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Perioperative Management of the Patient With Pulmonary Hypertension Daniel L. Fox, Amanda R. Stream and Todd Bull SEMIN CARDIOTHORAC VASC ANESTH published online 13 May 2014 DOI: 10.1177/1089253214534780 The online version of this article can be found at: http://scv.sagepub.com/content/early/2014/05/13/1089253214534780
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Perioperative Management of the Patient With Pulmonary Hypertension Daniel L. Fox, MD1, Amanda R. Stream, MD2, and Todd Bull, MD2
Abstract Patients with pulmonary hypertension are at increased risk for perioperative morbidity and mortality. Elective surgery is generally discouraged in this patient population; however, there are times when surgery is deemed necessary. Currently, there are no guidelines for the preoperative risk assessment or perioperative management of subjects with pulmonary hypertension. The majority of the literature evaluating perioperative risk factors and mortality rates is observational and includes subjects with multiple etiologies of pulmonary hypertension. Subjects with pulmonary arterial hypertension, also referred to as World Health Organization group I pulmonary hypertension, and particularly those receiving pulmonary arterial hypertension–specific therapy may be at increased risk. Perioperative management of these patients requires a solid understanding and careful consideration of the hemodynamic effects of anesthetic agents, positive pressure ventilation and volume shifts associated with surgery in order to prevent acute right ventricular failure. We reviewed the most recent data regarding perioperative morbidity and mortality for subjects with pulmonary hypertension in an effort to better guide preoperative risk assessment and perioperative management by a multidisciplinary team. Keywords cardiac surgery, cardiac anesthesia, cardiovascular risk, heart, outcome, PDE-5 inhibitors, perioperative mortality, pulmonary artery pressure, risk management
Introduction Pulmonary hypertension (PH) is defined as a mean pulmonary artery (PA) pressure greater or equal to 25 mm Hg. However, this simple definition belies the complexity of the numerous and heterogeneous collection of diseases and conditions that alter the normal function of the pulmonary vascular bed. The pulmonary vasculature is a highcapacitance, low-resistance circulation that, when functioning normally, can accept large increases in blood flow without significant increases in pressure. However, when this system is perturbed, the resultant consequences can be severe. PH is a major risk factor for adverse outcomes during and following surgery and thus it is important to understand the risks and the potential complications when these patients are being considered for operative intervention. This article will review the disease subtypes and current classification of patients with PH. We will then review the available literature describing surgical outcomes of patients with PH. Finally, we will highlight some important bedside management principles for PH patients who require surgical intervention.
Definition and Classification of Pulmonary Hypertension The hemodynamic definition of PH is a PA mean pressure ≥25 mm Hg. Pulmonary arterial hypertension (PAH) requires a PA mean pressure ≥25 mm Hg coupled with a pulmonary artery wedge pressure (PAWP) ≤15 mm Hg. New to the 2013 Nice World Symposium on Pulmonary Hypertension classification, the diagnosis also requires an elevated pulmonary vascular resistance (PVR) of >3 Woods units (WU).1 To accurately diagnose PH and formally assess its severity with the necessary degree of precision, a right heart catheterization (RHC) is requisite. Echocardiography is frequently used to screen for and assess the severity of PH, evaluate right ventricular (RV) 1
University of Colorado, Aurora, CO, USA University of Colorado Health Sciences Center, Aurora, CO, USA
2
Corresponding Author: Daniel L. Fox, University of Colorado Health Sciences Center, 1700 East 17th Avenue, Aurora, CO 80045, USA. Email: [email protected]
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Table 1. 2013 Nice World Symposium on Pulmonary Hypertension Updated Classification of Pulmonary Hypertension. I
II
III
IV V
Pulmonary arterial hypertension Idiopathic pulmonary arterial hypertension (PAH), heritable PAH, drug and toxin Induced, connective tissue disease associated, HIV associated, portal hypertension associated, congenital heart diseases, schistosomiasis Pulmonary hypertension due to left heart disease Left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, congenital/ acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies Pulmonary hypertension due to lung diseases or hypoxia Chronic obstructive pulmonary disease, interstitial lung disease, pulmonary diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental lung diseases Chronic thromboembolic pulmonary hypertension (CTEPH) Pulmonary hypertension due to multifactorial mechanisms Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis Metabolic disorders: glycogenstorage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis
Adapted From 2013 NICE World Symposium on Pulmonary Hypertension.1
dysfunction, and to follow patients longitudinally, though for complete assessment and diagnosis, RHC is critical. The most widely used method of estimating pulmonary artery pressure by standard echocardiography utilizes the velocity of the regurgitant tricuspid jet. This velocity is applied to the modified Bernoulli equation, P = 4(V2) + RA, where P = the estimated RV systolic pressure (which is equivalent to PA systolic pressure assuming no RV outflow obstruction), V = velocity in meters per second of the tricuspid regurgitant jet as measured by Doppler, and RA = the estimated right atrial pressure, as assessed by inferior vena cava size and collapsibility. Though the modified Bernoulli method of measuring RV systolic pressure (RVSP) is widely employed, we emphasize that this is an estimate of RV pressure and it is thus important to confirm the actual PA pressure by right heart catheterization.2 Pulmonary hypertension is divided clinically into 5 separate groups redefined at the Nice World Symposium on Pulmonary Hypertension, in 2013 (Table 1).1 These groups categorize PH based on the presumed etiology and the current understanding of the pathologic changes leading to the elevated PA pressures. World Health Organization (WHO)
group I disease includes patients with idiopathic PAH, heritable PAH, connective tissue disease–related PAH, HIV infection, portopulmonary hypertension, congenital heart diseases, and drug-induced disease, including anorexigenassociated PAH or methamphetamine-associated PAH. Though seemingly diverse in etiology, these conditions share common pathologic changes in the precapillary pulmonary vasculature. The endothelial and smooth muscle cells of the small pulmonary arteries proliferate in a highly abnormal, dysregulated manner, leading to the plexiform arteriopathy. Eventually, these angioproliferative vascular changes accumulate and obstruct a significant proportion of the vascular bed, thus increasing PA pressure and PVR, without effecting PAWP.4 Unchecked, these lesions ultimately result in right heart failure and death. World Health Organization group II PH is defined as pulmonary hypertension resulting from left-sided systolic or diastolic heart disease as well as left-sided valvular disease, manifested as a PCWP >15 mm Hg. Most commonly, this is because of left ventricular (LV) systolic dysfunction, LV hypertrophy with resultant diastolic dysfunction, or aortic or mitral valvular abnormalities. The elevated pressures of the left atrium are transmitted in a retrograde fashion, thus creating elevated pulmonary venous pressures, which are in turn, transmitted back to the pulmonary capillary bed and to the pulmonary arteries. WHO group III PH is defined as PH secondary to hypoxic lung disease such as chronic obstructive pulmonary disease, sleep-disordered breathing, the interstitial lung diseases, or altitudeinduced hypoxia. Chronic or intermittent hypoxia with resultant pulmonary artery smooth muscle cell hypertrophy is the underlying cause of PH in this disease group. WHO group IV PH results from chronic thromboembolic disease obstructing the pulmonary arterial bed. WHO group V PH is a heterogeneous group of diseases associated with PH with unclear or multifactorial mechanisms of disease and include conditions such as sarcoidosis, sickle cell disease, and myeloproliferative disorders.4 When conceptualizing pulmonary vascular disease, it is helpful to divide it based on the location of the pathologic lesion. In “precapillary” PH, the pressure elevation occurs proximal to the pulmonary capillary bed. This form of PH occurs in PAH, hypoxia-driven PH, PH associated with chronic thromboembolic disease. Conversely, “postcapillary” PH, also termed pulmonary venous hypertension, occurs with left heart disease or valvular disease, where the pressure elevation arises distal to the pulmonary capillary bed.
