- Email: [email protected]
Recent Advances in Chronic Thromboembolic Pulmonary Hypertension
EXPERT REVIEW John G.T. Augoustides, MD, FASE, FAHA Section Editor
Recent Advances in Chronic Thromboembolic Pulmonary Hypertension Erica Stein, MD,* Harish Ramakrishna, MD,† and John G.T. Augoustides, MD, FASE, FAHA‡ Surgical excellence in pulmonary thromboendarterectomy (PTE) for chronic thromboembolic pulmonary hypertension (CTEPH) has begun to spread around the world. The perioperative mortality for this procedure is typically under 10%. The maximal benefit from PTE is derived in those patients who have a high proximal clot burden that is surgically accessible, as outlined by the Jamieson classification. Residual pulmonary hypertension after successful PTE is common and increasingly is managed with maintenance oral pulmonary vasodilator therapy such as endothelin antagonists, phosphodiesterase inhibitors, and/or prostaglandins. The role of pulmonary vasodilator therapy in CTEPH before PTE is limited and should not delay definitive surgical therapy. Although plain deep hypothermic circulatory arrest (DHCA) is the classic technique for CTEPH, alternatives such as DHCA with antegrade cerebral perfusion are feasible as well. Prolonged mechanical ventilation after PTE remains common in part because of reperfusion pulmonary edema.
Careful perioperative management can reduce the incidence of this syndrome. Because ventilator-associated pneumonia is also a common complication after PTE, it represents a major opportunity for outcome improvement, particularly because there are multiple modalities for its prevention and prompt diagnosis. © 2011 Elsevier Inc. All rights reserved.
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management of pulmonary hypertension (PHTN), including CTEPH, which is classified as type-4 PHTN in the latest revised clinical classification.4-6 These advances have prompted multiple recent guideline statements, most recently from the American Heart Association (AHA).4-6 This expert review addresses the major innovations in CTEPH and PTE that are likely to significantly influence perioperative practice and therefore be relevant to the cardiovascular anesthesiologist.
HRONIC THROMBOEMBOLIC pulmonary hypertension (CTEPH) is characterized by pulmonary arterial obstruction caused by recurrent pulmonary embolism.1 The definition of CTEPH is a mean arterial pressure ⬎25 mmHg that persists for longer than 6 months after the diagnosis of pulmonary embolism.2 This syndrome develops in at least 4% of patients with acute pulmonary embolism but frequently is underdiagnosed because its development is asymptomatic in more than 50% of cases.1,2 The definitive therapy for CTEPH is pulmonary thromboendarterectomy (PTE), which involves surgical removal of organized thrombus and related fibrous tissue from the pulmonary arterial tree under periods of deep hypothermic circulatory arrest (DHCA) on cardiopulmonary bypass.3 The role of medical therapy in CTEPH beyond indefinite anticoagulation is likely to evolve yet further because of the advent of pulmonary vasodilator therapy such as endothelin blockers and phosphodiesterase inhibitors.1,2 There has been substantial progress in the diagnosis and
From the *Department of Anesthesiology, Ohio State University, Columbus, OH; †Cardiothoracic Anesthesiology, Mayo Clinic, Scottsdale, AZ; and ‡Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA. Address reprint requests to John G.T. Augoustides, MD, FASE, FAHA, Cardiothoracic Section, Anesthesiology and Critical Care, Dulles 680, HUP, 3400 Spruce Street, Philadelphia, PA 19104-4283. E-mail: [email protected] © 2011 Elsevier Inc. All rights reserved. 1053-0770/2504-0023$36.00/0 doi:10.1053/j.jvca.2011.03.182 744
Key words: chronic thromboembolic pulmonary hypertension, pulmonary thromboendarterectomy, clinical outcomes, Jamieson classification, right ventricular dysfunction, pulmonary hypertension, endothelins, bosentan, phosphodiesterases, sildenafil, prostaglandins, epoprostenol, treprostinil, direct thrombin inhibitors, dabigatran, factor Xa inhibitors, apixaban, rivaroxaban, guanylate cyclase, riociguat, deep hypothermic circulatory arrest, moderate hypothermia, selective antegrade cerebral perfusion, reperfusion pulmonary edema, ventilator-associated pneumonia, procalcitonin
WHAT ARE THE CURRENT OUTCOMES AFTER PTE?
Dr Jamieson and his team at the University of California, San Diego have the largest PTE experience in the world, with more than 2,500 procedures since 1970.7 Although the perioperative mortality rate for this entire series is 6.4%, it has fallen to 2.5% in the last 3 years because of yet further refinements in perioperative techniques.3,4 The San Diego group also recently has published their pediatric PTE experience, which, although small (N ⫽ 17), showed safety with a 0% perioperative mortality rate and clinical efficacy with significant improvements in hemodynamics and functional status.8 An important distinction in the pediatric group as compared with the adult group was the significantly increased risk of rethrombosis (38% v 4%), emphasizing the crucial role of aggressive anticoagulation in pediatric presentations of CTEPH. The PTE gradually has spread worldwide. There are currently more than 40 recent reports from around the world (N ⬎ 20; range, 21-236: 2005-2010).4 This surgical experience recently has been augmented by the formation of an international prospective CTEPH registry with participating centers in Europe and Canada.9 In a recent publication from this registry
Journal of Cardiothoracic and Vascular Anesthesia, Vol 25, No 4 (August), 2011: pp 744-748
CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION
(N ⫽ 679: 56.8% underwent PTE), the median age of surgical patients was 60 years.9 The in-hospital mortality rate was 4.7%. Further perioperative complications included neurologic issues (11.2%), bleeding (10.2%), pericardial effusion (8.3%), residual pulmonary hypertension (16.7%), pulmonary reperfusion edema (9.6%), extracorporeal membrane oxygenation (3.1%), and infection (18.8%: 65.7% of this subgroup had ventilatorassociated pneumonia). Neurologic complications were more common as DHCA time increased, 1.9% with DHCA ⬍20 minutes versus 18.4% with DHCA time ⬎60 minutes (odds ratio ⫽ 0.09; 95% confidence interval, 0.01-0.74). Furthermore, in this study, mortality at 1 year was 7.0%. The majority of patients evaluated at this time point had significant improvements in median pulmonary vascular resistance and functional status as measured by 6-minute walk distance and New York Heart Association functional class. The surgical techniques for PTE have matured and subsequently have generalized to multiple centers of excellence throughout the world. It is likely that this dissemination will continue throughout Asia in the coming years.10 This success story has been assisted significantly by the advances in perioperative management of the right ventricular dysfunction and pulmonary hypertension, which have been highlighted recently both in this Journal and elsewhere.1,11 ARE THERE PREDICTORS FOR ADVERSE CLINICAL OUTCOME AFTER PTE?
