk factors that includes examination of peripheral pulses and measurement of the ankle-brachial pressure index. The use of an IABP poses an additional risk on already compromised limbs, further impairing lower limb perfusion. When delayed wound healing occurs, assessment of limb perfusion and vascular interventions may be warranted. Treatment with treprostinil may have a place as intensive therapy to heal intractable wounds related to ischemia, particularly in the absence of a surgical target.
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