Abstract
Continuous prostanoid infusion is an established treatment for pulmonary arterial hypertension that has led to improvements in symptoms, exercise tolerance, and survival. Patients with pulmonary arterial hypertension (PAH) who develop sepsis frequently experience clinical and hemodynamic deterioration associated with poor outcomes. Successful management of sepsis involves identification of the source of infection, early antimicrobial administration, judicious fluid resuscitation, and continuation of specific PAH therapies. We describe successful management of a patient with idiopathic PAH receiving chronic intravenous prostacyclin therapy who developed an aortic root abscess due to Clostridium perfringens requiring emergent aortic root repair. Management involved imaging studies, removal of potential sources with administration of intravenous antibiotics, and cautious fluid administration with hemodynamic monitoring. A multidisciplinary group led by a PAH specialist worked cohesively before, during, and after surgical intervention and achieved a successful outcome.
Chronic intravenous prostanoid therapy is an effective treatment of pulmonary arterial hypertension (PAH); however, it is associated with central venous catheter bloodstream infections. 1 Management of bloodstream infections involves timely removal of the infected catheter and early antimicrobial administration to avoid complications, such as infective endocarditis. When infective endocarditis develops in patients with PAH, management is challenging and requires a multidisciplinary team approach. We report the successful management of a patient with idiopathic PAH treated with intravenous epoprostenol requiring emergent aortic valve surgery for treatment of Clostridium perfringens endocarditis.
CASE DESCRIPTION
A 48-year-old female with idiopathic PAH, previously World Health Organization (WHO) functional class (FC) II, reported exertional dyspnea with mild exertion and new lower-extremity edema. Ten days before the visit, she experienced 4 days of nonbloody diarrhea and fever that resolved but reported worsening fatigue and dyspnea. Medications included epoprostenol (Flolan, GlaxoSmithKline, Research Triangle Park, NC) 15 ng kg–1 minute–1, bosentan (Tracleer, Actelion, San Francisco) 125 mg twice daily, furosemide, warfarin, and gabapentin for treatment of paresthesias (Neurontin, Pfizer, New York). Before this acute illness, she had been treated with epoprostenol for 5 years, with an unchanged dose for 12 months that resulted in a 6-minute walk distance of 1,100 feet, and was considered WHO FC II. Right heart catheterization performed 1 year before the current illness revealed a right atrial pressure of 7 mmHg, pulmonary artery pressure of 70/26 mmHg (mean: 41 mmHg), pulmonary artery occlusion pressure of 11 mmHg, and cardiac output of 4.8 L minute–1. Initial physical examination revealed a blood pressure of 109/51 mmHg, pulse of 107 minute–1, temperature of 38.6°C, and saturation of peripheral oxygen of 94%. Physical examination revealed the left subclavian Hickman catheter site to be nontender without erythema, a 3/6 systolic murmur, a new diastolic murmur, and lower-extremity edema. Electrocardiogram showed sinus tachycardia with a first-degree atrioventricular block. Echocardiography revealed a right ventricular systolic pressure of 55–60 mmHg, an aortic valve vegetation, and newly detected moderate aortic insufficiency when compared with previous echocardiograms. The patient was hospitalized, and piperacillin, vancomycin, and levofloxacin treatment for endocarditis was initiated. On day 2, the Hickman catheter was removed and epoprostenol (15 ng kg–1 minute–1) continued through a peripherally inserted central venous catheter in the antecubital area. Daily blood cultures and the catheter tip culture remained sterile. On day 3, she became hypotensive and was transferred to the intensive care unit for initiation of intravenous norepinephrine. Clinical assessment revealed a febrile, anxious woman without jugular venous distention, and crackles were noted on auscultation. At the time, tachyarrthymias, gastrointestinal blood loss, and medication-induced hypotension due to discontinuation of epoprostenol as etiologies of her clinical deterioration