Pharmacologic Treatment of Pulmonary Hypertension When considering therapeutics for patients with pulmonary hypertension, an understanding of the specific WHO disease classification is paramount, as the primary therapy
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Fox et al of choice will be directed at the underlying pathobiology. Conventional therapies that apply broadly to patients with any form of PH include dietary modifications with optimization of volume status, minimizing sodium intake, supplemental oxygen to prevent hypoxia, diuretic therapy to decrease RV size and optimize RV Starling curve mechanics, and finally, consideration of anticoagulation. Over the past 2 decades, multiple PAH-specific therapies have arisen, leading to therapeutic options for the clinician. It is important to understand, however, that PAH-specific therapy has predominately been studies and approved in patients with WHO group I (PAH). Recently, 1 agent has gained Food and Drug Administration approval for use in WHO group IV disease (chronic thromboembolic pulmonary hypertension [CTEPH]). Endothelin receptor antagonists (ERAs) include bosentan, ambrisentan, and macitentan. These agents work directly on the smooth muscle cells of the pulmonary vasculature by binding to the endothelin A and B receptors or, in the case of ambrisentan, selectively to the endothelin A receptor. This binding exerts a vasodilatory and potentially antimitogenic effect on the smooth muscle cells of the vascular bed, thus leading to a decrease in pulmonary pressures via smooth muscle relaxation. Phosophdiesterase-5 inhibitors (PDE-5i) work via a nitric oxide–cyclic guanylate monophosphate (NO-cGMP) pathway. Sildenafil and tadalafil work to augment the NO-cGMP pathway, inhibiting the breakdown of PDE-5, thus increasing cGMP levels and allowing pulmonary artery smooth muscle cell relaxation. Riociguat, a newly approved agent, works via a dual mode of action, acting in synergy with endogenous NO and also directly stimulating cyclic guanylate cyclase independent of NO availability, collectively leading to pulmonary arterial smooth muscle relaxation. Riociguat has also been studied and Fodd and Drug Administration approved for use in patients with CTEPH (WHO group IV). Inhaled nitric oxide (iNO) may be administered to acutely exert direct vasodilatory effects on the pulmonary vasculature bed, also through cGMP stimulation. The benefits of this agent include the rapid onset of action and potent vasodilation of the precapillary pulmonary vasculature. It is rapidly metabolized in the peripheral vasculature and thus does not affect systemic blood pressures. It is frequently used during RHC in the initial assessment of PH to evaluate for “acute vasoreactivity.”1 Patients with PAH who meet the criteria for acute vasoreactivity are candidates for treatment with oral calcium channel blockers (see below). iNO can also be employed in patients on mechanical ventilation when there is concern for acute RV failure either in acute pulmonary hypertensive crisis or during the intra- or postoperative period when liberation from mechanical ventilation or worsening RV hemodynamics are complicating management. It is currently being studied
in a phase 2 trial as a chronic therapy for patients with PAH administered via nasal cannula.5 Complications related to iNO administration include the development of methhemoglobinemia, pulmonary edema in patients with elevated left atrial filling pressures (pulmonary venous hypertension), tachyphylaxis, and rebound pulmonary arteriole vasoconstriction with abrupt discontinuation, though this can typically be avoided by slow down-titration of the medication when clinically appropriate. An important class of PAH-specific therapy includes the prostacyclin analogues. Prostacyclin is produced predominantly by endothelial cells and induces potent vasodilation of the pulmonary arterial bed (though systemic arterial beds are also affected to some degree). Patients with PAH exhibit dysregulation of the prostacyclin synthetic pathways, which is purported to lead to pulmonary arteriole vasoconstriction. Specifically, patients with PAH display a reduction of prostacyclin synthase expression within the pulmonary arteries and arterioles. Prostacyclin analogues (treprostonil, iloprost, epoprostenol) delivered via continuous infusion (both intravenous and subcutaneous), inhaled, and most recently orally. The oral, subcutaneous, and inhaled formulations of prostacyclin therapy may be employed in moderate disease; however continuous intravenous prostacyclin therapy is advised for patients with advanced disease. The half-life of these agents varies, but is typically on the order of minutes to hours and a potent rebound vasoconstriction has been described, thus underscoring the importance of avoiding any interruption in administration of these agents, which is an important consideration during the perioperative period. A small percentage of patients with PAH (4% to 6%) are “acute vasoresponders,” thus demarcating them as candidates for the use of calcium channel blocker (CCB) therapy. Identification of this patient subpopulation is typically performed at the time of diagnosis through the use of a vasoreactivity test performed with and acute vasodilator (iNO, intravenous epoprostenol or intravenous adenosine). An acute vasoreactivity test is considered positive if the mean pulmonary artery pressure decreases by at least 10 mm Hg with a decrease to a value less than 40 mm Hg, without decrease in cardiac output.1,4 Patients who meet this definition of acute vasoreactivity are candidates for a trial of CCB therapy. Conversely, patients who fail to respond to acute vasoreactivity testing should not be placed on CCBs, as these may have deleterious effects such as systemic hypotension, decreased ionotropy, and worsening of ventilation–perfusion matching and resultant hypoxia.
Pulmonary Hypertension and Surgical Risk The majority of published data describing the surgical risk and perioperative management of patients with PH is
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observational with wide-ranging hemodynamic definitions of PH and varied patient populations. Perioperative mortality rates from single-center, retrospective studies of patients undergoing all forms of surgical procedures vary widely from 7% to 18%.6,7 The modern era of advanced PAH-specific therapy has led to an associated decrease in PH-associated mortality. As a result, providers are increasingly met with the dilemma of how to manage patients in need of surgical procedures. Though, in general, elective surgery is discouraged in patients with PAH, there are certainly circumstances when surgery is deemed necessary and appropriate. Management issues specific to this patient population include preoperative risk evaluation, minimization of adverse operative events, and prevention and treatment of acute RV dysfunction in the perioperative period.
Preoperative Risk Stratification Inherent Risk of the Surgical Procedure The most important factors to consider in preoperative risk assessment of subjects with PAH are the risk class of the surgical procedure itself, whether or not the surgery is emergent versus elective, the function of the right ventricle, and the patient’s New York Heart Association (NYHA) functional classification at the time of evaluation. A number of studies have evaluated risk class or type of surgical procedure as an outcome predictor for perioperative morbidity and mortality among subjects with PH. Ramakrishna et al6 evaluated 145 subjects with PH defined either by invasive hemodynamics or echocardiogram, 79 (54%) of whom were classified as WHO group I PH. In this cohort, the morbidity and mortality of different surgical procedures were evaluated, stratified by cardiac-specific risk class defined as minor, intermediate or major. Examples of minor or low cardiac risk procedures included endoscopic, dermatologic and breast surgeries. Intermediate or high cardiac risk procedures included abdominal, thoracic, head and neck, or vascular surgeries. There was an increase in perioperative morbidity but not mortality when comparing minor versus intermediate or major cardiac risk classes. Similarly, Lai et al8 demonstrated the level of surgical risk to be an independent predictor of postoperative morbidity, but not mortality. Finally, Price et al9 used invasive hemodynamic parameters to identify PH in 28 subjects, including 20 (72%) subjects with WHO group I disease. In this population, the presence of PH was an independent predictor of perioperative complications.9 Three studies have evaluated the relationship between the urgency (emergent vs elective) of surgical intervention and perioperative outcomes. The aforementioned studies by Lai et al,8 Price et al,9 and Meyer et al10 each evaluated the urgency of surgical intervention as a predictor of morbidity and mortality, with each suggesting a significantly higher risk with an emergent procedure. Each of these
studies showed an increased risk of major complications or death with emergent surgical procedures.8-10 Finally, a more recent retrospective review reported an overall mortality rate in subjects with PAH undergoing elective surgery to be 2% compared with 15% among those requiring emergent interventions.10
Risk of Noncardiac Surgery In a series of 21 patients with PAH undergoing 28 noncardiac surgery procedures, Minai et al7 noted that only 55% of patients requiring general anesthesia were successfully extubated in the operating room. Patients with moderate-tosevere PAH had an 18% mortality, with the majority of these patients experiencing hemodynamic complications in the perioperative period. In a retrospective study of 145 patients with PH (diagnosed by right-sided heart catheterization or Doppler echocardiography) undergoing noncardiac surgery, Ramakrishna et al6 reported a 7% early mortality within the first 30 days following the procedure, with respiratory failure (60%) and RV failure (50%) being the most frequent contributing factors to patient mortality. Price et al9 retrospectively reviewed complications in 28 patients with PH, primarily with WHO group I disease, who underwent noncardiac, surgery. In this small cohort, the majority of the complications occurred within 48 hours of surgery and again, most were related either to ventilatory or hemodynamic compromise. Overall, perioperative morbidity and mortality were 29% and 7%, respectively. This was followed by a case-control study by Kaw et al11 examining patients with PH undergoing noncardiac surgery, patients with preoperative PH displayed a higher risk of overall morbidity and mortality (26% vs 2.6%, P < .0001, odds ratio = 13). Postoperative heart failure (13.5% vs 1.3%, P < .001; odds ratio = 11.9), hemodynamic instability (P < .002), respiratory failure (P < .004), prolonged intubation (P = .002), and increased intensive care unit and hospital length of stay (P = .0008) were all more common in patients with documented PH compared with those without PH.11,12 The risk of perioperative complications was highest in patients with PAH or mixed PH (those with pulmonary capillary wedge pressure >15 mm Hg and PVR >3 WU). Though the data from each of these individual studies are small and not prospectively validated, collectively they suggest an increased risk for both morbidity and mortality for patients undergoing noncardiac surgical procedures. Meyer et al10 recently published the most comprehensive evaluation of perioperative outcomes in patients with pulmonary hypertension. In this multicenter, prospective observational study the perioperative mortality rate was 3.5% for patients with WHO group I PH (PAH) undergoing noncardiac surgery.10 The incidence of major complications was 6.1%, with key risk factors for major complications including an elevated right atrial pressure, a 6-minute walk distance less than 399 m at clinical assessment prior to surgery,
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Fox et al the preoperative use of vasopressors, and the need for emergency surgery. Additionally, several risks for potential perioperative complications were identified in patients with PH undergoing noncardiac surgery, including NYHA functional class >1, RVSP >70 mm Hg, and RVSP/systolic blood pressure >0.66. Perhaps most important, the mortality rate was 15% (2/13) in emergency procedures, compared with 2% (2/101) in nonemergency procedures (P = .01), thus underscoring the substantial risk that remains, particularly in the emergent surgical setting.