The major predictor of outcome after PTE is based on the Jamieson classification of CTEPH, namely the pattern of pulmonary arterial occlusion based on the anatomic location of the obstruction.12 Type-1 disease is defined as fresh thrombus in the main and/or lobar arteries (about 25% of cases). Type-2 disease is defined as chronic intimal thickening proximal to the segmental arteries (about 40% of cases). Type-2 disease may have organized thrombus. Type-3 disease is defined as intimal disease limited to the segmental arteries; this disease pattern is technically the most difficult and may represent CTEPH with resorption of the proximal clot burden (about 30% of cases). Type-4 disease is defined as distal arteriolar vasculopathy with no visible thromboembolic disease (⬍5% of cases). In the San Diego series (N ⫽ 202: 1998-2000), patients with distal disease (type 3 and type 4) had significantly increased tricuspid regurgitation and pulmonary vascular resistance (p ⬍ 0.0001) versus the patients with surgically accessible thromboembolic burden (type 1 and type 2).12 Patients with distal CTEPH types had increased inotropic requirements, hospital stays, and perioperative mortality.4,12 Patients with type-4 disease frequently account for most of the perioperative mortality after PTE. This patient subgroup in CTEPH does not benefit from PTE. The major focus in the current era is to enhance preoperative identification of type-4 disease so as to preclude these patients from PTE.13 The degrees of PHTN and/or right ventricular dysfunction are not regarded as contraindications to PTE.4 Patients with operable disease may derive immense clinical benefit with significant reduction of PHTN coupled with recovery of the right heart and resolution of severe tricuspid regurgitation.14,15 It remains an imperative that patients with type-4 CTEPH are diagnosed preoperatively because they qualify primarily for
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medical therapy and not PTE.16 Careful pulmonary angiography can reliably determine the thromboembolic pattern by formal criteria that correlate with clinical outcomes after PTE.17 A recent series from the United Kingdom (N ⫽ 314: 19972007) focused on the outcome importance of residual PHTN after PTE in patients with CTEPH (types 1, 2, and 3).18 Although all patients experienced a significant reduction in mean arterial pulmonary artery pressure (48 ⫾ 12 to 26 ⫾ 10 mmHg, p ⬍ 0.001), 31% of the cohort had residual PHTN, which was defined as mean pulmonary artery pressure ⱖ30 mmHg. Although residual PHTN after PTE did not affect 5-year survival, it significantly worsened functional status. Furthermore, the study highlighted the clinical necessity for further investigation of targeted medical therapy in this patient cohort who persisted with PHTN despite appropriate PTE. Residual PHTN is common after PTE. This finding is explained by the 2-compartment model proposed by Moser and Braunwald in 1973.2,19 This model recognizes that patients with CTEPH who have proximal mechanical obstruction also can have distal small vessel vasospasm as a microvascular phenomenon in the pulmonary vasculature.2,19,20 This distal vasculopathy provides a therapeutic target for selective pulmonary vasodilator therapy, which will be examined in detail in the following 2 sections. WHAT IS THE ROLE OF MEDICAL THERAPY BEFORE PTE?
Standard medical therapy for CTEPH includes chronic anticoagulation with warfarin for a goal international normalized ratio of 2 to 3.2 Although pulmonary vasodilator therapies have been tested in CTEPH before PTE, the evidence is very limited.21,22 A large retrospective study (n ⫽ 111 pulmonary vasodilator exposure and n ⫽ 244 control group: 2005 to 2007) examined the effects of monotherapy with bosentan (endothelin antagonist), sildenafil (phosphodiesterase inhibitor), or epoprostenol (prostaglandin) and combinations thereof.22 The investigators observed a significant increase in exposure to these medications in the study period despite their lack of perioperative benefit. They also documented that exposure to these medications often resulted in delayed referral for PTE, the proven therapy for this disease. Consequently, the recent AHA guideline strongly suggests that pulmonary vasodilator therapy should never delay evaluation for PTE (AHA class III recommendation, level of evidence B).4 Furthermore, the role of medical therapy in the management of CTEPH before PTE requires further study before any conclusive recommendations are possible.23 WHAT IS THE ROLE OF MEDICAL THERAPY AFTER PTE?
Patients with proven CTEPH require indefinite therapeutic anticoagulation in the absence of contraindications (AHA class I recommendation, level of evidence C).4 Until recently, this goal has been achieved with chronic warfarin titrated to a therapeutic international normalized ratio. Given the advent of novel oral anticoagulants, such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban, it is likely that warfarin therapy may be challenged by these newer anticoagulants.24 The advantages of these novel
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oral anticoagulants over warfarin include predictable pharmacologic profiles, freedom from routine coagulation monitoring, and limited food and drug interactions.24,25 The novel oral pulmonary vasodilators should be considered for patients with CTEPH who do not qualify for PTE or who have residual PHTN after PTE at an experienced center (AHA class IIb recommendation, level of evidence B).4 The rationale for chronic pulmonary vasodilator therapy in CTEPH includes the microvascular vasospasm first described by Moser and Braunwald19 as well as the outcome importance of residual PHTN after CTEPH.18 Although the rationale is attractive, the drug trials to date have failed to show a meaningful outcome advantage such as better effort tolerance or survival.26,27 It is likely in the future that the role of medical therapy in CTEPH gradually will expand as further insights into the multimodal pathogenesis of CTEPH take effect.28 Pulmonary vasodilator therapy may have a role in enhancing effort tolerance after successful PTE in a subset of patients who develop effortlimiting PHTN with exercise.29 A recent randomized trial (N ⫽ 157) evaluated endothelin blockade with bosentan in patients with inoperable CTEPH or residual PHTN after PTE.30 Although bosentan exposure reduced pulmonary vascular resistance, there were no improvements in effort tolerance and functional status. A recent metaanalysis of bosentan for CTEPH (10 studies) confirmed that bosentan therapy induces pulmonary vasodilation and suggested that bosentan therapy may improve functional status.31 The multiple international adult and pediatric bosentan registries show growing application of endothelin blockade in PHTN including CTEPH and suggest improving clinical outcomes and survival over time.32-34 Furthermore, a recent dataset from a prospective registry indicates that in the setting of failing bosentan monotherapy, combination therapy with a prostaglandin or phosphodiesterase inhibitor results in meaningful clinical improvement in PHTN.35 Endothelin blockade is a mainstay of oral pulmonary vasodilator therapy for PHTN including CTEPH. Although there are multiple trials in CTEPH evaluating phosphodiesterase blockade with sildenafil (4 trials: cumulative N ⫽ 139: 2003-2008) and prostaglandin therapy with epoprostenol and treprostinil (5 trials: cumulative N ⫽ 84: 20032007), they were not powered to show outcome effects beyond pulmonary vasodilation.4 In clinical practice, however, these agents as monotherapy and/or as components of combination therapy significantly improved long-term survival in CTEPH.36 Furthermore, a novel phosphodiesterase inhibitor, tadalafil, recently was approved for PHTN; its advantages include once daily dosing and an excellent safety profile.37 It will likely enter the medical therapeutic menu for CTEPH. Riociguat is a novel oral pulmonary vasodilator that stimulates guanylate cyclase to increase cyclic guanosine monophosphate, which mediates pulmonary vasodilation.38 This agent is not only the first agent in its class but also has potential application in CTEPH.39 This drug currently is undergoing evaluation in at least 3 randomized controlled CTEPH trials (full details available at www.clinicaltrials.gov, identifiers NCT00855465, NCT00910429, and NCT00454558). The results of these landmark trials will likely determine its future therapeutic role in CTEPH.
