REVIEW ARTICLEPaul G. Barash, MD

Giovanni Landoni, MDSection Editors

Pulmonary Hypertension and Noncardiac Surgery: Implicationsfor the Anesthesiologist

Leila Hosseinian, MD

From the Department of Anesthesiology, Icahn School of Medicineat Mount Sinai, New York, NY.

Address reprint requests to Leila Hosseinian, MD, Department ofAnesthesiology, Icahn School of Medicine at Mount Sinai, New York,NY. E-mail: leila.hosseinian@mountsinai.org© 2014 Elsevier Inc. All rights reserved.1053-0770/2601-0001$36.00/0http://dx.doi.org/10.1053/j.jvca.2013.11.017Key words: pulmonary hypertension, anesthesia, noncardiac sur-

gery, complication, risk factors, pulmonary artery pressure, afterloadreduction therapy

THE PERIOPERATIVE MANAGEMENT of patients withpulmonary hypertension (PH) is a growing concern for

anesthesiologists worldwide as more patients with PH arepresenting for elective noncardiac surgery. As a direct resultof increased awareness and discovery of new medical therapies,patients with PH not only have a longer life expectancy, butalso an improved quality of life.1 Despite these recentadvances, surgery still poses a significant risk for patients withPH.2–5 A considerable amount of data already have beenpublished showing increased mortality and morbidity inpatients undergoing cardiac surgery with PH.6–9 There are,however, much less data investigating the outcomes of patientswith PH in the setting of noncardiac surgery. In a retrospectivestudy by Ramakrishna et al, 42% of PH patients who under-went noncardiac surgery had 1 or more short-term morbidevents, and 7% of patients had early death, which was dueprimarily to respiratory or right ventricular (RV) failure.4 Theseoutcomes have been compared to other high-risk populationsundergoing noncardiac surgery such as elderly patients olderthan 80 years of age who experienced a mortality of 4.6%,10 orthose older than 65 years who experienced a mortality of3.4%.11 This review will discuss the classifications, patho-physiology, and the anesthetic management of patients with PHfor noncardiac surgery.

CASE PRESENTATION

A 67-year-old woman with World Health Organization (WHO)group 1 PH (pulmonary artery pressure 72/44/30 mmHg) presented fora below-the-knee amputation. Her exercise tolerance was poor, show-ing signs of dyspnea on minimal exertion, New York Heart Association(NYHA) class III. The patient had a history of calcinosis, Raynaud’s,esophageal dysmotility, sclerodactyly, and telangiectasia (CREST)syndrome. The anesthesiologist was notified by the surgeon about themedical complexity of this case a few weeks in advance in order toproperly prepare and initiate a thorough preoperative workup. Her chestcomputed tomography (CT) scan showed evidence of severe bron-chiectasis. Her pulmonary function test (PFT) results were normal withthe exception of her diffusion capacity of the lung for carbon monoxide(DLCO) being severely reduced (36% of predicted). She requiredsupplemental oxygen at home. Her transthoracic echocardiogram (TTE)showed normal left ventricular (LV) size and performance, severe RVdilation with moderate hypertrophy and severely reduced function. Onher right-heart catheterization, her pulmonary artery pressures (PAPs)were unresponsive to the treatment trials of a variety of therapies forPH, so her cardiac regimen only included aspirin, diuretics and digoxin.She was taking coumadin for prevention of thromboembolic events.Considering her comorbidities, the amputation had been delayed by thesurgeon, but her leg had now become gangrenous, making theamputation relatively urgent.

Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2

The patient had been optimized medically prior to the day of surgery.A regional anesthetic had been agreed upon by the patient, anesthesi-ologist, and surgeon. In lieu of this, the patient was to stop coumadin 5days prior to surgery. Since the indication for coumadin was her severelyreduced RV function, her cardiologist did not deem it necessary to bridgeher with low-molecular-weight heparins (LMWHs). It was decided thatan epidural anesthetic would be the ideal technique, as it could be usedintraoperatively as well as postoperatively for pain control withoutresulting in respiratory compromise. The patient, however, was veryanxious and did not want to be fully aware during the procedure. Adexmedetomidine infusion was administered in order to decrease thepatient’s level of awareness without causing any respiratory depression,which could cause an unwanted elevation of pulmonary vascularresistance (PVR). Intraoperative monitoring included an indwellingarterial catheter and a central venous line. The arterial catheter wasplaced prior to the administration of any sedation or epidural placement.After the successful placement of a catheter into the epidural space, a 7-French triple-lumen catheter was inserted into the patient’s right internaljugular vein. The epidural anesthetic was injected. In anticipation oflocal-anesthetic-induced sympaticolysis, the patient’s hemodynamicstatus was monitored closely and shifts were corrected promptly withintravenous vasoactive medications. The central venous pressure (CVP)during the case was kept close to the baseline CVP (15 mmHg) uponplacement of the central venous line. In addition to monitoring the CVP,the central line provided the anesthesia team with secure vascular accessin case the administration of vasoactive medications became necessary.Pulmonary vasodilators were not used since the patient’s right-heartcatheterization had shown no improvement with their use.

Intraoperatively, the case proceeded smoothly; hypoxia, hyper-carbia, acidosis, and pain were avoided. Hemodynamically, intra-vascular fluid administration was only to compensate for the smallamount of blood lost. The patient went to the intensive care unit (ICU)for close monitoring postoperatively. She did well during her ICU stayuntil the epidural catheter was removed. Pain control without theepidural was challenging. On postoperative day 6, the patient devel-oped respiratory distress, which resulted very precipitously in cardiacarrest from which she could not be resuscitated. An autopsy showedthat the patient suffered from a saddle embolus in her pulmonary artery.

014: pp ]]]–]]] 1

HOSSEINIAN2

DEFINITION AND CLASSIFICATION

Pulmonary hypertension is defined as a persistent elevationof mean PAP at rest of 25 mmHg or greater.12–14 PH wascategorized by the World Health Organization (WHO) in 2008into 5 different groups (Table 1).12–14 The group classificationis determined by the underlying pathophysiology. This diver-sity results in the need for different treatments and man-agement strategies that are group-specific. WHO Group 1,pulmonary arterial hypertension (PAH), is a disease of thedistal pulmonary arteries. This disease results in changes to thepulmonary vasculature, which include pulmonary arterial vaso-constriction, smooth muscle hypertrophy, intimal and adven-titial proliferation with eventual fibrosis, complex plexiformlesions, and thrombotic lesions.15–17 The changes in thepulmonary vasculature cause increases in PAP and PVRwithout an elevation of the pulmonary capillary wedge pressure(PCWP). Initially, the vascular remodeling can be characterizedas reversible vasoconstriction; however, eventually it willprogress to a fixed disease process, unresponsive to pulmonaryvasodilator therapy.18

These pathologic pulmonary arterial changes usually are notevident in WHO Group 2, which is a more common form ofPH. When elevated pulmonary artery systolic pressures (PASP)are detected on echocardiography, the etiology is most likelypulmonary venous hypertension due to left-heart disease. WHOGroup 2 makes up more than 65% of all patients diagnosed byechocardiography with PH.19 Although left-heart disease is themost common cause of PH, there is a paucity of data on the

