**6. Perioperative management of pulmonary hypertension**

#### **6.1. Preoperative assessment**

Patients with PH undergo surgical procedures with significantly higher risks for morbidity and mortality regardless of the etiologies of the PH, the types of surgery and the anesthetic technique [44] [45] [46] [47] [48] [49]. The clinical outcome is especially worse for those with Eisenmenger's syndrome. Kahn reported that patients with Eisenmenger's syndrome under‐ going cesarean section had mortality as high as 70% [50]. Although there is not an overabun‐ dance of literature regarding the development of postoperative pulmonary complications following noncardiac surgery, the few available studies demonstrate the increased risk associated with these surgical procedures. Preoperative medical optimization is therefore necessary. During preoperative risk assessment, one should take into account the type of surgery, the patient's functional status, the severity of the PH, the function of the right ventricle and any other co-morbidities. Generally superficial procedures and non-orthopedic proce‐ dures are associated with less hemodynamic and sympathetic nervous system perturbations than more invasive/traumatizing procedures. Orthopedic procedures with bony involvement can be quite stimulating for the patients and will increase the risk of elevating PVR and RV failure. Thoracic surgery is associated with significant changes in intrathoracic pressures, lung volumes and oxygenation, which may cause acute increases in PVR and decreased RV function [51]. Laparoscopic surgery requires pneumoperitoneum which may be poorly tolerated because it can decrease preload and increase afterload. Surgical procedures associated with rapid or massive blood loss will be poorly tolerated by patients with severe PH. WHO standardized the functional status definition as shown in Table-4.

History and Physical Exam: Preoperative evaluation should include a thorough history and physical examination with special attention to signs and symptoms of respiratory insufficiency and right ventricular dysfunction. Symptoms are typically nonspecific with the most frequent being progressive dyspnea. The signs depend on disease severity and include dyspnea at rest, low cardiac output with metabolic acidosis, hypoxemia, evidence of right heart failure (large V wave on jugular vein, peripheral edema, hepatomegaly), and syncope [52]. Laboratory studies and special tests should be determined by the surgical procedure that the patient is undergoing and the medication profile of the patient. Routine preoperative tests include electrocardiography (EKG), chest radiographs (CXR), complete blood counts (CBC), electro‐ lytes, baseline arterial blood gas analysis (ABG), room air oxygen saturation. Although ECG changes alone cannot determine disease severity or prognosis of PH [53] [54], the ECG may show signs of right ventricular hypertrophy, such as tall right precordial R waves, right axis deviation and right ventricular strain [55]. The chest radiography may show evidence of right ventricular hypertrophy (decreased retrosternal space, cardiomegaly, enlarged cardiac silhouette) or prominent pulmonary vasculature. CBC will help decide the necessity of preoperatively optimizing the hematocrit of the patients or not. Plasma electrolytes assess baseline electrolytes and acid-base disturbances.

**Figure 2.** Top: Apical four-chamber view (systole) showing enlarged right-side chambers with compressed and geo‐ metric distortion of an intrinsically normal LV secondary to marked RV pressure overload; severe TR. RA-right atrium; LA- left atrium. Bottom: Peak TR velocity of 4.68 m/s, with a peak gradient of 87.8 mm Hg indicating severe PH.

Patients with PH undergo surgical procedures with significantly higher risks for morbidity and mortality regardless of the etiologies of the PH, the types of surgery and the anesthetic technique [44] [45] [46] [47] [48] [49]. The clinical outcome is especially worse for those with Eisenmenger's syndrome. Kahn reported that patients with Eisenmenger's syndrome under‐ going cesarean section had mortality as high as 70% [50]. Although there is not an overabun‐ dance of literature regarding the development of postoperative pulmonary complications following noncardiac surgery, the few available studies demonstrate the increased risk associated with these surgical procedures. Preoperative medical optimization is therefore necessary. During preoperative risk assessment, one should take into account the type of surgery, the patient's functional status, the severity of the PH, the function of the right ventricle