Cardiac Surgery The negative impact of PH on cardiac surgical outcomes is well known from multiple analyses, with mortality rates of up to 25% observed in higher risk surgical cohorts.13-16 Although multiple factors are concurrently responsible for this increased risk, the risk of RV dysfunction and ischemia is significant, particularly after cessation of cardiopulmonary bypass. In a retrospective study of 2066 patients undergoing cardiopulmonary bypass, PH persisted as the only baseline variable independently predictive of perioperative mortality (odds ratio = 2.1).17 In patients undergoing elective mitral valve replacement, those with a mean pulmonary arterial pressure (PAP) >40 mm Hg had a higher mortality (10.5%) than those without PH (3.6%).12 The sentinel work of Paul Wood, explored the importance of elevation in PVR, and its reversibility in the outcomes of patients undergoing mitral valve surgery.12,18,19 Melby et al16 reported a significantly higher operative mortality in patients with PH (9%) who underwent aortic valve replacement as compared to patients with normal PA pressures (5%). Preoperative PH was also found to be an independent risk factor for decreased long-term survival in aortic stenosis (relative risk = 1.7, P = .02).16 Roselli et al20 document a similar experience in patients undergoing aortic valve replacement. In considering cardiac transplantation specifically, multiple studies suggest that PH and acute RV failure can account for 19% of the perioperative mortality and up to 50% of postprocedure complications.21 Although specific cutoffs for PAP and PVR are somewhat variable between cardiac transplant programs, it is generally agreed upon that the presence of PAH should be fully evaluated and reversibility assessed prior to proceeding to cardiac transplantation.
Implications of Pulmonary Hypertension on Intraoperative Physiology Subjects with PH are particularly vulnerable to the effects of both anesthesia and positive pressure ventilation required for procedures performed under general anesthesia and during the perioperative period. PAP is determined by left atrial pressure (LAP), cardiac output (CO), and PVR. These parameters are related by the fundamental equation
PAP = (CO × PVR) + LAP. Physiologic perturbations that occur during the perioperative period may precipitate worsening PH, RV ischemia, or RV dysfunction. Positive pressure ventilation may compromise venous return by increasing intrathoracic pressure, thus reducing RV preload and decreasing CO. Positive pressure ventilation has both direct and indirect effects on RV afterload. Increasing levels of positive end-expiratory pressure (PEEP) decrease RV preload by impeding venous return and increasing RV afterload with a resultant decrease in RV ejection fraction.22 Additionally, the relationship between tidal volume and PVR is U-shaped with PVR being lowest at functional residual capacity (FRC). At tidal volumes lower than FRC, alveolar arterioles undergo vasoconstriction due to atelectasis while tidal volumes larger than FRC can lead to compression of perialveolar arterioles by overdistension leading to increases in PVR.23 The overriding principles that should guide mechanical ventilation in patients with PH include use of tidal volumes at or near FRC with judicious use of PEEP. It is important to avoid both hypoxia and hypercarbia as both are potent pulmonary artery vasoconstrictors. Finally, other factors associated with the operative period including acidosis, pain, and blood loss can adversely affect pulmonary and systemic hemodynamics, further contributing to perioperative morbidity and mortality in subjects with PH. These adverse effects may be minimized by preservation of oxygen saturations >92%, maintenance of normocarbia, providing adequate pain control, and ensuring optimal RV filling pressures. Right ventricular volume overload associated with fluid shifts during surgery and rapid crystalloid or colloid administration may reduce LV cavity size and compromise LV filling due to ventricular interdependence, leading to decreased CO and hypotension. In the normal physiologic state, RV perfusion occurs during both systole and diastole because of the favorable gradient between systolic and diastolic aortic pressures and the corresponding RV endomyocardial pressures. In the setting of severe PH, elevated RV wall stress and thus RV endomyocardial pressure can approach aortic pressure, thus leading to compromised systolic RV coronary blood flow. As the right ventricle fails and RV end-diastolic pressure rises, diastolic perfusion becomes limited, contributing to RV ischemia and worsening RV function, leading to further reductions in CO and systemic blood pressure with an end result of eventual hemodynamic compromise.
Implications for Anesthetic Choices There are little data comparing outcomes of surgical procedures performed in patients with PH using local anesthesia versus general anesthesia. Price et al9 included 14 subjects who underwent general anesthesia and 14 subjects receiving regional anesthesia in their retrospective analysis. The subjects who received regional anesthesia
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had worse baseline hemodynamics, including higher mean PAP, lower cardiac index, and higher PVR than subjects undergoing general anesthesia. There was however a trend toward increased perioperative complications for subjects who received general anesthesia, n = 7 (75%) compared with regional anesthesia, n = 2 (25%) with a corresponding P = .12, though the small size of this study makes it difficult to interpret these results.9 Ideally, anesthesia should be carried out by an anesthesiologist expert in cardiovascular hemodynamics with experience in managing patients with PH. The use of both intraoperative right heart catheterization for continuous monitoring of the RV and PA pressures and cardiac outputs, along with intraoperative use of transesophageal echocardigram may be helpful in evaluating the patient’s volume status and response to therapy. Care must be taken to optimize RV filling by controlling heart rate and rhythm while maintaining the trans-septal gradient (LV systolic pressure minus RV systolic pressure). This can be accomplished by choosing anesthetic agents that act to reduce PVR while maintaining systemic vascular resistance (SVR) and enhance myocardial contractility. Volatile anesthetics reduce myocardial contractility in a dose related relationship, with variable effects on PVR, while some intravenous agents used for induction such as propofol and thiopental decrease both myocardial contractility and SVR. Etomidate may be a preferred induction agent for subjects with PH undergoing general anesthesia given that it has little effect on SVR, PVR, or myocardial contractility. For maintenance of anesthesia, combined techniques using both inhaled agents and intravenous agents have been suggested in an effort to minimize the adverse effects of any single agent. Use of the mainstream agents isoflurane, sevoflurane, and desflurane is considered safe as these agents have little effect on myocardial contractility at clinically relevant doses, and less adverse effects on pulmonary blood flow and PVR than historic agents such as halothane.23 Reflective of the adverse effects of anesthesia, Ramakrishna et al6 reported an increased risk of perioperative mortality with an odds ratio of 2.9 (1.03-4.6; P = .04) for subjects who underwent >3 hours of general anesthesia. Similarly, Price et al9 reported significantly longer operative times for subjects with PH who experienced postoperative complications compared with those who did not, 193 minutes (120-420) versus 124 minutes (45-465), P = .003, respectively.