Table 1. World Health Organization Classifica

Group Description Examples

1 Pulmonary arterial

hypertension

Idiopathic, heritable, drug- and t

induced, associated with:

connective tissue diseases, HI

infection, portal hypertension,

congenital heart disease,

schistosomiasis, chronic hem

anemia, persistent pulmonary

hypertension of the newborn

1’ PVOD and/or PCH

2 PH due to left-heart disease Chronic severe left-sided valve

disease, left ventricular systol

diastolic heart failure

3 PH due to lung disease and/

or hypoxia

COPD, interstitial lung disease, s

disordered breathing, alveolar

hypoventilation, chronic expo

to high altitudes

4 Chronic thromboembolic

PH

Thrombotic obstruction of the

pulmonary arteries

5 PH with unclear or

multifactorial mecha-

nisms

Myeloproliferative disorders,

splenectomy, sarcoidosis, glyc

storage disease, neurofibroma

vasculitis, thyroid disease, chr

renal failure on dialysis, tumo

obstruction, fibrosing mediast

Abbreviations: COPD, chronic obstructive pulmonary disease; LVEDP, le

PCH, pulmonary capillary hemangiomatosis; PCWP, pulmonary capillar

venoocclusive disease; PVR, pulmonary vascular resistance.

frequency of pathologic pulmonary vascular changes in thisheterogenous group of patients.15,20 In this setting, post-capillary PH-elevated PA pressures may be due to passiveback pressure due to elevations in left-heart pressures(Fig 1).21-23 Mixed PH includes increases in PAP due toelevated left heart filling pressures with “reactive” changes dueto superimposed pulmonary vasoconstriction and vascularremodeling.20,23–26 Groups 3, 4, and 5 represent a similarpathophysiology as in Group 1 since they all result inelevations of PAP and PVR with normal PCWP. The treatmentstrategies are also similar for groups 1, 3, 4, and 5 compared to2. Of note, although obstructive sleep apnea (OSA) is a causeof PH Group 3, only a minority of patients with OSA actuallydevelop PH. A recent retrospective study found only a 17%incidence of PH among OSA patients.27 Patients with OSA aremore likely to progress to PH if they have an additionalunderlying pulmonary disease.27 The presence of PH, regard-less of group classification, has been shown to be a marker ofpoor prognosis and increased mortality in patients with heartfailure.21,26,28

Signs and symptoms of pulmonary hypertension are non-specific and similar to those of heart failure, often resulting indelayed diagnosis (Table 2). Since exertional dyspnea andfatigue are the most common initial complaints, patients oftendiscount their symptoms and wait to seek medical attention.29

Eventually, when the RV is affected and starts to fail,PH patients will experience peripheral edema, hepato-megaly, ascites, and elevated jugular venous pressures.17,30

tion of Pulmonary Hypertension (2008)12

Classification Hemodynamics

oxin-

V

olytic

Pre-capillary PH Mean PAP(mmHg): 425

PCWP or LVEDP (mmHg): o15

PVR (dynes·s·cm-5): 4240

ic or

Post-capillary PH Mean PAP(mmHg): 425

Mixed PH PCWP or LVEDP (mmHg): 415

PVR (dynes·s·cm-5) o240

Post-capillary PHþ PVR (dynes·s·cm-5)

4240

leep-

sure

Pre-capillary PH Mean PAP(mmHg): 425

PCWP or LVEDP (mmHg): o15

PVR (dynes·s·cm-5): 4240

Pre-capillary PH Mean PAP(mmHg): 425

PCWP or LVEDP (mmHg): o15

PVR (dynes·s·cm-5): 4240

ogen

tosis,

onic

r

initis

Mean PAP(mmHg): 425

PCWP or LVEDP (mmHg): o15

PVR (dynes·s·cm-5): 4240

ft ventricular end-diastolic pressure; PAP, pulmonary artery pressures;

y wedge pressure; PH, pulmonary hypertension; PVOD, pulmonary

Fig 1. Hemodynamics of PH secondary to left-heart disease. Normal hemodynamics (top), PH in LHD with low PVR (middle), PH in LHD with

elevated PVR (bottom), as a consequence of pulmonary arterial vascular remodeling. PH, pulmonary hypertension; TPG, transpulmonary

gradient; LHD, left-heart disease; SVC, superior vena cava; IVC, inferior vena cava; RA, right atrium; RV, right ventricle; PA, pulmonary artery;

PC, pulmonary capillary; PV, pulmonary veins; LA, left atrium; LV, left ventricle; Ao, aorta. Used with permission from reference 23.

PULMONARY HYPERTENSTION AND NONCARDIAC SURGERY 3

Electrocardiogram (ECG) and chest x-ray (CXR) findings lackthe sensitivity or specificity necessary to use them as ascreening method.29

Although the gold standard for diagnosing a patient with PHrequires the use of right-heart catheterization, a TTE is the bestfirst-line noninvasive screening test.17,25,31 Echocardiographycan provide an estimate of PASP by utilizing the simplifiedBernoulli equation. A pressure gradient between the RV andright atrium (RA) can be obtained by measuring the peakvelocity of the tricuspid regurgitation jet. By inserting thisvelocity into the equation below, a gradient between the 2chambers can be derived. Finally, by adding this value to an

Table 2. History, Physical and Basic Exam Findings

in Patients with PH 29,35,56

Signs and Symptoms Exam Findings

Exertional dyspnea CXR

Fatigue Enlarged main and hilar PA shadows

Reduced exercise tolerance RV enlargement

Angina

Syncope Electrocardiogram

Peripheral edema Pre capillary

Hepatomegaly Right-axis deviation

Ascites RVH/RAE

Elevated jugular venous

pressure

S1Q3T3 pattern

Right bundle-branch block

Post Capillary

Q waves

LVH/LAE

Left bundle-branch block

Abbreviations: CXR, chest x-ray; LAE, left atrial enlargement; LVH,

left ventricular hypertrophy; PA, pulmonary artery; PH, pulmonary

hypertension; RAE, rate of absolute error; RV, right ventricular; RVH,

right ventricular hypertrophy.

estimate of the right atrial pressure the PASP can bedetermined.25,32

Equation 1: Calculating the PASP with the simplifiedBernoulli equation

ΔP = 4xV2

PASP = ΔP þ CVPIn addition, TTE noninvasively can determine RV and LV

size and function and the presence of valvular disease, helpingto determine the cause of PH and effects of PH on theheart.17,26,33 Fisher et al performed a prospective studycomparing TTE results within 1 hour after right-heart catheter-ization to compare hemodynamic estimates. In 48% of cases,there was either an overestimation or underestimation of PAPby less than 10 mmHg.30 In studies in which TTE correlation toright-heart catheterization data have been assessed, correlationcoefficients ranged between 0.31-0.93.29 The largest discrep-ancies occurred when PAP was less than 50 mmHg or greaterthan 100 mmHg.29,33 The ability to obtain accurate Dopplertricuspid jet velocities is very much operator-dependent and iswhat most limits the accuracy of echocardiography.26,29

Right-sided cardiac catheterization is the gold standard forevaluating PH.14 Left ventricular end-diastolic pressure(LVEDP), PCWP, left atrial pressure (LAP), and PVR can allbe measured, allowing clinicians to better determine theclassification of PH. Pulmonary-specific vasodilators are givenduring the procedure to determine the degree of vasoreactiv-ity.25,31,34 These results are extremely useful to guide treatmentmodalities.