**6. Perioperative management of pulmonary hypertension**

**6.1. Preoperative assessment**

208 Pulmonary Hypertension

Delayed post-exercise heart rate recovery (HRR) has been associated with disability and poor prognosis in chronic cardiopulmonary diseases. Ramos *et al* investigated the usefulness of HRR to predict exercise impairment and mortality in patients with PH. They studied 72 PH patients with varied etiologies [New York Heart Association (NYHA) classes' I-IV] and 21 age- and gender-matched controls. Both groups underwent a maximal incremental cardiopulmonary exercise test (CPET) with heart rate being recorded up to the fifth minute of recovery. Their results revealed that HRR was consistently lower in the patients compared with the controls (P <0.05). The best cutoff for HRR in 1 minute (HRR (1 min)) to discriminate the patients from the controls was 18 beats. Compared with patients with HRR (1 min) ≤ 18 (n = 40), those with HRR (1 min) >18 (n = 32) had better NYHA scores, resting hemodynamics and 6-minute walking distance (6MWD). In fact, HRR (1 min) >18 was associated with a range of maximal and submaximal CPET variables indicative of less severe exercise impairment (P < 0.05). The single independentpredictorofHRR(1min)≤18wasthe6MWD(oddsratio0.99,P<0.05).Onamultiple regressionanalysis that consideredonlyCPET-independentvariables,HRR(1min) ≤ 18was the single predictor of mortality (hazard ratio 1.19, P < 0.05). Thus they concluded preserved HRR(1 min) (>18 beats) is associated with less impaired responses to incremental exercise in patients with PH. To the contrary, a delayed HRR (1 min) response has negative prognostic implica‐ tions, a finding likely to be clinically useful when more complicated (and costlier) analyses provided by a full CPET are not available [56]. Minai *et al* had a similar finding: they evaluate the association between HRR at 1 minute of rest (HRR1) after 6-min walk test (6MW test) and clinical worsening in patients with IPAH. HRR (1 min) was defined as the difference in heart rate at the end of 6MW test and at 1 minute after completion of the 6MW test. Seventy-five consecutive patients with IPAH underwent 6MW test and were included in the analysis. The results showed those patients with HRR1 less than 16 (n = 30) were more likely to have clinical worsening (odds ratio, 9.7, P < 0.001) and shorter time to first clinical worsening event (TCW) (6.7 mo vs. 13 mo; P < 0.001) during follow-up. With multivariable analysis, the best predictors of clinical worsening were HRR (1 min) less than 16 (hazard ratio, 5.2, P = 0.002) and mean PAP (hazard ratio, 1.04, P = 0.02). Compared with the distance walked during the 6MW test (6MW test),HRR(1min)less than16wasabetterpredictorofclinicalworseningandTCW.Theaddition of HRR (1 min) increased the ability of 6MWD to predict clinical worsening events. HRR (1 min) after 6MW test is a strong predictor of clinical worsening and TCW in patients with IPAH. The addition of HRR (1 min) to 6MWD increases the capacity of 6MWD to predict clinical worsen‐ ing and TCW in patients with IPAH [56].

Doppler echocardiography, the speckle tracking method, acceleration time across the pul‐ monic valve, the pulmonary artery regurgitant jet method and the tricuspid regurgitant jet method [62]. The tricuspid regurgitant jet method is most commonly used for determination of the pulmonary artery systolic pressure (PASP). The simplified Bernoulli equation, Pressure