were excluded. Repeat echocardiography did not reveal a pericardial effusion, thus excluding cardiac tamponade, but demonstrated moderate aortic insufficiency. A radial artery catheter was placed and norepinephrine titrated to maintain a mean arterial blood pressure of ≥60 mmHg. Initiation of norepinephrine resulted in improved hemodynamics. On day 7, transesophageal echocardiography demonstrated an aortic root abscess with concern for an aortic dissection. Emergent surgery was scheduled with preoperative placement of a pulmonary artery catheter (Table 1). Epoprostenol and vasopressors were continued, and a preoperative oral dose of sildenafil (50 mg) was administered. General anesthesia produced further hypotension, the norepinephrine dose was increased (0.5 μg kg–1 minute–1), intravenous milrinone was initiated at a rate of 0.3 μg kg–1 minute–1 without a loading dose, and cardiopulmonary bypass was initiated. A median sternotomy approach was taken, with the intraoperative finding of an aortic valve leaflet perforation and a 2 × 1-cm root abscess dissecting underneath the noncoronary cusp into the aortic wall. Given these findings and development of myocardial ischemia, an aortic root homograft with coronary reimplantation was performed. Postoperatively, epoprostenol, milrinone, norepinephrine, and sildenafil were continued (Table 1). Furosemide (40 mg intravenously) was initiated 12 hours postoperatively. On postoperative day 3, she was extubated, and the pulmonary artery catheter was discontinued. On postoperative day 6, vasopressors were discontinued, and she was transferred to the medical floor. Subsequently, the intraoperative culture of the aortic leaflet revealed C. perfringens. She received piperacillin for a total of 4 weeks and oral metronidazole for 2 weeks. Before hospital discharge, transition from intravenous epoprostenol to inhaled iloprost (Ventavis, Actelion, San Francisco) occurred without complications. Five years after surgery, she is WHO FC II and receives inhaled iloprost, bosentan, furosemide, and sildenafil, caring for a disabled granddaughter and traveling around the country by bus and air. She was referred for lung transplantation but has declined for personal reasons. The treatment plan for clinical worsening is to prescribe subcutaneous treoprostinil.
Vasoactive medications and hemodynamic profile during perioperative period
Note: BP: blood pressure; PAOP: pulmonary artery occlusion pressure; PAP: pulmonary arterial pressure; RAP: right atrial pressure.
DISCUSSION
Bloodstream infections are a potential complication associated with continuous intravenous prostanoid therapy and are reported to occur with intravenous epoprostenol in 0.12–0.42 cases per 1,000 treatment-days.1,2 Notably, a similar rate of bloodstream infections was reported from a national database of 50,470 ambulatory patients receiving home infusion therapy in which tunneled central venous catheters accounted for 0.34 systemic infections per 1,000 catheter-days. 3 The organisms commonly isolated from epoprostenol-associated bloodstream infections are staphylococcus and corynebacterium, with gram-negative organisms less frequently and anaerobic infections rarely reported. 2 Bloodstream infections complicated by endocarditis have been reported in patients with chronic indwelling catheters 4 and congenital heart disease, 5 but to our knowledge, infective endocarditis in patients with PAH receiving intravenous prostanoids has not been reported. In this case, we were unable to isolate the organism from blood or the central venous catheter. The isolated organism, clostridium, is a gram-positive, anaerobic bacteria found in the human gastrointestinal and genitourinary tract that can manifest as gastroenteritis, bacteremia, soft-tissue infection, and rarely endocarditis. 6 Interestingly, a report described a 30-year-old patient with fever and diarrhea that resulted in C. perfringens bacteremia complicated by endocarditis who was successfully treated with a 6-week course of intravenous metronidazole and vancomycin. 7 Similarly, our patient experienced a bout of febrile gastroenteritis complicated by endocarditis, and we suspect that clostridium translocation from the bowel to the bloodstream occurred that led to the aortic valve abscess.