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IS DEEP HYPOTHERMIC CIRCULATORY ARREST ESSENTIAL FOR PTE?
The visualization of the pulmonary arteries during PTE requires a bloodless field, which typically has been achieved with intermittent periods of DHCA on cardiopulmonary bypass.3,7,8 The main strategy for cerebral protection in this scenario is profound hypothermia. This technique, however, has been associated with neurologic complications such as stroke, delirium, and chorea.9,40 A recent outcome trial from a multicenter PTE registry correlated neurologic complications with DHCA time, with the following rate of rise: 1.9% with DHCA ⬍20 minutes, 10.8% when DHCA was 21 to 40 minutes, 14.6% when DHCA was 41 to 60 minutes, and 18.4% when DHCA was ⬎60 minutes.9 A collaborative European trial showed in a small cohort (N⫽ 30: 2004-2005) that successful PTE could be performed on cardiopulmonary bypass at moderate hypothermia (defined as 28°32°C).41 In this small trial, however, the DHCA times were under 20 minutes (mean, 10.3 ⫾ 5.2 minutes; range, 2-19 minutes).41 This approach was modified by a group from Bologna who have described successful PTE (N ⫽ 40, 2004-2007) at moderate hypothermia with no DHCA but with aggressive venting of the left heart and titrated flows on cardiopulmonary bypass.42,43 The Cambridge Group at Papworth Hospital have developed a PTE technique that uses DHCA with selective antegrade cerebral perfusion.44 Selective cerebral perfusion is provided by an ascending aortic cannula with clamping of the ascending aorta below the cannula and clamping of the aortic arch between the left common carotid artery and the left subclavian artery. The aortic arch clamping also prevents flow to the bronchial arteries to ensure a bloodless field during the PTE. In their first review of this technique for PTE (N ⫽ 150: 20032006), the in-hospital mortality rate was 15% with no focal neurologic deficits.44 Selective antegrade cerebral perfusion allowed adequate visualization for PTE in 91% of cases with a mean cerebral perfusion time of 63 ⫾ 24 minutes.44 The Cambridge team concluded that DHCA with antegrade cerebral perfusion is an alternative to plain DHCA for PTE. They presently are conducting a randomized controlled trial of both techniques for PTE to evaluate which technique provides superior clinical outcomes (full details available at www. controlledtrials.com, with ISRCTN84972261. The results of this randomized trial may challenge the present standard surgical paradigm of plain DHCA for PTE. IS THE LUNG AT RISK AFTER PTE?
Prolonged postoperative mechanical ventilation is common after PTE. In a recent single-center series (N ⫽ 279: 19952009), 47.3% of patients required tracheal intubation and mechanical ventilation longer than 48 hours.45 In this series, multivariate predictors for prolonged mechanical ventilation after PTE were preoperative chronic obstructive pulmonary disease and preoperative cardiac dysfunction.45 In a recent Canadian PTE series (N ⫽ 106: 1995-2007), the average mechanical ventilation time was 7.8 days.46 Severe preoperative parenchymal lung disease is an independent predictor for perioperative mortality after PTE because it significantly decreases perioperative pulmonary reserve.47 A
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common etiology of lung injury after PTE in the early postoperative period is reperfusion pulmonary edema, which has a radiographic appearance of alveolar infiltrates distal to the pulmonary vessels that underwent endarterectomy. In a recent multicenter registry, the incidence of this syndrome was 9.6%.9 Although the incidence of this syndrome gradually has been decreasing over time, in severe cases, it may require temporary support with extracorporeal membrane oxygenation, which has an incidence of 3% to 6% in a recent series.9,48 The incidence of reperfusion pulmonary edema also can be reduced significantly by low stretch mechanical ventilation and minimizing inotropic support after cardiopulmonary bypass.49 It also is essential to minimize alveolar collapse in this scenario after PTE because pulmonary atelectasis will aggravate hypoxemia, pulmonary hypertension, and right-heart dysfunction.50 The investigators at the University of California, San Diego currently are conducting a randomized clinical trial in PTE patients to determine the effect of low stretch mechanical ventilation (defined as tidal volumes of 6 mL/kg ideal body weight) on the incidence of reperfusion lung injury, which is defined as severe hypoxemia and radiographic alveolar infiltrates within the first 72 hours after PTE (full details available at www.clinicaltrials.gov). Because prolonged tracheal intubation is common after PTE, it is expected that ventilator-associated pneumonia (VAP) would be prevalent in this high-risk surgical population. In recent multicenter PTE trials, the incidence of VAP in the intensive care unit was 10% to 12.5%.9,51 Given this high incidence, efforts to detect VAP as early as possible merit special emphasis. Recent evidence indicates that the biomarker procalcitonin can predict VAP before infection can be detected clinically, allowing for even earlier antibiotic therapy.51 The diagnostic performance of procalcitonin as a marker for infection after PTE was as follows: sensitivity, 86%; specificity, 83%; negative predictive value, 92%; and positive predictive value, 84%.51 Besides earlier diagnosis, decreasing levels of
procalcitonin also correlate with effective therapy and the resolution of infection, including VAP.52,53 Besides the earlier diagnosis of VAP after PTE, an aggressive approach to its prevention also is now feasible because of multiple recent advances.54-56 Modifications in the endotracheal tube design have focused on aspects such as antibiotic coatings and drainage of subglottic secretions.55,56 Oral decontamination, patient positioning, and aerosolized antibiotics also may have a role.54 Given that patients undergoing PTE are at high risk for VAP, a multifaceted evidence-based perioperative protocol for elimination of VAP would likely significantly improve important clinical outcomes after PTE. This is an important clinical and research opportunity for the high-volume PTE centers around the world. CONCLUSIONS
Surgical excellence in PTE for CTEPH has begun to generalize around the world. The perioperative mortality for this procedure is typically under 10%. The maximal benefit from PTE is derived in those patients who have a high proximal clot burden that is surgically accessible, as outlined by the Jamieson classification. Residual PHTN after successful PTE is common and increasingly is managed with maintenance oral pulmonary vasodilator therapy such as endothelin antagonists, phosphodiesterase inhibitors, and/or prostaglandins. The role of pulmonary vasodilator therapy in CTEPH before PTE is limited and should not delay definitive surgical therapy. Although plain DHCA is the classic technique for CTEPH, alternatives such as DHCA with antegrade cerebral perfusion are feasible as well. Prolonged mechanical ventilation after PTE remains common in part because of reperfusion pulmonary edema. Careful perioperative management can reduce the incidence of this syndrome. Because VAP is also a common complication after PTE, it represents a major opportunity for outcome improvement, particularly because there are multiple modalities for the prevention and earlier diagnosis of VAP.