continuous wave Doppler across the tricuspid valve regurgitant jet. In this case, RVSP ≈ PASP = 4V2 + RAP, where RVSP is the right ventricular systolic pressure and RAP is the right atrial pressure. The RVSP approximates PASP when no pulmonary valve stenosis or right ventric‐ ular outflow obstruction exists [62]. Although right heart catheterization (RHC) remains the gold standard for assessment of hemodynamic parameters in PH, advantages of echocardiog‐ raphy include wide availability, noninvasive modality, and lower costs. Intraoperatively, TEE allows dynamic interpretation and assessment of the therapeutic management of PH. Disad‐ vantages include the need for specialized training for interpretation, modest diagnostic accuracy and the correlation to PH as compared to RHC [ 62] [63]. Janda *et al*revealed that the correlation coefficient of systolic pulmonary artery pressure (PASP) by echocardiography as compared with PASP by RHC to be 0.70 (95% CI 0.67 to 0.73) as well as a summary sensitivity and specificity of 83% (95% CI 73 to 90) and 72% (95% CI 53 to 85), respectively for diagnostic accuracy of echocardiography for pulmonary hypertension [62]. The variability of echocar‐ diography to correlate to RHC is in part related to the underlying disease, lung conditions, time of the examination, and the skills of the echocardiographer [51] [64] [65]. Underestimation of PASP by echocardiography resulting in improper classification of PH (mild, moderate, severe) is more likely than overestimation, however inaccuracy in both under and overestimation occur with similar frequency [64]. Improvement in obtaining the tricuspid regur‐ gitant jet peak velocity has been found with the use of an intravenous bolus of agitated saline [58] [59] [66]. Despite the technical challenges and inaccuracies associated with echocardiog‐ raphy, it remains a useful tool, especially for perioperative management of patients with PH. For the initial evaluation, monitoring, and management of PH. Takatsuki *et al* evaluated the usefulness of tissue Doppler imaging (TDI) in assessment of disease severity and prognostic value in children with IPAH. The authors studied TDI velocities (systolic myocardial velocity, early diastolic myocardial relaxation velocity [Em], late diastolic myocardial velocity associ‐ ated with atrial contraction), brain natriuretic peptide, NYHA functional class, and hemody‐ namic parameters in 51 children (mean age; 11.6 years) with IPAH. Fifty-one healthy children with comparable demographics served as controls. They found that Tricuspid Em had significant inverse correlations with plasma brain natriuretic peptide levels (r= -0.60, P < 0.001), right ventricular end-diastolic pressure (r= -0.79, P < 0.001), and mean PAP (r=-0.67, P < 0.001). Em, Em/late diastolic myocardial velocity associated with atrial contraction ratio, and systolic myocardial velocity at mitral annulus, septum, and tricuspid annulus in IPAH were signifi‐ cantly reduced compared with controls. Statistically significant differences were observed in tricuspid Em between NYHA functional class II versus combined III and IV (mean and SD; 11.9 ± 4.2 cm/s versus 8.2 ± 3.6 cm/s, respectively, P= 0.002). Cumulative event-free survival rate was significantly lower when tricuspid Em was ≤8 cm/s (log-rank test, P< 0.001). So they believe Tricuspid Em velocity correlated with NYHA functional class as disease severity and

may serve as a useful prognostic marker in children with IPAH. [67].