Prevention and Treatment of Acute Right Ventricular Failure A primary objective for the anesthesiologist during the operative period for subjects with PH is prevention of acute RV dysfunction or what has also been referred to as acute pulmonary hypertensive crisis. Optimization of RV
function preoperatively and maintenance of RV function intraoperatively are achieved through continuation of preoperative PAH-specific therapies along with careful selection of anesthetic agents as discussed previously. As discussed above and outlined in Table 2, there are several classes of pharmacologic therapy approved for use in WHO group I PH and the recently approved agent (riociquat) for the treatment of WHO group IV PH (CTEPH). Though initiation of these therapies in the immediate perioperative period is discouraged, they sometimes are used as a part of a rescue strategy in the patient who is experiencing acute decompensation during or after operative intervention. Care must be used not to add these medications in the setting of an elevated left atrial filling pressure, as pulmonary edema can result. Abrupt discontinuation of PAH-specific medication is also to be avoided as this can result in rebound PH and adverse outcomes. This is most relevant in patients with severe PAH and with the use of parenteral prostanoids and iNO where sudden discontinuation can precipitate rebound PH with acute RV failure and death.24 Treatment of acute RV failure is targeted at reducing PVR, optimization of heart rate and rhythm, improvement of RV function, and the maintenance of the myocardial perfusion pressure. Neither bradycardia nor excessive tachycardia is well tolerated in PH, and tachyarrhythmias may lead to acute RV decompensation. Use of intravenous pulmonary arterial vasodilators including calcium channel blockers, nitroglycerin, nitroprusside and epoprostenol have all been employed to liberate patients from cardiopulmonary bypass25,26; however, none of these agents are specific to the pulmonary circulation and therefore may not be tolerated in acute RV failure due to systemic hypotension. Additionally, the use of systemically administered vasodilators carries the risk of inhibiting hypoxic vasoconstriction in the pulmonary circulation causing V/Q (ventilation/perfusion) mismatch and worsening hypoxemia. Use of PAH-specific therapies in the setting of acute RV failure for subjects with PH not previously on PAH-specific therapy or in addition to background PAH therapy has not been well studied and when initiated, is done to target specific physiologic end-point, typically with a right heart catheter in place for close hemodynamic monitoring. There are case reports of the use of PDE-5i for the treatment of acute RV dysfunction following heart transplant,27 though empiric data for this practice are lacking. Both inhaled epoprostenol and inhaled NO have been used successfully to wean subjects with PH and RV failure from cardiopulmonary bypass.28,29 Use of both oral and parenteral agents carries the risk of precipitating systemic hypotension while the inhaled agents have the potential benefit of causing preferential vasodilation of the pulmonary circulation in wellventilated lung zones with minimal effects on LV filling and systemic blood pressure. These “selective” effects are desirable for subjects with WHO group I PH; however,
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Fox et al Table 2. Pharmacologic Agents Available for treatment of Pulmonary Hypertension (All Therapies Approved for World Health Organization Group I Disease Unless Otherwise Indicated). Agent Prostanoids Epoprostenol Treprostonil Iloprost Endothelin receptor antagonists Bosentan Ambrisentan Macitentan Phosphodiesterase 5 inhibitors Sildenafil Tadalafil Soluble guanylate cyclase stimulant Riociguata Inhaled nitric oxide (iNO)
Route of Administration
Dosing Range
Continuous intravenous infusion Continuous intravenous or subcutaneous infusion Inhaled Inhaled
1-12 ng/kg/min, titrated for effect 0.625 to 1.25 ng/kg/min titrated for effect 3-9 inhalations 4 times daily 2.5-5 µg, up to 9 times daily
Oral Oral Oral
62.5-125 mg twice daily 5-10 mg daily 3-10 mg daily
Oral or intravenous Oral
20 mg every 8 hours 40 mg daily
Oral Inhaled
0.5-2.5 mg 3 times daily 5-80 ppm via continuous inhalation
Drug Half-Life 10-15 min 4h 4h 30 min 5h 10 h 18 h 4h 35 h 12 h Seconds to minutes
a
Approved for use in World Health Organization group IV disease (chronic thromboembolic pulmonary hypertension).
they may cause pulmonary edema in subjects with WHO group II disease due to pulmonary arteriolar vasodilation in the setting of an elevated PAWP. Inotropic agents, including dopamine, dobutamine, and milrinone all have potential beneficial effects in the treatment of acute RV dysfunction, but carry with them the associated risks of systemic hypotension and tachyarrythmias. Dopamine has been observed to increase CO without adversely affecting PVR,30,31 while dobutamine appears to improve RV contractility and decrease both PVR and SVR with less tachycardia than is associated with dopamine.32,33 The PDE-3 inhibitor milrinone has both positive iontropic and vasodilatory actions and has been successfully used in subjects with WHO group II PH post–ventricular assist device placement or cardiac transplantation.34,35 Milrinone has also been used successfully via the inhalational route in subjects with PH undergoing mitral valve replacement.36
Summary Despite recent advances in the field of pulmonary hypertension, there remain relatively little data available on the perioperative outcomes of subjects with PH and specifically those with PAH. The most recent literature including the only prospective study of perioperative outcomes for subjects with PAH continues to show increased risk for perioperative outcomes and death in this patient population. However, perioperative morbidity and mortality may be reduced by realizing the surgical risks related to PH, understanding the relevant physiology, and taking precautions to avoid perturbations in volume statues, acid-base disturbance, and administration of PH-specific medications.
Additionally, performing elective surgeries only on carefully selected patients at centers specializing in pulmonary hypertension is important to minimize perioperative morbidity and mortlity. Attempts to optimize RV function through the use of PAH specific therapies preoperatively should be pursued through a multidisciplinary approach and in consultation with a PAH specialist. More prospective studies are needed for subjects with PH undergoing both noncardiac and cardiac procedures. In the meantime subjects must be evaluated on an individual basis with the ultimate goal to minimize risk for the patient while erstwhile maintaining an optimized physiology for the right ventricle and the pulmonary vasculature. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 suppl):D34-D41. Erratum in J Am Coll Cardiol. 2014;63:746. 2. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167:735-740.
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3. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research “Work in progress”. Circulation. 2000;102:2781-2791. 4. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 suppl):S43-S54. 5. Inhaled nitric oxide/INOpulse DS for pulmonary arterial hypertension (PAH). http://clinicaltrials.gov/show/ NCT01457781. Accessed April 21, 2014. 6. Ramakrishna G, Sprung J, Ravi BS, Chandrasekaran K, McGoon MD. Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality. J Am Coll Cardiol. 2005;45: 1691-1699. 7. Minai OA, Venkateshiah SB, Arroliga AC. Surgical intervention in patients with moderate to severe pulmonary arterial hypertension. Conn Med. 2006;70:239-243. 8. Lai HC, Wang KY, Lee WL, Ting CT, Liu TJ. Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery. Br J Anaesth. 2007;99:184-190. 9. Price LC, Wort SJ, Finney SJ, Marino PS, Brett SJ. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169. 10. Meyer S, McLaughlin VV, Seyfarth HJ, et al. Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey. Eur Respir J. 2013;41:1302-1307. 11. Kaw R, Pasupuleti V, Deshpande A, Hamieh T, Walker E, Minai OA. Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery. Respir Med. 2011;105:619-624. 12. Baker C, Brock RC, Campbell M, Wood P. Valvotomy for mitral stenosis; a further report, on 100 cases. BMJ. 1952;1:1043-1055. 13. Reich DL, Bodian CA, Krol M, Kuroda M, Osinski T, Thys DM. Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg. 1999;89:814-822. 14. Malouf JF, Enriquez-Sarano M, Pellikka PA, et al. Severe pulmonary hypertension in patients with severe aortic valve stenosis: clinical profile and prognostic implications. J Am Coll Cardiol. 2002;40:789-795. 15. Kuralay E, Demírkiliç U, Oz BS, Cíngöz F, Tatar H. Primary pulmonary hypertension and coronary artery bypass surgery. J Card Surg. 2002;17:79-80. 16. Melby SJ, Moon MR, Lindman BR, Bailey MS, Hill LL, Damiano RJ Jr. Impact of pulmonary hypertension on outcomes after aortic valve replacement for aortic valve stenosis. J Thorac Cardiovasc Surg. 2011;141:1424-1430. 17. Reich DL, Bodian, Carol D, Krol M, Kuroda M, Osinski T, Thys MD. Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg. 1999;49:814-822. 18. Wood P, Besterman EM, Towers MK, McIlroy MB. The effect of acetylcholine on pulmonary vascular resistance and left atrial pressure in mitral stenosis. Br Heart J. 1957;19:279-286.