PATHOPHYSIOLOGY

A thorough understanding of the pathophysiology of PH isimperative to the successful anesthetic management of thesepatients (Fig 2). The fundamental problem for patients with PHis the ability of the RV to pump enough blood across the

Fig 2. The anesthestic management of PH requires maintenance of RV contractility, avoidance of hypotension and hypervolemia, and

elevations of PAP. CPP, coronary perfusion pressure; RV, right ventricle; PAP, pulmonary artery pressure; PA, pulmonary artery; RR, respiratory

rate; FRC, functional residual capacity.

Table 3. Ventricular Perfusion

BP systolic BP diastolic CPP systole CPP diastole

RV 25 mmHg 5 mmHg 95 mmHg 75 mmHg

LV 120 mmHg 5 mmHg 0 mmHg 75 mmHg

Ao 120 mmHg 80 mmHg

NOTE. Table 3 demonstrates the difference between LV and RV

perfusion during different phases of the cardiac cycle. While coronary

perfusion of the LV takes place largely during diastole due to the

equilibrium of pressure between the aorta and LV cavity in systole,

the perfusion of the RV is characterized as a bicyclic pheno-

menon. Changes to physiologic pulmonary hemodynamics, such as

PH, can lead to changes in perfusion of the RV, making it more

prone to ischemia. CPPsystole ¼ BPAoSystole � BPventricle systole;

CPPdiastole ¼ BPAoDiastole � BPventricle diastole

Abbreviations: Ao, aorta; BP, blood pressure; CPP, coronary perfu-

sion pressure; LV, left ventricle; RV, right ventricle.

HOSSEINIAN4

pulmonary bed, thus guaranteeing adequate LV preload. Alltherapeutic interventions and management strategies shouldfocus on this task.

The RV is a thin-walled (o5mm), highly compliant, after-load–sensitive, and geometrically–complex structure accus-tomed to contracting against the low-resistance pulmonarycirculation.35 Chronically elevated pressures in the pulmonarycirculation stimulate the RV to concentric hypertrophy in orderto maintain cardiac output in the face of elevated afterload.35–37

The right ventricular ejection fraction (RVEF) will precip-itously decline if an acute increase in afterload is encountered(eg, massive pulmonary embolism).35,36 Any perturbationcausing an increase in PAP, PVR, or depression of contrac-tility, as can happen during anesthesia and surgery, increasesthe risk of acute RV failure.

The RV also is prone to ischemia in patients with PH,especially those with RV hypertrophy since there is a greaterdependence on diastolic coronary flow as RV pressures andsystolic wall tension rise (Table 3).17,36,38 RV coronaryperfusion pressure is decreased with systemic hypotension orincreased RV pressure (RV hypertrophy) since blood flowthrough the right coronary artery is determined by a pressuregradient between the aorta and the RV. The RV stroke workalso is increased markedly due to RV hypertrophy, making itmore susceptible to ischemia.

As discussed above, concentric hypertrophy is the firstcompensatory mechanism to combat an increase in afterload. Ifthis increase in afterload is not recognized and treated, the RVwill begin to dilate. As the RV dilates, so does the tricuspidvalve annulus, which in turn leads to valvular incompetence,further exacerbating the volume status and ultimately leading toRV failure.37 This cycle is further perpetuated by a shift of theinterventricular septum from the right to the left, resulting incompression of the LV and reduction of LV end-diastolic

volume.39–41 Consequently, cardiac output will decline, and thepatient will show signs of inadequate tissue perfusion (Fig 3Aand 3B) (Video clips 1 and 2).30 Interventricular interdepend-ence is an important concept demonstrating the coupling of LVand RV systolic functions.36,40

The effect of PH and RV failure is not only a problem ofreduced forward flow but also that of increased back pressure(ie, CVP). End-organ perfusion is compromised severely in thesetting of low systemic blood pressure and elevated fillingpressures.

End Organ Perfusion Pressure = Mean arterial pressure(MAP) � CVP

Hypoperfusion of the kidneys leads to reduced urineproduction, resulting in increased activity of the renin-angiotensin-aldosterone system, which in turn promotes renalsodium and water retention and increases the release ofarginine vasopressin.42 This further accentuates the volume

Fig 3. (A) Transesophageal 4-chamber view showing leftward shift of the IVS during systole. Large RV cavity when compared to compressed

LV. RV, right ventricle; LV, left ventricle; IVS, interventricular septum. (B) Transgastric short-axis midpapillary view. “D sign” can be seen as

typical leftward shift of IVS into LV cavity. Dramatic size difference between RV and LV cavities. RV, right ventricle; LV, left ventricle; IVS,

interventricular septum.

PULMONARY HYPERTENSTION AND NONCARDIAC SURGERY 5

status, leading to a vicious cycle of increased cardiac fillingpressures, worsening RV dilation, and RV failure.

Liver dysfunction also reflects the status of heart failure.Passive hepatic congestion due to increased CVP, as occurs inright heart failure, primarily will cause elevations in bilirubin.43

A low-cardiac-output state or hypotension is associated withhepatic ischemia and will result in elevations in serum amino-transferases.43 Hyperbilirubinemia is a strong independentpredictor of an adverse prognosis in patients with pulmonaryhypertension.44

MANAGEMENT IN THE OPERATING ROOM

Preoperative Considerations

When assessing a patient with PH, the preoperativeevaluation should include assessment of the type of surgery,patient’s functional status, severity of disease, and the patient’scomorbidities.34 Discussions with consultants, including car-diologists and pulmonologists, may be necessary to assure fulloptimization prior to surgery. The patient’s primary carephysician (PCP) as well as many of the consultants frequentlyhave developed a long-standing relationship with the patientand, consequently, are able to provide the anesthesiologistwith the longitudinal/historic background of the patient’sdisease. Information derived from previous interventions,which might not be documented in the current chart, can beobtained and utilized to further optimize the patient’sperioperative plan.

Serious consideration of cancelling or postponing surgeryshould be made in patients with an exacerbation of heart failuresymptoms, marked hypoxia, or metabolic acidosis.34 Thesepatients should be optimized medically prior to any electiveprocedures. All of the appropriate testing, volume optimization,and symptom management, including the use of systemicvasodilators and inodilators, should be confirmed before theday of surgery.45 Useful preoperative tests include basic

laboratory studies, ECG, echocardiography, CXR, and right-heart catheterization. PFTs and arterial blood gas analysis canbe useful in patients with significant lung disease. Thenecessity of these studies depends on the severity of diseaseand type of surgery.