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7. Madani MM, Jamieson SW: Technical advances of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Semin Thorac Cardiovasc Surg 18:243-249, 2006 8. Madani MM, Wittine LM, Auger WR, et al: Chronic thromboembolic pulmonary hypertension in pediatric patients. J Thorac Cardiovasc Surg 141:624-630, 2011 9. Mayer E, Jenkins D, Lindner J, et al: Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: Results from an international prospective registry. J Thorac Cardiovasc Surg 141:702-710, 2011 10. Gu S, Liu Y, Su PX, et al: Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: Preliminary exploration in China. Chin Med (Engl) 123:979-983, 2010 11. Augoustides JG, Ochroch EA: Inhaled selective pulmonary vasodilators. Int Anesthesiol Clin 43:101-114, 2005 12. Thistlethwaite PA, Mo M, Madani MM, et al: Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg 124:12031211, 2002 13. Mookadam F, Mookadam M, Jiamsripong P, et al: Pulmonary thromboembolic disease spectrum: Diagnostic and therapeutic strategies. Expert Rev Cardiovasc Ther 7:1421-1428, 2009
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14. Thistlethwaite PA, Kemp A, Du L, et al: Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg 131:307-313, 2006 15. Sadeghi HM, Kimura BJ, Raisinghani A, et al: Does lowering of pulmonary arterial pressure eliminate severe functional tricuspid regurgitation? Insights from pulmonary thromboendarterectomy. J Am Coll Cardiol 44:126-132, 2004 16. Kim NH: Assessment of operability in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 3:584-588, 2006 17. Kunihara T, Moller M, Langer F, et al: Angiographic predictors of hemodynamic improvement after pulmonary endarterectomy. Ann Thorac Surg 90:957-964, 2010 18. Freed DH, Thomson BM, Beman M, et al: Survival after pulmonary thromboendarterectomy: Effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg 141:383-387, 2011 19. Moser KM, Braunwald NS: Successful surgical intervention in severe chronic thromboembolic pulmonary hypertension. Chest 64:29-35, 1973 20. Galie N, Kim NH: Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 3:571576, 2006 21. Nagaya N, Sasaki N, Ando M, et al: Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 123:338-343, 2003 22. Jensen KW, Kerr KM, Fedullo PF, et al: Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation 120:1248-1254, 2009 23. Keogh AM, Mayer E, Benza RL, et al: Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol 54:S67-S77, 2009 24. Galanis T, Thomson L, Palladino M, et al: New oral anticoagulants. J Thromb Thrombolysis 31:310-320, 2011 25. Levy JH, Key NS, Azran MS: Novel oral anticoagulants: Implications in the perioperative setting. Anesthesiology 113:726-745, 2010 26. Fedullo P, Kerr KM, Kim NH, et al: Chronic thromboembolic pulmonary hypertension. Am J Respi Crit Care Med 2011 [Epub ahead of print] 27. Bresser P, Pepke-Zaba J, Jais X, et al: Medical therapies for chronic thromboembolic pulmonary hypertension: An evolving treatment paradigm. Proc Am Thorac Soc 3:594-600, 2006 28. Lang I: Advances in understanding the pathogenesis of chronic thromboembolic pulmonary hypertension. Br J Haematol 149:478-483, 2010 29. Bonderman D, Martischnig AM, Vonbank K, et al: Right ventricular load at exercise is a cause of persistent exercise limitation in patients with normal resting pulmonary vascular resistance after pulmonary endarterectomy. Chest 139:122-127, 2011 30. Jais X, D’Armini AM, Jansa P, et al: Bosentan effects in inoperable forms of chronic thromboembolic pulmonary hypertension (BENEFIT): A randomized, placebo-controlled trial. J Am Coll Cardiol 52:2127-2134, 2008 31. Becattini C, Manina G, Busti C, et al: Bosentan for chronic thromboembolic pulmonary hypertension: Findings from a systematic review and meta-analysis. Thromb Res 126:e51-e56, 2010 32. Zhang R, Dai LZ, Xie P, et al: Survival of chinese patients with pulmonary arterial hypertension in the modern management era. Chest 2011 [Epub ahead of print] 33. Keogh A, Strange G, McNeil K, et al: The bosentan patient registry: Long-term survival in pulmonary arterial hypertension. Intern Med J 41:227-234, 2011 34. Hislop AA, Moledina S, Foster H, et al: Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Resp J 2010 [Epub ahead of print] 35. Keogh A, Strange G, Kotlyar E, et al: Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: An Australian collaborative report. Intern Med J 41:235-244, 2011
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36. Seyfarth HJ, Halank M, Wilkens H, et al: Standard PAH therapy improves long-term survival in CTEPH patients. Clin Res Cardiol 99:553-556, 2010 37. Levin YD, White RJ: Novel therapeutic approaches in pulmonary arterial hypertension: focus on tadalafil. Drugs Today (Barc) 47:145-156, 2011 38. Schermuly RT, Janssen W, Weissmann N, et al: Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 20:567-576, 2011 39. Kim NH: Riociguat: An upcoming therapy in chronic thromboembolic pulmonary hypertension. Eur Respir Rev 19:68-71, 2010 40. Surie S, Tijssen MAJ, Biervliet JD, et al: Chorea in adults following pulmonary endarterectomy. Mov Disord 25:1101-1104, 2010 41. Macchiarini P, Kamiya H, Hagl C, et al: Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: Is deep hypothermia required? Eur J Cardiothorac Surg 30:237-243, 2006 42. Mikus PM, Dell’Amore A, Pastore S, et al: Pulmonary endarterectomy: Is there an alternative to profound hypothermia with cardiocirculatory arrest? Eur J Cardiothorac Surg 30:563-565, 2006 43. Mikus PM, Mikus E, Martin-Suarez S, et al: Pulmonary endarterectomy: An alternative to circulatory arrest and deep hypothermia: Mid-term results. Eur J Cardiothorac Surg 34:159-163, 2008 44. Thomson B, Tsui SSI, Dunning J, et al: Pulmonary endarterectomy is possible and effective without the use of complete circulatory arrest. Eur J Cardiothorac Surg 33:157-163, 2008 45. Kunihara T, Gerdts J, Groesdonk H, et al: Predictors of postoperative outcome after pulmonary endarterectomy from a 14-year experience with 279 patients. Eur J Cardiothorac Surg 2011 [Epub ahead of print] 46. Rubens FD, Bourke