, where V is the peak velocity, is used to approximate the PASP by

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211

gradient (P1 – P2) = 4V2

Additional tests which can potentially benefit patients include echocardiography, right heart catheterization, pulmonary function testing, ventilation/perfusion (V/Q) scanning, pulmonary angiography, spiral computed tomography, serologic testing, liver function testing, and Nterminal pro-B-type natriuretic peptide (NT-proBNP). Among these available tests, echocar‐ diography is probably the best screening study. Echocardiography is used to assess right ventricular (RV) size, function and estimate pulmonary artery pressures [52]. Echocardiogra‐ phy is a useful tool for both assessment and monitoring of disease progression in PH. Although transthoracic echocardiography is the most widely used modality for this purpose, especially for the initial PH evaluation, transesophageal echocardiography (TEE) can be a more useful technology for patients with poor acoustic windows and for intraoperative monitoring. Compared to other monitoring modalities, TEE can be particularly useful in narrowing the differential diagnoses for intraoperative hemodynamic instability (hypovolemia, hypervole‐ mia, right or left ventricular ischemia/failure) and in formulating a therapeutic plan. Multiple echocardiographic methods, M-mode, 2D and real-time 3D have been utilized to assess PH. The usual echocardiographic findings associated with PH include the following: 1). enlarged right atrial or right ventricular (RV) chambers; 2) mid-systolic closure or notching of the pulmonary valve; 3) diminished or absent atrial wave of the pulmonary valve; 4) intraven‐ tricular septal flattening; 5) paradoxical systolic motion of the intraventricular septum (IVS) toward the left ventricle; 6) a dilated inferior vena cava with reduced respiratory variability; 7) increased IVS/posterior left ventricular (LV) wall ratio (>1); 8) increased RV end-diastolic volume index; 9) increased RV endsystolic volume index, and 10) decreased RV ejection fraction [58] [59] [60]. 11). right ventricular enlargement with tricuspid regurgitation, small left ventricle with an asymmetric hypetrophic wall, with ventricular stiffness and diastolic incompetence [61]. Methods used to determine PAP by echocardiography include: measure‐ ment of the tricuspid annular plane systolic excursion (TAPSE), two-dimensional strain, tissue

Doppler echocardiography, the speckle tracking method, acceleration time across the pul‐ monic valve, the pulmonary artery regurgitant jet method and the tricuspid regurgitant jet method [62]. The tricuspid regurgitant jet method is most commonly used for determination of the pulmonary artery systolic pressure (PASP). The simplified Bernoulli equation, Pressure gradient (P1 – P2) = 4V2 , where V is the peak velocity, is used to approximate the PASP by continuous wave Doppler across the tricuspid valve regurgitant jet. In this case, RVSP ≈ PASP = 4V2 + RAP, where RVSP is the right ventricular systolic pressure and RAP is the right atrial pressure. The RVSP approximates PASP when no pulmonary valve stenosis or right ventric‐ ular outflow obstruction exists [62]. Although right heart catheterization (RHC) remains the gold standard for assessment of hemodynamic parameters in PH, advantages of echocardiog‐ raphy include wide availability, noninvasive modality, and lower costs. Intraoperatively, TEE allows dynamic interpretation and assessment of the therapeutic management of PH. Disad‐ vantages include the need for specialized training for interpretation, modest diagnostic accuracy and the correlation to PH as compared to RHC [ 62] [63]. Janda *et al*revealed that the correlation coefficient of systolic pulmonary artery pressure (PASP) by echocardiography as compared with PASP by RHC to be 0.70 (95% CI 0.67 to 0.73) as well as a summary sensitivity and specificity of 83% (95% CI 73 to 90) and 72% (95% CI 53 to 85), respectively for diagnostic accuracy of echocardiography for pulmonary hypertension [62]. The variability of echocar‐ diography to correlate to RHC is in part related to the underlying disease, lung conditions, time of the examination, and the skills of the echocardiographer [51] [64] [65]. Underestimation of PASP by echocardiography resulting in improper classification of PH (mild, moderate, severe) is more likely than overestimation, however inaccuracy in both under and overestimation occur with similar frequency [64]. Improvement in obtaining the tricuspid regur‐ gitant jet peak velocity has been found with the use of an intravenous bolus of agitated saline [58] [59] [66]. Despite the technical challenges and inaccuracies associated with echocardiog‐ raphy, it remains a useful tool, especially for perioperative management of patients with PH. For the initial evaluation, monitoring, and management of PH. Takatsuki *et al* evaluated the usefulness of tissue Doppler imaging (TDI) in assessment of disease severity and prognostic value in children with IPAH. The authors studied TDI velocities (systolic myocardial velocity, early diastolic myocardial relaxation velocity [Em], late diastolic myocardial velocity associ‐ ated with atrial contraction), brain natriuretic peptide, NYHA functional class, and hemody‐ namic parameters in 51 children (mean age; 11.6 years) with IPAH. Fifty-one healthy children with comparable demographics served as controls. They found that Tricuspid Em had significant inverse correlations with plasma brain natriuretic peptide levels (r= -0.60, P < 0.001), right ventricular end-diastolic pressure (r= -0.79, P < 0.001), and mean PAP (r=-0.67, P < 0.001). Em, Em/late diastolic myocardial velocity associated with atrial contraction ratio, and systolic myocardial velocity at mitral annulus, septum, and tricuspid annulus in IPAH were signifi‐ cantly reduced compared with controls. Statistically significant differences were observed in tricuspid Em between NYHA functional class II versus combined III and IV (mean and SD; 11.9 ± 4.2 cm/s versus 8.2 ± 3.6 cm/s, respectively, P= 0.002). Cumulative event-free survival rate was significantly lower when tricuspid Em was ≤8 cm/s (log-rank test, P< 0.001). So they believe Tricuspid Em velocity correlated with NYHA functional class as disease severity and may serve as a useful prognostic marker in children with IPAH. [67].