Patients with PH undergoing noncardiac surgery are atincreased risk of morbidity and mortality.5 Predictors ofmorbidity and mortality include history of pulmonary embo-lism, chronic kidney disease, NYHA functional class II orgreater, intermediate-to-high risk or emergency surgery, sur-gery duration greater than 3 hours, high PAP, right-axisdeviation, RV hypertrophy, RV myocardial performance indexgreater than 0.75, RV systolic pressure/systolic blood pressureratio greater than 0.66, and intraoperative vasopressor use.2,4

Perioperative morbidity occurred in 15% to 42% of patientsand included congestive heart failure, hemodynamic instabil-ity, sepsis, respiratory failure, longer need for ventilatorsupport, longer ICU length of stay, and more frequent 30-day readmission rate.2,4 A full discussion regarding theincreased risk of morbidity and mortality must be explainedto the patient.46

Monitoring

Next, decisions need to be made regarding intraoperativemonitoring. The placement of invasive arterial lines is useful,allowing for rapid recognition of hemodynamic deteriorationand arterial blood gas monitoring in order to facilitate main-tenance of adequate oxygenation and normocarbia. It must beemphasized that aside from the numeric values, there is aplethora of information that can be obtained by inspecting thewaveform of the arterial pulse. Patients in cardiac failure showa diminished pulse pressure resulting from low stroke volume.In addition, respiratory fluctuations in the arterial waveform canbe indicative of hypovolemia or tamponade. It is important,however, not to become fixated on one monitoring value, butuse multiple clinical and laboratory parameters to obtain the

HOSSEINIAN6

true clinical picture. Central venous pressure measurementmonitors right heart filling pressures and can be helpful inguiding volume management and optimizing end-organ perfu-sion.18 The utility of pulmonary artery (PA) catheterizationrecently has been questioned by the results of numerous trials,showing either no benefit of pulmonary artery catheterizationversus standard central venous catheterization or even anincreased risk of adverse outcomes.47–49 In addition, there isa greater risk of PA rupture when floating a PA catheter in apatient with PH.50 While these studies have investigated theutility of PA catheters in high-risk surgical patients andcritically ill patients, there is a paucity of data exploring thebenefit of PA catheters in the PH subpopulation. The ability tomonitor PA pressures and assess therapeutic interventionscould be of potential benefit in this group of patients.

The use of transesophageal echo (TEE) allows for real-timemonitoring of cardiac contractility and noninvasive estimationof systolic PAPs and volume status. It enables continuous real-time monitoring, allowing the anesthesiologist to diagnoseacute changes in cardiac function. Therapeutic interventionsswiftly can be implemented should signs of hemodynamiccompromise arise.51 Currently, no guidelines exist for the roleof TEE as an intraoperative monitor for patients with pulmo-nary hypertension.

Anesthetic Techniques

There are no specific anesthetic techniques proven to besafest in patients with PH.18,35,52,53 Regional or neuraxialanesthesia may be useful because they block sympathetic tone,thereby preventing precipitous increases in PVR, which, inturn, can lead to decreased flow across the pulmonary bed,resulting in a decline in LV preload. This anesthetic method,however, must be used cautiously due to potential hypotensionfrom a loss of vascular tone. Epidural anesthesia has theadvantage over a spinal because it can be bolused slowly,allowing titration to hemodynamics. Postoperatively, regionaltechniques allow for superb pain control without depressingrespiratory drive as is often encountered with the use ofsystemic narcotics.46 Avoidance of hypoxia and hypercarbiain this case improves PVR. Unfortunately, not all patients arecandidates for neuraxial anesthesia because these techniquesare contraindicated in patients being anticoagulated or receiv-ing certain antiplatelet medications.54 Monitored anesthesiacare (MAC) with conscious sedation can prove to be morechallenging as hypoxia and hypercarbia are not well toleratedin patients with PH. A general anesthetic with a secure airwayallows the anesthesiologist to have greatest control over thepatient’s respiratory status. Since there is no proven benefit toany anesthetic technique, the decision regarding which techni-que is used depends on the type of surgery, patient preference,and comorbidities.34

Intraoperative Management Goals

Regardless of chosen anesthetic technique, the clinicianmust understand that patients with PH have marginal cardiacreserve. Periods of arterial hypotension commonly areencountered during both neuraxial as well as generalanesthesia. While heart-healthy patients can tolerate these

brief periods of systemic hypotension, patients with PHhave a much more limited cardiac reserve and brief periodsof hypotension will inadvertently lead to RV ischemia,further promoting systemic hypotension, which, in turn,will eventually lead to hemodynamic collapse. Extremevigilance is required by the anesthesiologist to promptlyrecognize the etiology responsible for the systemic hypo-tension and swiftly implement therapeutic interventions.The etiology of systemic hypotension is always the resultof an abnormality in one, or in a combination, of thefollowing 5 factors: Afterload, preload, contractility,rhythm, and rate.

Afterload

Hypoxia, hypercarbia, acidosis, hyperinflation or hypoinfla-tion of the lungs, and hypothermia all result in pulmonaryvasoconstriction. PVR is lowest at lung volumes closest tofunctional residual capacity (FRC) (Fig 4).35,55,56 Hyperinflationof the lungs or atelectasis results in compression of intra-alveolar and extra-alveolar vessels.57 High positive end-expir-atory pressure (PEEP) greater than 15 mmHg also compressesthe vasculature in well-ventilated areas of the lung, resulting inincreased blood flow to less-ventilated areas. This, in turn,causes an increased ventilation/perfusion (V/Q) mismatch,resulting in decreased PaO2 and an increase in PVR.35,58

Preload

Maintaining normal RV function in patients with pulmonaryhypertension presents the clinician with the difficult task ofcarefully balancing intraoperative fluid administration. Bothhypovolemia as well as hypervolemia will lead to a suboptimalposition on Starling’s curve. The ability of the RV tocompensate for acute changes in volume status is compromisedin patients with PH. Only a perfectly optimized (euvolemic)RV will maintain its ability to contract against the increasedafterload of the pulmonary circulation.56 The CVP often iscited as a marker to assess volume status. It must be stressed,however, that the relationship between filling pressure andventricular volume only can be determined if ventricularcompliance is known. This usually is not the case in patientswith PH since many chronic compensatory mechanisms havetaken place to tolerate elevated PA pressures. Devices that arebased on pulse contour analysis (FloTrac™/Vigileo™ and thePiCCOplus™) also have been shown to reliably assess volumestatus in healthy patients. Unfortunately, there are no datainvestigating their effectiveness and reliability in the PHsubpopulation.46 While echocardiography can assess ventricu-lar size and function, it must be noted that ventricular size canbe misleading since many “sick” hearts have the tendency toremodel. Ventricular remodeling can increase end-diastolicvolume by a manifold, making a snapshot acquisition ofventricular size difficult to interpret. Consequently, in patientswith chronic cardiac pathology, it is better to follow trendsrather than one-time absolute values. These trends should becorrelated to hemodynamics (blood pressure, heart rate) andlaboratory values (mixed venous saturation, lactate) and requireconstant fine-tuning until the “sweet spot” can been found.Despite a plethora of monitors, the assessment of volume status

Fig 4. The relationship between lung volume and pulmonary

vascular resistance. RV, residual volume; FRC, functional residual

capacity; TLC, total lung capacity. Used with permission from

reference 56.

PULMONARY HYPERTENSTION AND NONCARDIAC SURGERY 7

remains one of the most challenging aspects of modern-dayanesthetic care and is, in most part, dependent on the skill andexperience of the clinician taking care of the patient.

Contractility

The ejection fraction (EF) frequently is used as a surrogatemarker to describe the intrinsic contractile strength of themyocardium. While it makes sense from a didactic standpointto look at preload, afterload, contractility, rhythm, and rate asisolated parameters; in reality, they are all intertwined. Forexample, a rapid increase in RV afterload (eg, pulmonaryembolism) inadvertently will lead to a significant reduction inRV contractility. Many anesthetic agents have negative ino-tropic effects and can further depress an already strained RV.