19. Davies H, Williams J, Wood P. Lung stiffness in states of abnormal pulmonary blood flow and pressure. Br Heart J. 1962;24:129-138. 20. Roselli EE, Abdel Azim A, Houghtaling PL, Jaber WA, Blackstone EH. Pulmonary hypertension is associated with worse early and late outcomes after aortic valve replacement: implications for transcatheter aortic valve replacement. J Thorac Cardiovasc Surg. 2012;144:1067.e2-1074.e2. 21. Nilsson J, Algotsson L, Hoglund P, Luhrs C, Brandt J. Comparison of 19 pre-operative risk stratification models in open-heart surgery. Eur Heart J. 2006;27:867-874. 22. Biondi JW, Schulman DS, Soufer R, et al. The effect of incremental positive end-expiratory pressure on right ventricular hemodynamics and ejection fraction. Anesth Analg. 1988;67:144-151. 23. Fischer LG, Van Aken H, Burkle H. Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists. Anesth Analg. 2003;96:1603-1616. 24. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917-1928. 25. Ziskind Z, Pohoryles L, Mohr R, et al. The effect of lowdose intravenous nitroglycerin on pulmonary hypertension immediately after replacement of a stenotic mitral valve. Circulation. 1985;72(3 pt 2):II164-II169. 26. Lowson SM. Alternatives to nitric oxide. Br Med Bull. 2004;70:119-131. 27. De Santo LS, Mastroianni C, Romano G, et al. Role of sildenafil in acute posttransplant right ventricular dysfunction: successful experience in 13 consecutive patients. Transplant Proc. 2008;40:2015-2018. 28. Rex S, Missant C, Claus P, Buhre W, Wouters PF. Effects of inhaled iloprost on right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence: a randomized placebo-controlled trial in an experimental model of acute pulmonary hypertension. Crit Care. 2008;12(5):R113. 29. Winterhalter M, Simon A, Fischer S, et al. Comparison of inhaled iloprost and nitric oxide in patients with pulmonary hypertension during weaning from cardiopulmonary bypass in cardiac surgery: a prospective randomized trial. J Cardiothorac Vasc Anesth. 2008;22:406-413. 30. Holloway EL, Polumbo RA, Harrison DC. Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J. 1975;37:482-485. 31. Schreuder WO, Schneider AJ, Groeneveld AB, Thijs LG. Effect of dopamine vs norepinephrine on hemodynamics in septic shock. Emphasis on right ventricular performance. Chest. 1989;95:1282-1288. 32. Ferrario M, Poli A, Previtali M, et al. Hemodynamics of volume loading compared with dobutamine in severe right ventricular infarction. Am J Cardiol. 1994;74:329-333. 33. Acosta F, Sansano T, Palenciano CG, et al. Effects of dobutamine on right ventricular function and pulmonary circulation in pulmonary hypertension during liver transplantation. Transplant Proc. 2005;37:3869-3870.
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Fox et al 34. Kihara S, Kawai A, Fukuda T, et al. Effects of milrinone for right ventricular failure after left ventricular assist device implantation. Heart Vessels. 2002;16:69-71. 35. Eichhorn EJ, Konstam MA, Weiland DS, et al. Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart
failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1987;60:1329-1333. 36. Wang H, Gong M, Zhou B, Dai A. Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery. Adv Ther. 2009;26:462-468.
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Perioperative Management of the Patient With Pulmonary Hypertension Daniel L. Fox, Amanda R. Stream and Todd Bull SEMIN CARDIOTHORAC VASC ANESTH published online 13 May 2014 DOI: 10.1177/1089253214534780 The online version of this article can be found at: http://scv.sagepub.com/content/early/2014/05/13/1089253214534780
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Perioperative Management of the Patient With Pulmonary Hypertension Daniel L. Fox, MD1, Amanda R. Stream, MD2, and Todd Bull, MD2
Abstract Patients with pulmonary hypertension are at increased risk for perioperative morbidity and mortality. Elective surgery is generally discouraged in this patient population; however, there are times when surgery is deemed necessary. Currently, there are no guidelines for the preoperative risk assessment or perioperative management of subjects with pulmonary hypertension. The majority of the literature evaluating perioperative risk factors and mortality rates is observational and includes subjects with multiple etiologies of pulmonary hypertension. Subjects with pulmonary arterial hypertension, also referred to as World Health Organization group I pulmonary hypertension, and particularly those receiving pulmonary arterial hypertension–specific therapy may be at increased risk. Perioperative management of these patients requires a solid understanding and careful consideration of the hemodynamic effects of anesthetic agents, positive pressure ventilation and volume shifts associated with surgery in order to prevent acute right ventricular failure. We reviewed the most recent data regarding perioperative morbidity and mortality for subjects with pulmonary hypertension in an effort to better guide preoperative risk assessment and perioperative management by a multidisciplinary team. Keywords cardiac surgery, cardiac anesthesia, cardiovascular risk, heart, outcome, PDE-5 inhibitors, perioperative mortality, pulmonary artery pressure, risk management
Introduction Pulmonary hypertension (PH) is defined as a mean pulmonary artery (PA) pressure greater or equal to 25 mm Hg. However, this simple definition belies the complexity of the numerous and heterogeneous collection of diseases and conditions that alter the normal function of the pulmonary vascular bed. The pulmonary vasculature is a highcapacitance, low-resistance circulation that, when functioning normally, can accept large increases in blood flow without significant increases in pressure. However, when this system is perturbed, the resultant consequences can be severe. PH is a major risk factor for adverse outcomes during and following surgery and thus it is important to understand the risks and the potential complications when these patients are being considered for operative intervention. This article will review the disease subtypes and current classification of patients with PH. We will then review the available literature describing surgical outcomes of patients with PH. Finally, we will highlight some important bedside management principles for PH patients who require surgical intervention.
Definition and Classification of Pulmonary Hypertension The hemodynamic definition of PH is a PA mean pressure ≥25 mm Hg. Pulmonary arterial hypertension (PAH) requires a PA mean pressure ≥25 mm Hg coupled with a pulmonary artery wedge pressure (PAWP) ≤15 mm Hg. New to the 2013 Nice World Symposium on Pulmonary Hypertension classification, the diagnosis also requires an elevated pulmonary vascular resistance (PVR) of >3 Woods units (WU).1 To accurately diagnose PH and formally assess its severity with the necessary degree of precision, a right heart catheterization (RHC) is requisite. Echocardiography is frequently used to screen for and assess the severity of PH, evaluate right ventricular (RV) 1
University of Colorado, Aurora, CO, USA University of Colorado Health Sciences Center, Aurora, CO, USA
2
Corresponding Author: Daniel L. Fox, University of Colorado Health Sciences Center, 1700 East 17th Avenue, Aurora, CO 80045, USA. Email: [email protected]
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Table 1. 2013 Nice World Symposium on Pulmonary Hypertension Updated Classification of Pulmonary Hypertension. I
II
III
IV V
Pulmonary arterial hypertension Idiopathic pulmonary arterial hypertension (PAH), heritable PAH, drug and toxin Induced, connective tissue disease associated, HIV associated, portal hypertension associated, congenital heart diseases, schistosomiasis Pulmonary hypertension due to left heart disease Left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, congenital/ acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies Pulmonary hypertension due to lung diseases or hypoxia Chronic obstructive pulmonary disease, interstitial lung disease, pulmonary diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental lung diseases Chronic thromboembolic pulmonary hypertension (CTEPH) Pulmonary hypertension due to multifactorial mechanisms Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis Metabolic disorders: glycogenstorage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis
Adapted From 2013 NICE World Symposium on Pulmonary Hypertension.1
dysfunction, and to follow patients longitudinally, though for complete assessment and diagnosis, RHC is critical. The most widely used method of estimating pulmonary artery pressure by standard echocardiography utilizes the velocity of the regurgitant tricuspid jet. This velocity is applied to the modified Bernoulli equation, P = 4(V2) + RA, where P = the estimated RV systolic pressure (which is equivalent to PA systolic pressure assuming no RV outflow obstruction), V = velocity in meters per second of the tricuspid regurgitant jet as measured by Doppler, and RA = the estimated right atrial pressure, as assessed by inferior vena cava size and collapsibility. Though the modified Bernoulli method of measuring RV systolic pressure (RVSP) is widely employed, we emphasize that this is an estimate of RV pressure and it is thus important to confirm the actual PA pressure by right heart catheterization.2 Pulmonary hypertension is divided clinically into 5 separate groups redefined at the Nice World Symposium on Pulmonary Hypertension, in 2013 (Table 1).1 These groups categorize PH based on the presumed etiology and the current understanding of the pathologic changes leading to the elevated PA pressures. World Health Organization (WHO)
group I disease includes patients with idiopathic PAH, heritable PAH, connective tissue disease–related PAH, HIV infection, portopulmonary hypertension, congenital heart diseases, and drug-induced disease, including anorexigenassociated PAH or methamphetamine-associated PAH. Though seemingly diverse in etiology, these conditions share common pathologic changes in the precapillary pulmonary vasculature. The endothelial and smooth muscle cells of the small pulmonary arteries proliferate in a highly abnormal, dysregulated manner, leading to the plexiform arteriopathy. Eventually, these angioproliferative vascular changes accumulate and obstruct a significant proportion of the vascular bed, thus increasing PA pressure and PVR, without effecting PAWP.4 Unchecked, these lesions ultimately result in right heart failure and death. World Health Organization group II PH is defined as pulmonary hypertension resulting from left-sided systolic or diastolic heart disease as well as left-sided valvular disease, manifested as a PCWP >15 mm Hg. Most commonly, this is because of left ventricular (LV) systolic dysfunction, LV hypertrophy with resultant diastolic dysfunction, or aortic or mitral valvular abnormalities. The elevated pressures of the left atrium are transmitted in a retrograde fashion, thus creating elevated pulmonary venous pressures, which are in turn, transmitted back to the pulmonary capillary bed and to the pulmonary arteries. WHO group III PH is defined as PH secondary to hypoxic lung disease such as chronic obstructive pulmonary disease, sleep-disordered breathing, the interstitial lung diseases, or altitudeinduced hypoxia. Chronic or intermittent hypoxia with resultant pulmonary artery smooth muscle cell hypertrophy is the underlying cause of PH in this disease group. WHO group IV PH results from chronic thromboembolic disease obstructing the pulmonary arterial bed. WHO group V PH is a heterogeneous group of diseases associated with PH with unclear or multifactorial mechanisms of disease and include conditions such as sarcoidosis, sickle cell disease, and myeloproliferative disorders.4 When conceptualizing pulmonary vascular disease, it is helpful to divide it based on the location of the pathologic lesion. In “precapillary” PH, the pressure elevation occurs proximal to the pulmonary capillary bed. This form of PH occurs in PAH, hypoxia-driven PH, PH associated with chronic thromboembolic disease. Conversely, “postcapillary” PH, also termed pulmonary venous hypertension, occurs with left heart disease or valvular disease, where the pressure elevation arises distal to the pulmonary capillary bed.