M, Hynes M, et al: Surgery for chronic thromboembolic pulmonary hypertension—Inclusive experience from a national referral center. Ann Thorac Surg 83:1075-1081, 2007 47. Condiffe R, Kiely DG, Gibbs JS, et al: Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension. Eur Resp J 33:332-338, 2009 48. Berman M, Tsui S, Vuylsteke A, et al: Successful extracorporeal membrane oxygenation support after pulmonary thromboendarterectomy. Ann Thorac Surg 86:1261-1267, 2008 49. Mares P, Gilbert TB, Tschemko EM, et al: Pulmonary artery thromboendarterectomy: A comparison of two different postoperative treatment strategies. Anesth Analg 90:267-273, 2000 50. Imanaka H, Takeuchi M, Tachibana K, et al: Effects of open lung approach policy on mechanical ventilation duration in postoperative patients with chronic thromboembolism with pulmonary hypertension: A case-matched study. Anaesth Intens Care 38:461-466, 2008 51. Maruna P, Kunstyr J, Piocova KM, et al: Predictors of infection after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Eur J Cardiothorac Surg 39:195-200, 2011 52. Tschaikowsky K, Hedwig-Geissing M, Braun GG, et al: Predictive value of procalcitonin, interleukin-6 and C-reactive protein for survival in postoperative patients with severe sepsis. J Crit Care 26: 54-64, 2011 53. Bloos F, Marshall JC, Dellinger RP, et al: Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: A multicenter observational study. Crit Care 15:R88, 2011 54. Rewa O, Muscedere J: Ventilator-associated pneumonia: Update on etiology, prevention and management. Curr Infect Dis Rep 2011 [Epub ahead of print] 55. Lorente L, Blot S, Relio J: New issues and controversies in the prevention of ventilator-associated pneumonia. Am J Resp Crit Care Med 1832:870-876, 2010 56. Deem S, Treggiari MM: New endotracheal tubes designed to prevent ventilator-associated pneumonia: Do they make a difference? Respir Care 55:1046-1055, 2010
Recent Advances in Chronic Thromboembolic Pulmonary Hypertension Erica Stein, MD,* Harish Ramakrishna, MD,† and John G.T. Augoustides, MD, FASE, FAHA‡ Surgical excellence in pulmonary thromboendarterectomy (PTE) for chronic thromboembolic pulmonary hypertension (CTEPH) has begun to spread around the world. The perioperative mortality for this procedure is typically under 10%. The maximal benefit from PTE is derived in those patients who have a high proximal clot burden that is surgically accessible, as outlined by the Jamieson classification. Residual pulmonary hypertension after successful PTE is common and increasingly is managed with maintenance oral pulmonary vasodilator therapy such as endothelin antagonists, phosphodiesterase inhibitors, and/or prostaglandins. The role of pulmonary vasodilator therapy in CTEPH before PTE is limited and should not delay definitive surgical therapy. Although plain deep hypothermic circulatory arrest (DHCA) is the classic technique for CTEPH, alternatives such as DHCA with antegrade cerebral perfusion are feasible as well. Prolonged mechanical ventilation after PTE remains common in part because of reperfusion pulmonary edema.
Careful perioperative management can reduce the incidence of this syndrome. Because ventilator-associated pneumonia is also a common complication after PTE, it represents a major opportunity for outcome improvement, particularly because there are multiple modalities for its prevention and prompt diagnosis. © 2011 Elsevier Inc. All rights reserved.
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management of pulmonary hypertension (PHTN), including CTEPH, which is classified as type-4 PHTN in the latest revised clinical classification.4-6 These advances have prompted multiple recent guideline statements, most recently from the American Heart Association (AHA).4-6 This expert review addresses the major innovations in CTEPH and PTE that are likely to significantly influence perioperative practice and therefore be relevant to the cardiovascular anesthesiologist.
HRONIC THROMBOEMBOLIC pulmonary hypertension (CTEPH) is characterized by pulmonary arterial obstruction caused by recurrent pulmonary embolism.1 The definition of CTEPH is a mean arterial pressure ⬎25 mmHg that persists for longer than 6 months after the diagnosis of pulmonary embolism.2 This syndrome develops in at least 4% of patients with acute pulmonary embolism but frequently is underdiagnosed because its development is asymptomatic in more than 50% of cases.1,2 The definitive therapy for CTEPH is pulmonary thromboendarterectomy (PTE), which involves surgical removal of organized thrombus and related fibrous tissue from the pulmonary arterial tree under periods of deep hypothermic circulatory arrest (DHCA) on cardiopulmonary bypass.3 The role of medical therapy in CTEPH beyond indefinite anticoagulation is likely to evolve yet further because of the advent of pulmonary vasodilator therapy such as endothelin blockers and phosphodiesterase inhibitors.1,2 There has been substantial progress in the diagnosis and
From the *Department of Anesthesiology, Ohio State University, Columbus, OH; †Cardiothoracic Anesthesiology, Mayo Clinic, Scottsdale, AZ; and ‡Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA. Address reprint requests to John G.T. Augoustides, MD, FASE, FAHA, Cardiothoracic Section, Anesthesiology and Critical Care, Dulles 680, HUP, 3400 Spruce Street, Philadelphia, PA 19104-4283. E-mail: [email protected] © 2011 Elsevier Inc. All rights reserved. 1053-0770/2504-0023$36.00/0 doi:10.1053/j.jvca.2011.03.182 744
Key words: chronic thromboembolic pulmonary hypertension, pulmonary thromboendarterectomy, clinical outcomes, Jamieson classification, right ventricular dysfunction, pulmonary hypertension, endothelins, bosentan, phosphodiesterases, sildenafil, prostaglandins, epoprostenol, treprostinil, direct thrombin inhibitors, dabigatran, factor Xa inhibitors, apixaban, rivaroxaban, guanylate cyclase, riociguat, deep hypothermic circulatory arrest, moderate hypothermia, selective antegrade cerebral perfusion, reperfusion pulmonary edema, ventilator-associated pneumonia, procalcitonin
WHAT ARE THE CURRENT OUTCOMES AFTER PTE?