Rhythm

Maintaining sinus rhythm is ideal during the perioperativeperiod. Atrioventricular coupling is essential in optimizing

Table 4. Pulmonary Vas

Group Names PVR mPAP CI SV

Vasodilator Nitroprusside ↓↓↓ ↓↓ ↑↑ ↓↓↓

Nitroglycerin

Nesiritide

PDE-3 inhibitor Milrinone ↓↓↓ ↓ ↑↑↑ ↓↓↓

Prostacyclin Epoprostenol ↓↓↓ ↓ ↑↑ ↓↓↓

Prostacyclin analogs Iloprost ↓↓↓ ↓↓ ↑↑ ↓↓

Treprostinil

Nitric Oxide iNO ↓↓↓↓ ↓ ↓ aa

Abbreviations: CI, cardiac index; iNO, inhaled nitric oxide; IV, intravenous

3 inhibitor; PVR, pulmonary vascular resistance; SQ, subcutaneous; SVR,

preload of the RV as it improves RV diastolic filling. A lossof sinus rhythm, as can be seen in atrial fibrillation, may lead toacute hemodynamic deterioration. Depending upon the degreeof compromise, rapid synchronized direct current cardioversionor pharmacologic rate and/or rhythm control will beneceassary.56

Rate

A heart rate between 60 and 90 beats per minute (bpm) isphysiologic and is best in order to maintain optimal RVperformance. Bradycardia leads to overdistention of the RV,which, in turn, increases wall tension and oxygen consumption.Cardiac output also is reduced since it is the product of heartrate and stroke volume.56 Heart rates faster than 110 bpm canbe equally problematic since the time spent in diastole isdramatically shortened, leading to inadequate ventricular fill-ing, resulting in reduced stroke volume and cardiac output.

PHARMACOLOGIC MANAGEMENT

The fundamental principal of pharmacologic treatment of PHintraoperatively centers on the use of pulmonary vasodilators todecrease RV afterload, inotropes to support RV contractility,and vasoconstrictors to support coronary perfusion and volumeoptimization (Fig 2). Currently, the majority of drug develop-ment has focused on patients with WHO Group-1 PAH.46,59

At this time, pulmonary vasodilator therapy only has beenapproved for WHO Group 1 but also is being used-off label inother groups without the evidence obtained through largerandomized controlled trials (Table 4).60,61 Smaller trials haveindicated a potential use for phosphodiesterase-5 inhibitors inWHO Group-2 patients.60,62,63 The pathophysiology that isunique to WHO Group-1 patients focuses on the findings thatthe vascular endothelium of these patients has reduced levels ofNO synthase and prostacyclin, resulting in the inability of thesevessels to properly vasodilate.64 In addition, these patients haveelevated levels of thromboxane and endothelin-1, both of whichresult in vasoconstriction.18 Consequently, the equipoisebetween vasodilator and vasoconstrictor influences has beenshifted towards the side of vasoconstriction, resulting in anincrease in PVR. The results obtained from right-heart catheter-ization are essential in understanding the reactivity of theindividual patient’s pulmonary vasculature so that the clinician

odilators25,63,65,75–77

R Administration Side Effects

IV

IV or inhaled Arrhythmias

IV Tachyphylaxis, jaw pain, flushing, headache,

nausea, vomiting, diarrhea

Inhaled

SQ/IV/inhaled

Inhaled Methemoglobinemia; rebound PH; expensive

; mPAP, mean pulmonary artery pressure; PDE-3, phosphodiesterase-

systemic venous resistance;.

HOSSEINIAN8

can tailor treatment options towards the patient’s individualpathophysiologic picture.

RV Afterload Reduction

Calcium Channel Blockers (Nifedipine, Diltiazem)

Systemic vasodilators have limited use in treating PH asonly a small subset of patients are vasoreactive to CCBs.65

CCBs cause vasodilation and a decline in PAP and havevarious degrees of negative inotropic effects.36 Systemichypotension that results can cause significant hemodynamiccompromise.66 A small fraction of patients with PH areresponsive to these drugs. They are not useful intraoperativelyfor acutely reducing PAP. Patients taking them preoperativelyshould continue their use perioperatively.

Vasodilators (Nitroglycerin, Nitroprusside, Nesiritide)

These agents lower PAP by increasing venous capacitance,which reduces the hydrostatic component of PH secondary toleft-heart disease.25 These IV agents can be used intraoper-atively with caution as they can result in a decline in SVR(Table 4).

Phosphodiesterase-3 and -5 Inhibitors (PDE3 and 5)

PDE-3 inhibitors, milrinone, amrinone, and enoximone in-crease intracellular cyclic adenosine monophosphate (cAMP),enhancing cardiac contractility (Table 4). They also cause directpulmonary and systemic vasodilation.25 IV milrinone can be usedintraoperatively both as an inotrope and pulmonary vasodilator;however, systemic hypotension and arrhythmias are side effectsthat may restrict its use.31 Trials with oral enoximone in heartfailure patients have failed to demonstrate improvement in out-comes, so it has not been approved for use in the United States.25

PDE-5 inhibitors prevent cyclic guanosine monophosphate(cGMP) degradation, leading to reductions in intracellularcalcium levels, smooth muscle relaxation, and inhibition ofcellular proliferation. PDE5 is highly expressed in the lung.Sildenafil was the first PDE-5 inhibitor to be approved by theFDA to augment pulmonary vasodilation. Systemic vasodilationis modest although a greater problem with intravenous admin-istration. In a recent small randomized control trial of patientswith heart failure with preserved ejection fraction who hadevidence of reactive PH, they showed decreased PVR andimproved LV diastolic function, RV function, and quality of lifewhen treated with sildenafil.17,61,67 It also has been shown tohave direct positive inotropic effects on the RV. This is the onlyclass of pulmonary vasodilator for which there is some evidenceto support its use in WHO Group-2 patients.61,67 Other PDE-5inhibitors less widely used include tadalafil and vardenafil.

Endothelin-Receptor Antagonists (ERAs) (Bosentan,Ambrisentan)

Endothelin is a potent endogenous vasoconstrictor thatstimulates vascular smooth muscle cell proliferation andinduces fibrosis. ETA receptors are found on vascular smoothmuscle cells and mediate vasoconstriction and proliferation.65

ETB receptors are found on endothelial cells and vascularsmooth muscle cells and induce NO synthase and othervasodilators. ETA receptors are upregulated and ETB receptors

are downregulated in PH.25 There is little evidence to supporttheir use in Group-2 PH; however, they are useful in PH Group1.61 Both bosentan and ambrisentan are oral medications andshould be continued perioperatively but are not useful fortreating acute exacerbation of PH in the operating room.