Pharmacologic Treatment of Pulmonary Hypertension When considering therapeutics for patients with pulmonary hypertension, an understanding of the specific WHO disease classification is paramount, as the primary therapy
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Fox et al of choice will be directed at the underlying pathobiology. Conventional therapies that apply broadly to patients with any form of PH include dietary modifications with optimization of volume status, minimizing sodium intake, supplemental oxygen to prevent hypoxia, diuretic therapy to decrease RV size and optimize RV Starling curve mechanics, and finally, consideration of anticoagulation. Over the past 2 decades, multiple PAH-specific therapies have arisen, leading to therapeutic options for the clinician. It is important to understand, however, that PAH-specific therapy has predominately been studies and approved in patients with WHO group I (PAH). Recently, 1 agent has gained Food and Drug Administration approval for use in WHO group IV disease (chronic thromboembolic pulmonary hypertension [CTEPH]). Endothelin receptor antagonists (ERAs) include bosentan, ambrisentan, and macitentan. These agents work directly on the smooth muscle cells of the pulmonary vasculature by binding to the endothelin A and B receptors or, in the case of ambrisentan, selectively to the endothelin A receptor. This binding exerts a vasodilatory and potentially antimitogenic effect on the smooth muscle cells of the vascular bed, thus leading to a decrease in pulmonary pressures via smooth muscle relaxation. Phosophdiesterase-5 inhibitors (PDE-5i) work via a nitric oxide–cyclic guanylate monophosphate (NO-cGMP) pathway. Sildenafil and tadalafil work to augment the NO-cGMP pathway, inhibiting the breakdown of PDE-5, thus increasing cGMP levels and allowing pulmonary artery smooth muscle cell relaxation. Riociguat, a newly approved agent, works via a dual mode of action, acting in synergy with endogenous NO and also directly stimulating cyclic guanylate cyclase independent of NO availability, collectively leading to pulmonary arterial smooth muscle relaxation. Riociguat has also been studied and Fodd and Drug Administration approved for use in patients with CTEPH (WHO group IV). Inhaled nitric oxide (iNO) may be administered to acutely exert direct vasodilatory effects on the pulmonary vasculature bed, also through cGMP stimulation. The benefits of this agent include the rapid onset of action and potent vasodilation of the precapillary pulmonary vasculature. It is rapidly metabolized in the peripheral vasculature and thus does not affect systemic blood pressures. It is frequently used during RHC in the initial assessment of PH to evaluate for “acute vasoreactivity.”1 Patients with PAH who meet the criteria for acute vasoreactivity are candidates for treatment with oral calcium channel blockers (see below). iNO can also be employed in patients on mechanical ventilation when there is concern for acute RV failure either in acute pulmonary hypertensive crisis or during the intra- or postoperative period when liberation from mechanical ventilation or worsening RV hemodynamics are complicating management. It is currently being studied
in a phase 2 trial as a chronic therapy for patients with PAH administered via nasal cannula.5 Complications related to iNO administration include the development of methhemoglobinemia, pulmonary edema in patients with elevated left atrial filling pressures (pulmonary venous hypertension), tachyphylaxis, and rebound pulmonary arteriole vasoconstriction with abrupt discontinuation, though this can typically be avoided by slow down-titration of the medication when clinically appropriate. An important class of PAH-specific therapy includes the prostacyclin analogues. Prostacyclin is produced predominantly by endothelial cells and induces potent vasodilation of the pulmonary arterial bed (though systemic arterial beds are also affected to some degree). Patients with PAH exhibit dysregulation of the prostacyclin synthetic pathways, which is purported to lead to pulmonary arteriole vasoconstriction. Specifically, patients with PAH display a reduction of prostacyclin synthase expression within the pulmonary arteries and arterioles. Prostacyclin analogues (treprostonil, iloprost, epoprostenol) delivered via continuous infusion (both intravenous and subcutaneous), inhaled, and most recently orally. The oral, subcutaneous, and inhaled formulations of prostacyclin therapy may be employed in moderate disease; however continuous intravenous prostacyclin therapy is advised for patients with advanced disease. The half-life of these agents varies, but is typically on the order of minutes to hours and a potent rebound vasoconstriction has been described, thus underscoring the importance of avoiding any interruption in administration of these agents, which is an important consideration during the perioperative period. A small percentage of patients with PAH (4% to 6%) are “acute vasoresponders,” thus demarcating them as candidates for the use of calcium channel blocker (CCB) therapy. Identification of this patient subpopulation is typically performed at the time of diagnosis through the use of a vasoreactivity test performed with and acute vasodilator (iNO, intravenous epoprostenol or intravenous adenosine). An acute vasoreactivity test is considered positive if the mean pulmonary artery pressure decreases by at least 10 mm Hg with a decrease to a value less than 40 mm Hg, without decrease in cardiac output.1,4 Patients who meet this definition of acute vasoreactivity are candidates for a trial of CCB therapy. Conversely, patients who fail to respond to acute vasoreactivity testing should not be placed on CCBs, as these may have deleterious effects such as systemic hypotension, decreased ionotropy, and worsening of ventilation–perfusion matching and resultant hypoxia.
Pulmonary Hypertension and Surgical Risk The majority of published data describing the surgical risk and perioperative management of patients with PH is
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observational with wide-ranging hemodynamic definitions of PH and varied patient populations. Perioperative mortality rates from single-center, retrospective studies of patients undergoing all forms of surgical procedures vary widely from 7% to 18%.6,7 The modern era of advanced PAH-specific therapy has led to an associated decrease in PH-associated mortality. As a result, providers are increasingly met with the dilemma of how to manage patients in need of surgical procedures. Though, in general, elective surgery is discouraged in patients with PAH, there are certainly circumstances when surgery is deemed necessary and appropriate. Management issues specific to this patient population include preoperative risk evaluation, minimization of adverse operative events, and prevention and treatment of acute RV dysfunction in the perioperative period.