Dr Jamieson and his team at the University of California, San Diego have the largest PTE experience in the world, with more than 2,500 procedures since 1970.7 Although the perioperative mortality rate for this entire series is 6.4%, it has fallen to 2.5% in the last 3 years because of yet further refinements in perioperative techniques.3,4 The San Diego group also recently has published their pediatric PTE experience, which, although small (N ⫽ 17), showed safety with a 0% perioperative mortality rate and clinical efficacy with significant improvements in hemodynamics and functional status.8 An important distinction in the pediatric group as compared with the adult group was the significantly increased risk of rethrombosis (38% v 4%), emphasizing the crucial role of aggressive anticoagulation in pediatric presentations of CTEPH. The PTE gradually has spread worldwide. There are currently more than 40 recent reports from around the world (N ⬎ 20; range, 21-236: 2005-2010).4 This surgical experience recently has been augmented by the formation of an international prospective CTEPH registry with participating centers in Europe and Canada.9 In a recent publication from this registry
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(N ⫽ 679: 56.8% underwent PTE), the median age of surgical patients was 60 years.9 The in-hospital mortality rate was 4.7%. Further perioperative complications included neurologic issues (11.2%), bleeding (10.2%), pericardial effusion (8.3%), residual pulmonary hypertension (16.7%), pulmonary reperfusion edema (9.6%), extracorporeal membrane oxygenation (3.1%), and infection (18.8%: 65.7% of this subgroup had ventilatorassociated pneumonia). Neurologic complications were more common as DHCA time increased, 1.9% with DHCA ⬍20 minutes versus 18.4% with DHCA time ⬎60 minutes (odds ratio ⫽ 0.09; 95% confidence interval, 0.01-0.74). Furthermore, in this study, mortality at 1 year was 7.0%. The majority of patients evaluated at this time point had significant improvements in median pulmonary vascular resistance and functional status as measured by 6-minute walk distance and New York Heart Association functional class. The surgical techniques for PTE have matured and subsequently have generalized to multiple centers of excellence throughout the world. It is likely that this dissemination will continue throughout Asia in the coming years.10 This success story has been assisted significantly by the advances in perioperative management of the right ventricular dysfunction and pulmonary hypertension, which have been highlighted recently both in this Journal and elsewhere.1,11 ARE THERE PREDICTORS FOR ADVERSE CLINICAL OUTCOME AFTER PTE?
The major predictor of outcome after PTE is based on the Jamieson classification of CTEPH, namely the pattern of pulmonary arterial occlusion based on the anatomic location of the obstruction.12 Type-1 disease is defined as fresh thrombus in the main and/or lobar arteries (about 25% of cases). Type-2 disease is defined as chronic intimal thickening proximal to the segmental arteries (about 40% of cases). Type-2 disease may have organized thrombus. Type-3 disease is defined as intimal disease limited to the segmental arteries; this disease pattern is technically the most difficult and may represent CTEPH with resorption of the proximal clot burden (about 30% of cases). Type-4 disease is defined as distal arteriolar vasculopathy with no visible thromboembolic disease (⬍5% of cases). In the San Diego series (N ⫽ 202: 1998-2000), patients with distal disease (type 3 and type 4) had significantly increased tricuspid regurgitation and pulmonary vascular resistance (p ⬍ 0.0001) versus the patients with surgically accessible thromboembolic burden (type 1 and type 2).12 Patients with distal CTEPH types had increased inotropic requirements, hospital stays, and perioperative mortality.4,12 Patients with type-4 disease frequently account for most of the perioperative mortality after PTE. This patient subgroup in CTEPH does not benefit from PTE. The major focus in the current era is to enhance preoperative identification of type-4 disease so as to preclude these patients from PTE.13 The degrees of PHTN and/or right ventricular dysfunction are not regarded as contraindications to PTE.4 Patients with operable disease may derive immense clinical benefit with significant reduction of PHTN coupled with recovery of the right heart and resolution of severe tricuspid regurgitation.14,15 It remains an imperative that patients with type-4 CTEPH are diagnosed preoperatively because they qualify primarily for
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medical therapy and not PTE.16 Careful pulmonary angiography can reliably determine the thromboembolic pattern by formal criteria that correlate with clinical outcomes after PTE.17 A recent series from the United Kingdom (N ⫽ 314: 19972007) focused on the outcome importance of residual PHTN after PTE in patients with CTEPH (types 1, 2, and 3).18 Although all patients experienced a significant reduction in mean arterial pulmonary artery pressure (48 ⫾ 12 to 26 ⫾ 10 mmHg, p ⬍ 0.001), 31% of the cohort had residual PHTN, which was defined as mean pulmonary artery pressure ⱖ30 mmHg. Although residual PHTN after PTE did not affect 5-year survival, it significantly worsened functional status. Furthermore, the study highlighted the clinical necessity for further investigation of targeted medical therapy in this patient cohort who persisted with PHTN despite appropriate PTE. Residual PHTN is common after PTE. This finding is explained by the 2-compartment model proposed by Moser and Braunwald in 1973.2,19 This model recognizes that patients with CTEPH who have proximal mechanical obstruction also can have distal small vessel vasospasm as a microvascular phenomenon in the pulmonary vasculature.2,19,20 This distal vasculopathy provides a therapeutic target for selective pulmonary vasodilator therapy, which will be examined in detail in the following 2 sections. WHAT IS THE ROLE OF MEDICAL THERAPY BEFORE PTE?
Standard medical therapy for CTEPH includes chronic anticoagulation with warfarin for a goal international normalized ratio of 2 to 3.2 Although pulmonary vasodilator therapies have been tested in CTEPH before PTE, the evidence is very limited.21,22 A large retrospective study (n ⫽ 111 pulmonary vasodilator exposure and n ⫽ 244 control group: 2005 to 2007) examined the effects of monotherapy with bosentan (endothelin antagonist), sildenafil (phosphodiesterase inhibitor), or epoprostenol (prostaglandin) and combinations thereof.22 The investigators observed a significant increase in exposure to these medications in the study period despite their lack of perioperative benefit. They also documented that exposure to these medications often resulted in delayed referral for PTE, the proven therapy for this disease. Consequently, the recent AHA guideline strongly suggests that pulmonary vasodilator therapy should never delay evaluation for PTE (AHA class III recommendation, level of evidence B).4 Furthermore, the role of medical therapy in the management of CTEPH before PTE requires further study before any conclusive recommendations are possible.23 WHAT IS THE ROLE OF MEDICAL THERAPY AFTER PTE?