Prostacyclin (Epoprostenol, Iloprost)

Prostacyclin is a product of endothelial arachadonic acidmetabolism and causes smooth muscle relaxation by increasingproduction of cAMP, inhibits smooth muscle proliferation, andinhibits platelet aggregation.18,59,66 Epoprostenol is FDAapproved for the treatment of PH. It has a short half-life(3 minutes) so it is administered as a continuous IV infusion, orit can be inhaled. Epoprostenol acutely improves PAP andPVR, making it useful in the OR.25 It can be used on anoutpatient basis, but it needs to be administered through apermanent tunneled catheter. Treprostinil is a prostacyclinanalog with an extended elimination half-life.66 It can beadministered via inhalation, a continuous subcutaneous infu-sion, or an intravenous infusion. Iloprost is a prostacyclinanalog, which is aerosolized.64 Because it is inhaled, it has thepotential to improve ventilation perfusion matching by increas-ing blood flow to well-ventilated areas of the lung.66 Its shorthalf-life (20-30 minutes) requires it to be administered 6 to 9times daily (Table 4).18

Inhaled NO (iNO)

Through activation of cGMP, iNO relaxes pulmonaryvessels. It rapidly acts to decrease PVR, so it is a particularlyuseful drug intraoperatively.57,68 It dilates the pulmonary bedwithout decreasing SVR because it is delivered as a rapidly-acting gas and is deactivated immediately when it binds withhemoglobin in red blood cells.69,70 Because it is only deliveredto ventilated regions of the lung, iNO can improve V/Qmismatch, so only the vasculature involved with ventilationis dilated.18 It can be delivered via facemask, nasal cannula,and endotracheal tube. Because of the risk of reboundpulmonary hypertension, iNO should never be discontinuedabruptly (Table 4).71,72

Inotropes

Inotropes should be considered when there is evidence ofinadequate oxygen delivery due to the inability of the myo-cardium to contract against increased PVR. There are a varietyof drugs that are able to enhance RV contractility. Dopamineactivates dopaminergic receptors at doses less than 5 μg/kg/min, β1-receptors at doses between 5 to 10 μg/kg/min, and α1-receptors at doses greater than 10 μg/kg/min. Although theroutine use of dopamine has not been supported in this setting,at low doses (up to 16 μg/kg/min), it can improve CO withoutincreasing PVR.55 Its ability to improve RV ejection fraction,however, has not been proven.73 Isoproterenol is a nonselectiveβ-agonist. It has both positive inotropic and chronotropicproperties, thereby increasing cardiac output. It also producespulmonary and peripheral vasodilation.74 Its use in pulmonaryhypertension is limited secondary to it causing tachycardia,arrhythmias, and increasing myocardial oxygen consumption.31

PULMONARY HYPERTENSTION AND NONCARDIAC SURGERY 9

Dobutamine is primarily a beta-agonist with minimal alpha-receptor agonist activity. It works through β1-receptor-mediatedincreases in myocardial contractility and β2 stimulation, whichinduces vasodilation and decreases afterload. Dobutaminefunctions by increasing cAMP levels, resulting in inotropicstimulation. At doses up to 5 μg/kg/min, it increases myocar-dial contractility and reduces PVR and SVR. At doses exceed-ing 10 μg/kg/min, dobutamine leads to tachycardia andincreased oxygen consumption without providing any addi-tional improvement in PVR.57,75 Epinephrine is a potent,nonselective α-and β-agonist. It is an inotrope that maintainsSVR because of its α1 activity. It causes increased cardiacoutput without altering the PVR/SVR ratio. Its use has not beenwell-studied in PH; however, it has been shown to improve RVcontractility in patients with RV dysfunction in septic shock.55

Milrinone is a PDE-3 inhibitor. It is particularly useful inPH because it exerts positive inotropic action as well as avascular smooth muscle relaxing effect, resulting in decreasingPVR, SVR, and increasing RV contractility.46,76 Milrinone anddobutamine can work synergistically as both drugs increasecAMP levels via 2 separate mechanisms.77 Levosimendansensitizes troponin-C to intracellular calcium, resulting inincreased contractility without increased oxygen consump-tion.55 It also has a vasodilatory effect by opening ATP-sensitive potassium channels in smooth muscle cells to causesmooth muscle relaxation.78 This results in improved diastolicfunction, decrease in PVR, and improved myocardial contrac-tility without increasing oxygen consumption. A recent large-scale trial, Survival of Patients with Acute Heart Failure inNeed of Intravenous Inotropic Support (SURVIVE), showed nostatistically significant benefit of levosimendan over dobut-amine on all-cause mortality at 31 or 180 days.79 However, in apost hoc analysis of the data, levosimendan may be superior atreducing mortality during the first few weeks of treatmentcompared to dobutamine in patients with a history of con-gestive heart failure who were taking beta-blocker therapywhen they were hospitalized with acute decompensations.80

Levosimendan has not yet been approved in the United States;however, is used in Europe and South America.

POSTOPERATIVE MANAGEMENT

Close monitoring of these patients postoperatively iscritical as this is the time period in which most unwantedevents occur. Morbidity and mortality usually are seen severaldays postoperatively due to volume shifts, progressive increasein PVR and worsening RV function.34,58 Depending on theinvasiveness of surgery and severity of disease, patients mayneed to be admitted to an ICU for closer monitoring. Vaso-dilator therapy started in the OR should be continued in theICU and eventually transitioned to the patient’s outpatientregimen. Respiratory failure is the most common postoperativecomplication.4 A plan for pain control should be established toavoid catecholamine-induced pulmonary vasoconstriction.However, high doses of opioid-based analgesics should beavoided as they can result in respiratory depression. As in theoperating room, hypoxia, hypercarbia, and acidosis need to beavoided.

CONCLUSION

Despite increased understanding and better medical manage-ment of patients with PH, their perioperative care continues torepresent a challenge. The case presented in this reviewhighlights the importance of anesthesiologists participatingnot only in the intraoperative care but also in the preoperativeworkup and postoperative management of this highly complexpatient population. Taking care of these patients perioperativelydemands a multidisciplinary approach with excellent commu-nication among anesthesiologist, surgeon, and consultants. Asexperts in physiology and pharmacology, anesthesiologistspossess a unique skill set that enables them to take on aleading role when caring for patients with PH undergoingsurgical or interventional procedures. Anesthesiologists shouldnot shy away but embrace this challenge.

APPENDIX A. SUPPORTING INFORMATION

Supplementary data associated with this article can be foundin the online version at http://dx.doi.org/10.1053/j.jvca.2013.11.017.