Preoperative Risk Stratification Inherent Risk of the Surgical Procedure The most important factors to consider in preoperative risk assessment of subjects with PAH are the risk class of the surgical procedure itself, whether or not the surgery is emergent versus elective, the function of the right ventricle, and the patient’s New York Heart Association (NYHA) functional classification at the time of evaluation. A number of studies have evaluated risk class or type of surgical procedure as an outcome predictor for perioperative morbidity and mortality among subjects with PH. Ramakrishna et al6 evaluated 145 subjects with PH defined either by invasive hemodynamics or echocardiogram, 79 (54%) of whom were classified as WHO group I PH. In this cohort, the morbidity and mortality of different surgical procedures were evaluated, stratified by cardiac-specific risk class defined as minor, intermediate or major. Examples of minor or low cardiac risk procedures included endoscopic, dermatologic and breast surgeries. Intermediate or high cardiac risk procedures included abdominal, thoracic, head and neck, or vascular surgeries. There was an increase in perioperative morbidity but not mortality when comparing minor versus intermediate or major cardiac risk classes. Similarly, Lai et al8 demonstrated the level of surgical risk to be an independent predictor of postoperative morbidity, but not mortality. Finally, Price et al9 used invasive hemodynamic parameters to identify PH in 28 subjects, including 20 (72%) subjects with WHO group I disease. In this population, the presence of PH was an independent predictor of perioperative complications.9 Three studies have evaluated the relationship between the urgency (emergent vs elective) of surgical intervention and perioperative outcomes. The aforementioned studies by Lai et al,8 Price et al,9 and Meyer et al10 each evaluated the urgency of surgical intervention as a predictor of morbidity and mortality, with each suggesting a significantly higher risk with an emergent procedure. Each of these
studies showed an increased risk of major complications or death with emergent surgical procedures.8-10 Finally, a more recent retrospective review reported an overall mortality rate in subjects with PAH undergoing elective surgery to be 2% compared with 15% among those requiring emergent interventions.10
Risk of Noncardiac Surgery In a series of 21 patients with PAH undergoing 28 noncardiac surgery procedures, Minai et al7 noted that only 55% of patients requiring general anesthesia were successfully extubated in the operating room. Patients with moderate-tosevere PAH had an 18% mortality, with the majority of these patients experiencing hemodynamic complications in the perioperative period. In a retrospective study of 145 patients with PH (diagnosed by right-sided heart catheterization or Doppler echocardiography) undergoing noncardiac surgery, Ramakrishna et al6 reported a 7% early mortality within the first 30 days following the procedure, with respiratory failure (60%) and RV failure (50%) being the most frequent contributing factors to patient mortality. Price et al9 retrospectively reviewed complications in 28 patients with PH, primarily with WHO group I disease, who underwent noncardiac, surgery. In this small cohort, the majority of the complications occurred within 48 hours of surgery and again, most were related either to ventilatory or hemodynamic compromise. Overall, perioperative morbidity and mortality were 29% and 7%, respectively. This was followed by a case-control study by Kaw et al11 examining patients with PH undergoing noncardiac surgery, patients with preoperative PH displayed a higher risk of overall morbidity and mortality (26% vs 2.6%, P < .0001, odds ratio = 13). Postoperative heart failure (13.5% vs 1.3%, P < .001; odds ratio = 11.9), hemodynamic instability (P < .002), respiratory failure (P < .004), prolonged intubation (P = .002), and increased intensive care unit and hospital length of stay (P = .0008) were all more common in patients with documented PH compared with those without PH.11,12 The risk of perioperative complications was highest in patients with PAH or mixed PH (those with pulmonary capillary wedge pressure >15 mm Hg and PVR >3 WU). Though the data from each of these individual studies are small and not prospectively validated, collectively they suggest an increased risk for both morbidity and mortality for patients undergoing noncardiac surgical procedures. Meyer et al10 recently published the most comprehensive evaluation of perioperative outcomes in patients with pulmonary hypertension. In this multicenter, prospective observational study the perioperative mortality rate was 3.5% for patients with WHO group I PH (PAH) undergoing noncardiac surgery.10 The incidence of major complications was 6.1%, with key risk factors for major complications including an elevated right atrial pressure, a 6-minute walk distance less than 399 m at clinical assessment prior to surgery,
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Fox et al the preoperative use of vasopressors, and the need for emergency surgery. Additionally, several risks for potential perioperative complications were identified in patients with PH undergoing noncardiac surgery, including NYHA functional class >1, RVSP >70 mm Hg, and RVSP/systolic blood pressure >0.66. Perhaps most important, the mortality rate was 15% (2/13) in emergency procedures, compared with 2% (2/101) in nonemergency procedures (P = .01), thus underscoring the substantial risk that remains, particularly in the emergent surgical setting.
Cardiac Surgery The negative impact of PH on cardiac surgical outcomes is well known from multiple analyses, with mortality rates of up to 25% observed in higher risk surgical cohorts.13-16 Although multiple factors are concurrently responsible for this increased risk, the risk of RV dysfunction and ischemia is significant, particularly after cessation of cardiopulmonary bypass. In a retrospective study of 2066 patients undergoing cardiopulmonary bypass, PH persisted as the only baseline variable independently predictive of perioperative mortality (odds ratio = 2.1).17 In patients undergoing elective mitral valve replacement, those with a mean pulmonary arterial pressure (PAP) >40 mm Hg had a higher mortality (10.5%) than those without PH (3.6%).12 The sentinel work of Paul Wood, explored the importance of elevation in PVR, and its reversibility in the outcomes of patients undergoing mitral valve surgery.12,18,19 Melby et al16 reported a significantly higher operative mortality in patients with PH (9%) who underwent aortic valve replacement as compared to patients with normal PA pressures (5%). Preoperative PH was also found to be an independent risk factor for decreased long-term survival in aortic stenosis (relative risk = 1.7, P = .02).16 Roselli et al20 document a similar experience in patients undergoing aortic valve replacement. In considering cardiac transplantation specifically, multiple studies suggest that PH and acute RV failure can account for 19% of the perioperative mortality and up to 50% of postprocedure complications.21 Although specific cutoffs for PAP and PVR are somewhat variable between cardiac transplant programs, it is generally agreed upon that the presence of PAH should be fully evaluated and reversibility assessed prior to proceeding to cardiac transplantation.
Implications of Pulmonary Hypertension on Intraoperative Physiology Subjects with PH are particularly vulnerable to the effects of both anesthesia and positive pressure ventilation required for procedures performed under general anesthesia and during the perioperative period. PAP is determined by left atrial pressure (LAP), cardiac output (CO), and PVR. These parameters are related by the fundamental equation
PAP = (CO × PVR) + LAP. Physiologic perturbations that occur during the perioperative period may precipitate worsening PH, RV ischemia, or RV dysfunction. Positive pressure ventilation may compromise venous return by increasing intrathoracic pressure, thus reducing RV preload and decreasing CO. Positive pressure ventilation has both direct and indirect effects on RV afterload. Increasing levels of positive end-expiratory pressure (PEEP) decrease RV preload by impeding venous return and increasing RV afterload with a resultant decrease in RV ejection fraction.22 Additionally, the relationship between tidal volume and PVR is U-shaped with PVR being lowest at functional residual capacity (FRC). At tidal volumes lower than FRC, alveolar arterioles undergo vasoconstriction due to atelectasis while tidal volumes larger than FRC can lead to compression of perialveolar arterioles by overdistension leading to increases in PVR.23 The overriding principles that should guide mechanical ventilation in patients with PH include use of tidal volumes at or near FRC with judicious use of PEEP. It is important to avoid both hypoxia and hypercarbia as both are potent pulmonary artery vasoconstrictors. Finally, other factors associated with the operative period including acidosis, pain, and blood loss can adversely affect pulmonary and systemic hemodynamics, further contributing to perioperative morbidity and mortality in subjects with PH. These adverse effects may be minimized by preservation of oxygen saturations >92%, maintenance of normocarbia, providing adequate pain control, and ensuring optimal RV filling pressures. Right ventricular volume overload associated with fluid shifts during surgery and rapid crystalloid or colloid administration may reduce LV cavity size and compromise LV filling due to ventricular interdependence, leading to decreased CO and hypotension. In the normal physiologic state, RV perfusion occurs during both systole and diastole because of the favorable gradient between systolic and diastolic aortic pressures and the corresponding RV endomyocardial pressures. In the setting of severe PH, elevated RV wall stress and thus RV endomyocardial pressure can approach aortic pressure, thus leading to compromised systolic RV coronary blood flow. As the right ventricle fails and RV end-diastolic pressure rises, diastolic perfusion becomes limited, contributing to RV ischemia and worsening RV function, leading to further reductions in CO and systemic blood pressure with an end result of eventual hemodynamic compromise.