Patients with proven CTEPH require indefinite therapeutic anticoagulation in the absence of contraindications (AHA class I recommendation, level of evidence C).4 Until recently, this goal has been achieved with chronic warfarin titrated to a therapeutic international normalized ratio. Given the advent of novel oral anticoagulants, such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban, it is likely that warfarin therapy may be challenged by these newer anticoagulants.24 The advantages of these novel
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oral anticoagulants over warfarin include predictable pharmacologic profiles, freedom from routine coagulation monitoring, and limited food and drug interactions.24,25 The novel oral pulmonary vasodilators should be considered for patients with CTEPH who do not qualify for PTE or who have residual PHTN after PTE at an experienced center (AHA class IIb recommendation, level of evidence B).4 The rationale for chronic pulmonary vasodilator therapy in CTEPH includes the microvascular vasospasm first described by Moser and Braunwald19 as well as the outcome importance of residual PHTN after CTEPH.18 Although the rationale is attractive, the drug trials to date have failed to show a meaningful outcome advantage such as better effort tolerance or survival.26,27 It is likely in the future that the role of medical therapy in CTEPH gradually will expand as further insights into the multimodal pathogenesis of CTEPH take effect.28 Pulmonary vasodilator therapy may have a role in enhancing effort tolerance after successful PTE in a subset of patients who develop effortlimiting PHTN with exercise.29 A recent randomized trial (N ⫽ 157) evaluated endothelin blockade with bosentan in patients with inoperable CTEPH or residual PHTN after PTE.30 Although bosentan exposure reduced pulmonary vascular resistance, there were no improvements in effort tolerance and functional status. A recent metaanalysis of bosentan for CTEPH (10 studies) confirmed that bosentan therapy induces pulmonary vasodilation and suggested that bosentan therapy may improve functional status.31 The multiple international adult and pediatric bosentan registries show growing application of endothelin blockade in PHTN including CTEPH and suggest improving clinical outcomes and survival over time.32-34 Furthermore, a recent dataset from a prospective registry indicates that in the setting of failing bosentan monotherapy, combination therapy with a prostaglandin or phosphodiesterase inhibitor results in meaningful clinical improvement in PHTN.35 Endothelin blockade is a mainstay of oral pulmonary vasodilator therapy for PHTN including CTEPH. Although there are multiple trials in CTEPH evaluating phosphodiesterase blockade with sildenafil (4 trials: cumulative N ⫽ 139: 2003-2008) and prostaglandin therapy with epoprostenol and treprostinil (5 trials: cumulative N ⫽ 84: 20032007), they were not powered to show outcome effects beyond pulmonary vasodilation.4 In clinical practice, however, these agents as monotherapy and/or as components of combination therapy significantly improved long-term survival in CTEPH.36 Furthermore, a novel phosphodiesterase inhibitor, tadalafil, recently was approved for PHTN; its advantages include once daily dosing and an excellent safety profile.37 It will likely enter the medical therapeutic menu for CTEPH. Riociguat is a novel oral pulmonary vasodilator that stimulates guanylate cyclase to increase cyclic guanosine monophosphate, which mediates pulmonary vasodilation.38 This agent is not only the first agent in its class but also has potential application in CTEPH.39 This drug currently is undergoing evaluation in at least 3 randomized controlled CTEPH trials (full details available at www.clinicaltrials.gov, identifiers NCT00855465, NCT00910429, and NCT00454558). The results of these landmark trials will likely determine its future therapeutic role in CTEPH.
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IS DEEP HYPOTHERMIC CIRCULATORY ARREST ESSENTIAL FOR PTE?
The visualization of the pulmonary arteries during PTE requires a bloodless field, which typically has been achieved with intermittent periods of DHCA on cardiopulmonary bypass.3,7,8 The main strategy for cerebral protection in this scenario is profound hypothermia. This technique, however, has been associated with neurologic complications such as stroke, delirium, and chorea.9,40 A recent outcome trial from a multicenter PTE registry correlated neurologic complications with DHCA time, with the following rate of rise: 1.9% with DHCA ⬍20 minutes, 10.8% when DHCA was 21 to 40 minutes, 14.6% when DHCA was 41 to 60 minutes, and 18.4% when DHCA was ⬎60 minutes.9 A collaborative European trial showed in a small cohort (N⫽ 30: 2004-2005) that successful PTE could be performed on cardiopulmonary bypass at moderate hypothermia (defined as 28°32°C).41 In this small trial, however, the DHCA times were under 20 minutes (mean, 10.3 ⫾ 5.2 minutes; range, 2-19 minutes).41 This approach was modified by a group from Bologna who have described successful PTE (N ⫽ 40, 2004-2007) at moderate hypothermia with no DHCA but with aggressive venting of the left heart and titrated flows on cardiopulmonary bypass.42,43 The Cambridge Group at Papworth Hospital have developed a PTE technique that uses DHCA with selective antegrade cerebral perfusion.44 Selective cerebral perfusion is provided by an ascending aortic cannula with clamping of the ascending aorta below the cannula and clamping of the aortic arch between the left common carotid artery and the left subclavian artery. The aortic arch clamping also prevents flow to the bronchial arteries to ensure a bloodless field during the PTE. In their first review of this technique for PTE (N ⫽ 150: 20032006), the in-hospital mortality rate was 15% with no focal neurologic deficits.44 Selective antegrade cerebral perfusion allowed adequate visualization for PTE in 91% of cases with a mean cerebral perfusion time of 63 ⫾ 24 minutes.44 The Cambridge team concluded that DHCA with antegrade cerebral perfusion is an alternative to plain DHCA for PTE. They presently are conducting a randomized controlled trial of both techniques for PTE to evaluate which technique provides superior clinical outcomes (full details available at www. controlledtrials.com, with ISRCTN84972261. The results of this randomized trial may challenge the present standard surgical paradigm of plain DHCA for PTE. IS THE LUNG AT RISK AFTER PTE?