REFERENCES

1. O’Callaghan DS, Humbert M: A critical analysis of survival inpulmonary arterial hypertension. Eur Respir Rev 21:218-222, 20122. Kaw R, Pasupuleti V, Deshpande A, et al: Pulmonary hyper-

tension: An important predictor of outcomes in patients undergoingnon-cardiac surgery. Respir Med 105:619-624, 20113. Lai H-C, Lai H-C, Wang K-Y, et al: Severe pulmonary hyper-

tension complicates postoperative outcome of non-cardiac surgery. Br JAnaesth 99:184-190, 20074. Ramakrishna G, Sprung J, Ravi BS, et al: Impact of Pulmonary

Hypertension on the Outcomes of Noncardiac Surgery. J Am CollCardiol 45:1691-1699, 20055. Price LC, Montani D, Jaïs X, et al: Noncardiothoracic nonobstetric

surgery in mild-to-moderate pulmonary hypertension. Eur Respir J 35:1294-1302, 20106. Reich DL, Bodian CA, Krol M, et al: Intraoperative hemodynamic

predictors of mortality, stroke, and myocardial infarction after coronaryartery bypass surgery. Anesth Analg 89:814-822, 1999

7. Ghoreishi M, Evans CF, DeFilippi CR, et al: Pulmonary hyper-tension adversely affects short- and long-term survival after mitralvalve operation for mitral regurgitation: implications for timing ofsurgery. J Thorac Cardiovasc Surg 142:1439-1452, 20118. Melby SJ, Moon MR, Lindman BR, et al: Impact of pulmonary

hypertension on outcomes after aortic valve replacement for aorticvalve stenosis. J Thorac Cardiovasc Surg 141:1424-1430, 20119. Cesnjevar RA, Feyrer R, Walther F, et al: High-risk mitral valve

replacement in severe pulmonary hypertension–30 years experience.Eur J Cardiothorac Surg 13:344-352, 199810. Liu LL, Leung JM: Predicting adverse postoperative outcomes

in patients aged 80 years or older. J Am Geriatr Soc 48:405412,200011. Gerson MC, Hurst JM, Hertzberg VS, et al: Prediction of cardiac

and pulmonary complications related to elective abdominal andnoncardiac thoracic surgery in geriatric patients. Am J Med 88:101-107, 1990

HOSSEINIAN10

12. Simonneau G, Robbins IM, Beghetti M, et al: Updated clinicalclassification of pulmonary hypertension. J Amer CollCardiol 54:S43-s54, 200913. McLaughlin VV, Archer SL, Badesch DB, et al: ACCF/AHA

2009 expert consensus document on pulmonary hypertension. Circu-lation 119:2250-2294, 200914. Galiè N, Hoeper MM, Humbert M, et al: ESC/ERS Guidelines

for the diagnosis and treatment of pulmonary hypertension. Eur Heart J30:2493-2537, 200915. Chazova I, Loyd JE, Zhdanov VS, et al: Pulmonary artery

adventitial changes and venous involvement in primary pulmonaryhypertension. Am J Pathol 146:389-397, 199516. Pietra GG, Capron F, Stewart S, et al: Pathologic assessment of

vasculopathies in pulmonary hypertension. J Amer Coll Cardiol 43:25S-32S, 200417. Shah SJ: Pulmonary hypertension. JAMA 308:13661374, 201218. MacKnight B, Martinez EA, Simon BA: Anesthetic management

of patients with pulmonary hypertension. Semin Cardiothorac VascAnesth 12:91-96, 200819. Strange G, Playford D, Stewart S, et al: Pulmonary hypertension:

Prevalence and mortality in the Armadale echocardiography cohort.Heart 98:1805-1811, 201220. Oudiz RJ: Pulmonary hypertension associated with left-sided

heart disease. Clinics in Chest Medicine 28:233241-x, 200721. Lam CSP, Roger VL, Rodeheffer RJ, et al: Pulmonary hyper-

tension in heart failure with preserved ejection fraction: A community-based study. J Amer Coll Cardiol 53:1119-1126, 200922. Segers VFM, Brutsaert DL, De Keulenaer GW: Pulmonary

hypertension and right heart failure in heart failure with preserved leftventricular ejection fraction. Curr Opin Cardiol 27:273-280, 201223. Haddad F, Kudelko K, Mercier O, et al: Pulmonary hypertension

associated with left heart disease: Characteristics, emerging concepts,and treatment strategies. Prog Cardiovasc Disease 54:154-167, 201124. Delgado JF, Conde E, Sánchez V, et al: Pulmonary vascular

remodeling in pulmonary hypertension due to chronic heart failure. EurJ Heart Fail 7:1011-1016, 200525. Fang JC, DeMarco T, Givertz MM, et al: World Health

Organization Pulmonary Hypertension group 2: Pulmonary hyper-tension due to left heart disease in the adult–a summary statementfrom the Pulmonary Hypertension Council of the International Societyfor Heart and Lung Transplantation. J Heart Lung Transplant 31:913933, 201226. de Jesus Perez V, Zamanian R, Haddad F: Diagnosis and

management of pulmonary hypertension associated with left ventriculardiastolic dysfunction. Pulm Circ 2:163, 201227. Friedman SE, Andrus BW: Obesity and pulmonary hypertension:

A review of pathophysiologic mechanisms. J Obes 2012:1-9, 201228. Maya Guglin MDP, MD HK: Pulmonary hypertension in heart

failure. J Card Fail 16:461-474, 201029. Trow TK, McArdle JR: Diagnosis of pulmonary arterial hyper-

tension. Clin Chest Med 28:59-73, 200730. Fisher MR, Forfia PR, Chamera E, et al: Accuracy of Doppler

echocardiography in the hemodynamic assessment of pulmonaryhypertension. Am J Respir Crit Care Med 179:615621, 200931. Thunberg CA, Gaitan BD, Grewal A, et al: Pulmonary hyper-

tension in patients undergoing cardiac surgery: Pathophysiology,perioperative management, and outcomes. J Cardiothorac Vasc. Anesth27:551-572, 201332. Schmeisser A, Schroetter H, Braun-Dulleaus RC: Management

of pulmonary hypertension in left heart disease. Ther Adv CardiovascDis 7:131-151, 201333. Bossone E, Duong-Wagner TH, Paciocco G, et al: Echocardio-

graphic features of primary pulmonary hypertension. J Am SocEchocardiogr 12:655-662, 1999

34. McGlothlin D, Ivascu N, Heerdt PM: Anesthesia and pulmonaryhypertension. Prog Cardiovasc Dis 55:199-217, 201235. Fischer LG, Van Aken H, Bürkle H: Management of pulmonary

hypertension: Physiological and pharmacological considerations foranesthesiologists. Anesth Analg 96:1603-1616, 200336. Rich S: Right ventricular adaptation and maladaptation in

chronic pulmonary arterial hypertension. Cardiol Clin 30:257-269,201237. Haddad F, Doyle R, Murphy DJ, et al: Right ventricular function

in cardiovascular disease, part II: Pathophysiology, clinical importance,and management of right ventricular failure. Circulation 117:1717-1731, 200838. Vlahakes GJ, Turley K, Hoffman JI: The pathophysiology of

failure in acute right ventricular hypertension: Hemodynamic andbiochemical correlations. Circulation 63:87-95, 198139. Klima UP, Lee M-Y, Guerrero JL, et al: Determinants of

maximal right ventricular function: Role of septal shift. J ThoracCardiovasc Surg 123:72-80, 200240. Saleh S, Liakopoulos OJ, Buckberg GD: The septal motor

of biventricular function. Eur J Cardiothorac Surg 29(Suppl 1):S126-S138, 200641. Matthews JC, McLaughlin V: Acute right ventricular failure in

the setting of acute pulmonary embolism or chronic pulmonaryhypertension: A detailed review of the pathophysiology, diagnosisand management. Curr Cardiol Rev 4:49-59, 200842. Schrier RW, Bansal S: Pulmonary hypertension, right ventricular

failure, and kidney: Different from left ventricular failure? Clin J AmSoc Nephrol 3:12321237, 200843. Allen LA, Felker GM, Pocock S, et al: Liver function abnormal-