Implications for Anesthetic Choices There are little data comparing outcomes of surgical procedures performed in patients with PH using local anesthesia versus general anesthesia. Price et al9 included 14 subjects who underwent general anesthesia and 14 subjects receiving regional anesthesia in their retrospective analysis. The subjects who received regional anesthesia
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had worse baseline hemodynamics, including higher mean PAP, lower cardiac index, and higher PVR than subjects undergoing general anesthesia. There was however a trend toward increased perioperative complications for subjects who received general anesthesia, n = 7 (75%) compared with regional anesthesia, n = 2 (25%) with a corresponding P = .12, though the small size of this study makes it difficult to interpret these results.9 Ideally, anesthesia should be carried out by an anesthesiologist expert in cardiovascular hemodynamics with experience in managing patients with PH. The use of both intraoperative right heart catheterization for continuous monitoring of the RV and PA pressures and cardiac outputs, along with intraoperative use of transesophageal echocardigram may be helpful in evaluating the patient’s volume status and response to therapy. Care must be taken to optimize RV filling by controlling heart rate and rhythm while maintaining the trans-septal gradient (LV systolic pressure minus RV systolic pressure). This can be accomplished by choosing anesthetic agents that act to reduce PVR while maintaining systemic vascular resistance (SVR) and enhance myocardial contractility. Volatile anesthetics reduce myocardial contractility in a dose related relationship, with variable effects on PVR, while some intravenous agents used for induction such as propofol and thiopental decrease both myocardial contractility and SVR. Etomidate may be a preferred induction agent for subjects with PH undergoing general anesthesia given that it has little effect on SVR, PVR, or myocardial contractility. For maintenance of anesthesia, combined techniques using both inhaled agents and intravenous agents have been suggested in an effort to minimize the adverse effects of any single agent. Use of the mainstream agents isoflurane, sevoflurane, and desflurane is considered safe as these agents have little effect on myocardial contractility at clinically relevant doses, and less adverse effects on pulmonary blood flow and PVR than historic agents such as halothane.23 Reflective of the adverse effects of anesthesia, Ramakrishna et al6 reported an increased risk of perioperative mortality with an odds ratio of 2.9 (1.03-4.6; P = .04) for subjects who underwent >3 hours of general anesthesia. Similarly, Price et al9 reported significantly longer operative times for subjects with PH who experienced postoperative complications compared with those who did not, 193 minutes (120-420) versus 124 minutes (45-465), P = .003, respectively.
Prevention and Treatment of Acute Right Ventricular Failure A primary objective for the anesthesiologist during the operative period for subjects with PH is prevention of acute RV dysfunction or what has also been referred to as acute pulmonary hypertensive crisis. Optimization of RV
function preoperatively and maintenance of RV function intraoperatively are achieved through continuation of preoperative PAH-specific therapies along with careful selection of anesthetic agents as discussed previously. As discussed above and outlined in Table 2, there are several classes of pharmacologic therapy approved for use in WHO group I PH and the recently approved agent (riociquat) for the treatment of WHO group IV PH (CTEPH). Though initiation of these therapies in the immediate perioperative period is discouraged, they sometimes are used as a part of a rescue strategy in the patient who is experiencing acute decompensation during or after operative intervention. Care must be used not to add these medications in the setting of an elevated left atrial filling pressure, as pulmonary edema can result. Abrupt discontinuation of PAH-specific medication is also to be avoided as this can result in rebound PH and adverse outcomes. This is most relevant in patients with severe PAH and with the use of parenteral prostanoids and iNO where sudden discontinuation can precipitate rebound PH with acute RV failure and death.24 Treatment of acute RV failure is targeted at reducing PVR, optimization of heart rate and rhythm, improvement of RV function, and the maintenance of the myocardial perfusion pressure. Neither bradycardia nor excessive tachycardia is well tolerated in PH, and tachyarrhythmias may lead to acute RV decompensation. Use of intravenous pulmonary arterial vasodilators including calcium channel blockers, nitroglycerin, nitroprusside and epoprostenol have all been employed to liberate patients from cardiopulmonary bypass25,26; however, none of these agents are specific to the pulmonary circulation and therefore may not be tolerated in acute RV failure due to systemic hypotension. Additionally, the use of systemically administered vasodilators carries the risk of inhibiting hypoxic vasoconstriction in the pulmonary circulation causing V/Q (ventilation/perfusion) mismatch and worsening hypoxemia. Use of PAH-specific therapies in the setting of acute RV failure for subjects with PH not previously on PAH-specific therapy or in addition to background PAH therapy has not been well studied and when initiated, is done to target specific physiologic end-point, typically with a right heart catheter in place for close hemodynamic monitoring. There are case reports of the use of PDE-5i for the treatment of acute RV dysfunction following heart transplant,27 though empiric data for this practice are lacking. Both inhaled epoprostenol and inhaled NO have been used successfully to wean subjects with PH and RV failure from cardiopulmonary bypass.28,29 Use of both oral and parenteral agents carries the risk of precipitating systemic hypotension while the inhaled agents have the potential benefit of causing preferential vasodilation of the pulmonary circulation in wellventilated lung zones with minimal effects on LV filling and systemic blood pressure. These “selective” effects are desirable for subjects with WHO group I PH; however,
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Fox et al Table 2. Pharmacologic Agents Available for treatment of Pulmonary Hypertension (All Therapies Approved for World Health Organization Group I Disease Unless Otherwise Indicated). Agent Prostanoids Epoprostenol Treprostonil Iloprost Endothelin receptor antagonists Bosentan Ambrisentan Macitentan Phosphodiesterase 5 inhibitors Sildenafil Tadalafil Soluble guanylate cyclase stimulant Riociguata Inhaled nitric oxide (iNO)
Route of Administration
Dosing Range
Continuous intravenous infusion Continuous intravenous or subcutaneous infusion Inhaled Inhaled
1-12 ng/kg/min, titrated for effect 0.625 to 1.25 ng/kg/min titrated for effect 3-9 inhalations 4 times daily 2.5-5 µg, up to 9 times daily
Oral Oral Oral
62.5-125 mg twice daily 5-10 mg daily 3-10 mg daily
Oral or intravenous Oral
20 mg every 8 hours 40 mg daily
Oral Inhaled
0.5-2.5 mg 3 times daily 5-80 ppm via continuous inhalation
Drug Half-Life 10-15 min 4h 4h 30 min 5h 10 h 18 h 4h 35 h 12 h Seconds to minutes
a
Approved for use in World Health Organization group IV disease (chronic thromboembolic pulmonary hypertension).
they may cause pulmonary edema in subjects with WHO group II disease due to pulmonary arteriolar vasodilation in the setting of an elevated PAWP. Inotropic agents, including dopamine, dobutamine, and milrinone all have potential beneficial effects in the treatment of acute RV dysfunction, but carry with them the associated risks of systemic hypotension and tachyarrythmias. Dopamine has been observed to increase CO without adversely affecting PVR,30,31 while dobutamine appears to improve RV contractility and decrease both PVR and SVR with less tachycardia than is associated with dopamine.32,33 The PDE-3 inhibitor milrinone has both positive iontropic and vasodilatory actions and has been successfully used in subjects with WHO group II PH post–ventricular assist device placement or cardiac transplantation.34,35 Milrinone has also been used successfully via the inhalational route in subjects with PH undergoing mitral valve replacement.36
Summary Despite recent advances in the field of pulmonary hypertension, there remain relatively little data available on the perioperative outcomes of subjects with PH and specifically those with PAH. The most recent literature including the only prospective study of perioperative outcomes for subjects with PAH continues to show increased risk for perioperative outcomes and death in this patient population. However, perioperative morbidity and mortality may be reduced by realizing the surgical risks related to PH, understanding the relevant physiology, and taking precautions to avoid perturbations in volume statues, acid-base disturbance, and administration of PH-specific medications.
Additionally, performing elective surgeries only on carefully selected patients at centers specializing in pulmonary hypertension is important to minimize perioperative morbidity and mortlity. Attempts to optimize RV function through the use of PAH specific therapies preoperatively should be pursued through a multidisciplinary approach and in consultation with a PAH specialist. More prospective studies are needed for subjects with PH undergoing both noncardiac and cardiac procedures. In the meantime subjects must be evaluated on an individual basis with the ultimate goal to minimize risk for the patient while erstwhile maintaining an optimized physiology for the right ventricle and the pulmonary vasculature. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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