Prolonged postoperative mechanical ventilation is common after PTE. In a recent single-center series (N ⫽ 279: 19952009), 47.3% of patients required tracheal intubation and mechanical ventilation longer than 48 hours.45 In this series, multivariate predictors for prolonged mechanical ventilation after PTE were preoperative chronic obstructive pulmonary disease and preoperative cardiac dysfunction.45 In a recent Canadian PTE series (N ⫽ 106: 1995-2007), the average mechanical ventilation time was 7.8 days.46 Severe preoperative parenchymal lung disease is an independent predictor for perioperative mortality after PTE because it significantly decreases perioperative pulmonary reserve.47 A
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common etiology of lung injury after PTE in the early postoperative period is reperfusion pulmonary edema, which has a radiographic appearance of alveolar infiltrates distal to the pulmonary vessels that underwent endarterectomy. In a recent multicenter registry, the incidence of this syndrome was 9.6%.9 Although the incidence of this syndrome gradually has been decreasing over time, in severe cases, it may require temporary support with extracorporeal membrane oxygenation, which has an incidence of 3% to 6% in a recent series.9,48 The incidence of reperfusion pulmonary edema also can be reduced significantly by low stretch mechanical ventilation and minimizing inotropic support after cardiopulmonary bypass.49 It also is essential to minimize alveolar collapse in this scenario after PTE because pulmonary atelectasis will aggravate hypoxemia, pulmonary hypertension, and right-heart dysfunction.50 The investigators at the University of California, San Diego currently are conducting a randomized clinical trial in PTE patients to determine the effect of low stretch mechanical ventilation (defined as tidal volumes of 6 mL/kg ideal body weight) on the incidence of reperfusion lung injury, which is defined as severe hypoxemia and radiographic alveolar infiltrates within the first 72 hours after PTE (full details available at www.clinicaltrials.gov). Because prolonged tracheal intubation is common after PTE, it is expected that ventilator-associated pneumonia (VAP) would be prevalent in this high-risk surgical population. In recent multicenter PTE trials, the incidence of VAP in the intensive care unit was 10% to 12.5%.9,51 Given this high incidence, efforts to detect VAP as early as possible merit special emphasis. Recent evidence indicates that the biomarker procalcitonin can predict VAP before infection can be detected clinically, allowing for even earlier antibiotic therapy.51 The diagnostic performance of procalcitonin as a marker for infection after PTE was as follows: sensitivity, 86%; specificity, 83%; negative predictive value, 92%; and positive predictive value, 84%.51 Besides earlier diagnosis, decreasing levels of
procalcitonin also correlate with effective therapy and the resolution of infection, including VAP.52,53 Besides the earlier diagnosis of VAP after PTE, an aggressive approach to its prevention also is now feasible because of multiple recent advances.54-56 Modifications in the endotracheal tube design have focused on aspects such as antibiotic coatings and drainage of subglottic secretions.55,56 Oral decontamination, patient positioning, and aerosolized antibiotics also may have a role.54 Given that patients undergoing PTE are at high risk for VAP, a multifaceted evidence-based perioperative protocol for elimination of VAP would likely significantly improve important clinical outcomes after PTE. This is an important clinical and research opportunity for the high-volume PTE centers around the world. CONCLUSIONS
Surgical excellence in PTE for CTEPH has begun to generalize around the world. The perioperative mortality for this procedure is typically under 10%. The maximal benefit from PTE is derived in those patients who have a high proximal clot burden that is surgically accessible, as outlined by the Jamieson classification. Residual PHTN after successful PTE is common and increasingly is managed with maintenance oral pulmonary vasodilator therapy such as endothelin antagonists, phosphodiesterase inhibitors, and/or prostaglandins. The role of pulmonary vasodilator therapy in CTEPH before PTE is limited and should not delay definitive surgical therapy. Although plain DHCA is the classic technique for CTEPH, alternatives such as DHCA with antegrade cerebral perfusion are feasible as well. Prolonged mechanical ventilation after PTE remains common in part because of reperfusion pulmonary edema. Careful perioperative management can reduce the incidence of this syndrome. Because VAP is also a common complication after PTE, it represents a major opportunity for outcome improvement, particularly because there are multiple modalities for the prevention and earlier diagnosis of VAP.
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36. Seyfarth HJ, Halank M, Wilkens H, et al: Standard PAH therapy improves long-term survival in CTEPH patients. Clin Res Cardiol 99:553-556, 2010 37. Levin YD, White RJ: Novel therapeutic approaches in pulmonary arterial hypertension: focus on tadalafil. Drugs Today (Barc) 47:145-156, 2011 38. Schermuly RT, Janssen W, Weissmann N, et al: Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 20:567-576, 2011 39. Kim NH: Riociguat: An upcoming therapy in chronic thromboembolic pulmonary hypertension. Eur Respir Rev 19:68-71, 2010 40. Surie S, Tijssen MAJ, Biervliet JD, et al: Chorea in adults following pulmonary endarterectomy. Mov Disord 25:1101-1104, 2010 41. Macchiarini P, Kamiya H, Hagl C, et al: Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: Is deep hypothermia required? Eur J Cardiothorac Surg 30:237-243, 2006 42. Mikus PM, Dell’Amore A, Pastore S, et al: Pulmonary endarterectomy: Is there an alternative to profound hypothermia with cardiocirculatory arrest? Eur J Cardiothorac Surg 30:563-565, 2006 43. Mikus PM, Mikus E, Martin-Suarez S, et al: Pulmonary endarterectomy: An alternative to circulatory arrest and deep hypothermia: Mid-term results. Eur J Cardiothorac Surg 34:159-163, 2008 44. Thomson B, Tsui SSI, Dunning J, et al: Pulmonary endarterectomy is possible and effective without the use of complete circulatory arrest. Eur J Cardiothorac Surg 33:157-163, 2008 45. Kunihara T, Gerdts J, Groesdonk H, et al: Predictors of postoperative outcome after pulmonary endarterectomy from a 14-year experience with 279 patients. Eur J Cardiothorac Surg 2011 [Epub ahead of print] 46. Rubens FD, Bourke M, Hynes M, et al: Surgery for chronic thromboembolic pulmonary hypertension—Inclusive experience from a national referral center. Ann Thorac Surg 83:1075-1081, 2007 47. Condiffe R, Kiely DG, Gibbs JS, et al: Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension. Eur Resp J 33:332-338, 2009 48. Berman M, Tsui S, Vuylsteke A, et al: Successful extracorporeal membrane oxygenation support after pulmonary thromboendarterectomy. Ann Thorac Surg 86:1261-1267, 2008 49. Mares P, Gilbert TB, Tschemko EM, et al: Pulmonary artery thromboendarterectomy: A comparison of two different postoperative treatment strategies. Anesth Analg 90:267-273, 2000 50. Imanaka H, Takeuchi M, Tachibana K, et al: Effects of open lung approach policy on mechanical ventilation duration in postoperative patients with chronic thromboembolism with pulmonary hypertension: A case-matched study. Anaesth Intens Care 38:461-466, 2008 51. Maruna P, Kunstyr J, Piocova KM, et al: Predictors of infection after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Eur J Cardiothorac Surg 39:195-200, 2011 52. Tschaikowsky K, Hedwig-Geissing M, Braun GG, et al: Predictive value of procalcitonin, interleukin-6 and C-reactive protein for survival in postoperative patients with severe sepsis. J Crit Care 26: 54-64, 2011 53. Bloos F, Marshall JC, Dellinger RP, et al: Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: A multicenter observational study. Crit Care 15:R88, 2011 54. Rewa O, Muscedere J: Ventilator-associated pneumonia: Update on etiology, prevention and management. Curr Infect Dis Rep 2011 [Epub ahead of print] 55. Lorente L, Blot S, Relio J: New issues and controversies in the prevention of ventilator-associated pneumonia. Am J Resp Crit Care Med 1832:870-876, 2010 56. Deem S, Treggiari MM: New endotracheal tubes designed to prevent ventilator-associated pneumonia: Do they make a difference? Respir Care 55:1046-1055, 2010