ities and outcome in patients with chronic heart failure: Data from theCandesartan in Heart Failure: Assessment of Reduction in Mortalityand Morbidity (CHARM) program. Eur J Heart Fail 11:170-177, 200944. Kramer MR, Marshall SE, Tiroke A, et al: Clinical significance

of hyperbilirubinemia in patients with pulmonary hypertensionundergoing heart-lung transplantation. J Heart Lung Transplant 10:317-321, 199145. Pritts CD, Pearl RG: Anesthesia for patients with pulmonary

hypertension. Curr Opin Anaesthesiol 23:411416, 201046. Gille J, Seyfarth H-J, Gerlach S, et al: Perioperative anesthesio-

logical management of patients with pulmonary hypertension. Anes-thesiol Res Pract 2012:1-16, 201247. Shah MR, Hasselblad V, Stevenson LW, et al: Impact of the

pulmonary artery catheter in critically ill patients: Meta-analysis ofrandomized clinical trials. JAMA 294:1664-1670, 200548. Rhodes A, Cusack RJ, Newman PJ, et al: A randomised,

controlled trial of the pulmonary artery catheter in critically ill patients.Intensive Care Med 28:256-264, 200249. Sandham JD, Hull RD, Brant RF, et al: A randomized, controlled

trial of the use of pulmonary-artery catheters in high-risk surgicalpatients. N Engl J Med 348:5-14, 200350. Bussières JS: Iatrogenic pulmonary artery rupture. Curr Opin

Anaesthesiol 20:48-52, 200751. Foresman RN, Connors CW: Severe pulmonary hypertension

and right ventricular failure complicate a total abdominal hysterectomy.Semin Cardiothorac Vasc Anesth 15:179-182, 201252. Teo YW, Greenhalgh DL: Update on anaesthetic approach to

pulmonary hypertension. Eur J Anaesthesiol 27:317-323, 201053. Meyer S, McLaughlin VV, Seyfarth H-J, et al: Outcomes of

noncardiac, nonobstetric surgery in patients with PAH: An internationalprospective survey. Eur Respir J 41:1302-1307, 201354. Horlocker TT, Wedel DJ, Rowlingson JC, et al: Regional

anesthesia in the patient receiving antithrombotic or thrombolytictherapy: Society of regional anesthesia and pain medicine evidence-based guidelines (3rd ed). Reg Anesth Pain Med 35:64-101, 2010

PULMONARY HYPERTENSTION AND NONCARDIAC SURGERY 11

55. Poor HD, Ventetuolo CE: Pulmonary Hypertension in the IntensiveCare Unit. Prog Cardiovasc Dis Elsevier Inc 55:187-198, 201256. Strumpher J, Jacobsohn E: Pulmonary hypertension and right

ventricular dysfunction: Physiology and perioperative management.J Cardiothorac Vasc Anesth 25:687-704, 201157. Subramaniam K, Yared J-P: Management of pulmonary hyper-

tension in the operating room. Semin Cardiothorac Vasc Anesth 11:119-136, 200758. Salehi A: Pulmonary hypertension: A review of pathophysiology

and anesthetic management. Am J Ther 19:377-383, 201259. Waxman AB, Zamanian RT: Pulmonary arterial hypertension:

New insights into the optimal role of current and emerging prostacyclintherapies. Am J Cardiol 111:1A-16A, 201360. Guglin M: Pulmonary vasodilation in acute and chronic heart

failure: Empiricism and evidence. Curr Heart Fail Rep 8:219-225, 201161. Guazzi M, Borlaug BA: Pulmonary hypertension due to left heart

disease. Circulation 126:975990, 201262. Wilson SR, Ghio S, Scelsi L, et al: Pulmonary hypertension and

right ventricular dysfunction in left heart disease (group 2 pulmonaryhypertension). Prog Cardiovasc Dis 55:104-118, 201263. Kalogeropoulos AP, Georgiopoulou VV, Borlaug BA, et al: Left

ventricular dysfunction with pulmonary hypertension: Part 2: Prog-nosis, noninvasive evaluation, treatment, and future research. CircHeart Fail 6:584-593, 201364. Olschewski H, Walmarth D, Schermuly R, et al: Aerosolized

prostacylin and iloprost in severe pulmonary hypertension. Ann InternMed 124:820-824, 199665. Baliga RS, MacAllister RJ, Hobbs AJ: New perspectives for the

treatment of pulmonary hypertension. Brit J Pharmacol 163:125-140, 201166. Ventetuolo CE, Klinger JR, WHO Group. 1 pulmonary arterial

hypertension: Current and investigative therapies. Prog Cardiovasc Dis55:89-103, 201267. Lewis GD, Lachmann J, Camuso J, et al: Sildenafil improves

exercise hemodynamics and oxygen uptake in patients with systolicheart failure. Circulation 115:59-66, 200768. Stobierska-Dzierzek B, Awad H, Michler RE: The evolving

management of acute right-sided heart failure in cardiac transplantrecipients. J Am Coll Cardiol 38:923-931, 2001

69. Frostell C, Fratacci MD, Wain JC, et al: Inhaled nitric oxide. Aselective pulmonary vasodilator reversing hypoxic pulmonary vaso-constriction. Circulation 83:2038-2047, 199170. Gow AJ, Stamler JS: Reactions between nitric oxide and

haemoglobin under physiological conditions. Nature 391:169-173,199871. Christenson J, Lavoie A, O’Connor M, et al: The incidence and

pathogenesis of cardiopulmonary deterioration after abrupt withdrawalof inhaled nitric oxide. Am J Respir Crit Care Med 161:1443-1449, 200072. Atz AM, Adatia I, Wessel DL: Rebound pulmonary hypertension

after inhalation of nitric oxide. Ann Thorac Surg 62:1759-1764,199673. Schreuder WO, Schneider AJ, Groeneveld AB, et al: Effect of

dopamine vs norepinephrine on hemodynamics in septic shock.Emphasis on right ventricular performance. Chest 95:1282-1288, 198974. Mentzer RM, Alegre CA, Nolan SP: The effects of dopamine and

isoproterenol on the pulmonary circulation. J Thorac Cardiovasc Surg71:807-814, 197675. Zamanian RT, Haddad F, Doyle RL, et al: Management

strategies for patients with pulmonary hypertension in the intensivecare unit. Crit Care Med 35:2037-2050, 200776. Chen EP, Bittner HB, Davis RD, et al: Milrinone improves

pulmonary hemodynamics and right ventricular function in chronicpulmonary hypertension. Ann. Thorac Surg 63:814-821, 199777. Feneck RO, Sherry KM, Withington PS, et al: Comparison of the

hemodynamic effects of milrinone with dobutamine in patients aftercardiac surgery. J Cardiothorac Vasc Anesth 15:306-315, 200178. Channick RN, Hoch RC, Newhart JW, et al: Improvement in

pulmonary hypertension and hypoxemia during nitric oxide inhalationin a patient with end-stage pulmonary fibrosis. Am J Respir Crit CareMed 149:811-814, 199479. Mebazaa A, Nieminen MS, Packer M, et al: Levosimendan vs

dobutamine for patients with acute decompensated heart failure: TheSURVIVE Randomized Trial. JAMA 297:1883-1891, 200780. Mebazaa A, Nieminen MS, Filippatos GS, et al: Levosimendan

vs. dobutamine: Outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail 11:304-311, 2009