Sepsis-induced worsening of PAH is associated with increased morbidity and mortality.8,9 In patients with PAH, management of sepsis involves identification and removal of the infectious source, early antimicrobial administration, continuation of PAH therapies, and judicious fluid administration. Yet, despite these measures, when surgical intervention is required, it is associated with a mortality rate of 7%–18%. 10 A multicenter study of 114 patients with PAH undergoing noncardiac surgery reported major complications in 6% and death in 3.5% of patients, and emergency surgery was associated with a mortality rate of 15%. 11 Moreover, cardiac surgery in patients with pulmonary hypertension is associated with a higher complication rate and a mortality rate of 25% compared with noncardiac surgery. 10 The increased risk of complications and death in patients with PAH who require surgery is due to acute right ventricular decompensation during peri- and postoperative periods. During induction, maintenance, and emergence of general anesthesia, patients are exposed to vasodilation, hypoxia, hypoventilation, sympathetic stimulation, and fluid shifts that lead to elevated pulmonary artery pressures and/or worsening of right ventricular function. Patients with PAH tolerate these physiologic changes poorly; hence, there is great apprehension when surgical intervention is required in this group of patients. 10
To optimize surgical outcomes in patients with PAH, measures should be implemented to prevent the need for surgical intervention and mitigate the complications associated with sepsis. In our case, early antibiotic administration and removal of the central venous catheter was performed. Management of sepsis involves fluid resuscitation; however, liberal fluid administration may precipitate acute right ventricular decompensation and hemodynamic instability. 12 In this setting, it is imperative not to discontinue or reduce epoprostenol, since either of these actions can precipitate pulmonary hypertensive crisis, manifesting as an elevation in pulmonary artery pressures, right ventricular dysfunction, and systemic hypotension. Initial monitoring with an intra-arterial catheter was useful. Administration of PAH-specific medication before surgery can mitigate worsening of RV function.
In our case, inhaled nitric oxide was not available for use in this clinical situation, nor was intravenous sildenafil. Oral sildenafil (50 mg) was administered by mouth preoperatively.13,14 During and after surgery, hemodynamic management was guided by an intra-arterial catheter and a pulmonary artery catheter that provided for judicious fluid administration and infusion of vasopressors and inotropes. 12 The advantages of using a pulmonary artery catheter are the measurements of cardiac output, pulmonary artery pressures, and mixed venous oxygen saturations to guide vasopressor and fluid administration. The disadvantages of the use of a pulmonary artery catheter include the invasive nature of this monitoring device, the limited accuracy of the thermodilution cardiac output measurements, especially in the presence of tricuspid regurgitation, and overreliance on pulmonary artery occlusion pressure to administer or restrict fluids. In our case, fluid administration and restriction were guided by systemic blood pressure, pulmonary artery pressure, cardiac output, and mixed venous blood measurements. Fluid administration was limited and red blood cell products administered to a target hemoglobin concentration of 8 g dL–1.
Emergent surgical intervention was thought necessary, given the concern for an aortic abscess with dissection, and a multidisciplinary team was assembled, consisting of a PAH specialist, a cardiothoracic surgeon, and a cardiac anesthesiologist. Our multidisciplinary team met to develop formal as well as contingency plans of care. Before induction with general anesthesia, fentanyl and valium were provided, followed by rapid-sequence intubation with a non-depolarizing muscle relaxant to minimize hemodynamic decompensation. 15 Subsequently, mechanical ventilation with 8 mL kg–1 tidal volume and minimal positive end-expiratory pressure were provided and cardiopulmonary bypass initiated to provide hemodynamic stability. 15 Upon discontinuation of cardiopulmonary bypass, norepinephrine and milrinone were provided with no changes to epoprostenol infusion. Regarding milrinone for use with this group of patients, we have had effective clinical experience using intravenous milrinone without a loading dose; this has been reported by other investigators.16,17 Postoperative management involved mechanical ventilation with hemodynamic support and analgesia. 10
In conclusion, patients with PAH may experience bacteremia complicated by endocarditis. Successful emergency surgical treatment of endocarditis may be achieved by a multidisciplinary team with attention to early use of antibiotics, judicious fluid resuscitation, intravenous prostanoid therapy, and vasopressor administration.