min) (>18 beats) is associated with less impaired responses to incremental exercise in patients with PH. To the contrary, a delayed HRR (1 min) response has negative prognostic implica‐ tions, a finding likely to be clinically useful when more complicated (and costlier) analyses provided by a full CPET are not available [56]. Minai *et al* had a similar finding: they evaluate the association between HRR at 1 minute of rest (HRR1) after 6-min walk test (6MW test) and clinical worsening in patients with IPAH. HRR (1 min) was defined as the difference in heart rate at the end of 6MW test and at 1 minute after completion of the 6MW test. Seventy-five consecutive patients with IPAH underwent 6MW test and were included in the analysis. The results showed those patients with HRR1 less than 16 (n = 30) were more likely to have clinical worsening (odds ratio, 9.7, P < 0.001) and shorter time to first clinical worsening event (TCW) (6.7 mo vs. 13 mo; P < 0.001) during follow-up. With multivariable analysis, the best predictors of clinical worsening were HRR (1 min) less than 16 (hazard ratio, 5.2, P = 0.002) and mean PAP (hazard ratio, 1.04, P = 0.02). Compared with the distance walked during the 6MW test (6MW test),HRR(1min)less than16wasabetterpredictorofclinicalworseningandTCW.Theaddition of HRR (1 min) increased the ability of 6MWD to predict clinical worsening events. HRR (1 min) after 6MW test is a strong predictor of clinical worsening and TCW in patients with IPAH. The addition of HRR (1 min) to 6MWD increases the capacity of 6MWD to predict clinical worsen‐

Additional tests which can potentially benefit patients include echocardiography, right heart catheterization, pulmonary function testing, ventilation/perfusion (V/Q) scanning, pulmonary angiography, spiral computed tomography, serologic testing, liver function testing, and Nterminal pro-B-type natriuretic peptide (NT-proBNP). Among these available tests, echocar‐ diography is probably the best screening study. Echocardiography is used to assess right ventricular (RV) size, function and estimate pulmonary artery pressures [52]. Echocardiogra‐ phy is a useful tool for both assessment and monitoring of disease progression in PH. Although transthoracic echocardiography is the most widely used modality for this purpose, especially for the initial PH evaluation, transesophageal echocardiography (TEE) can be a more useful technology for patients with poor acoustic windows and for intraoperative monitoring. Compared to other monitoring modalities, TEE can be particularly useful in narrowing the differential diagnoses for intraoperative hemodynamic instability (hypovolemia, hypervole‐ mia, right or left ventricular ischemia/failure) and in formulating a therapeutic plan. Multiple echocardiographic methods, M-mode, 2D and real-time 3D have been utilized to assess PH. The usual echocardiographic findings associated with PH include the following: 1). enlarged right atrial or right ventricular (RV) chambers; 2) mid-systolic closure or notching of the pulmonary valve; 3) diminished or absent atrial wave of the pulmonary valve; 4) intraven‐ tricular septal flattening; 5) paradoxical systolic motion of the intraventricular septum (IVS) toward the left ventricle; 6) a dilated inferior vena cava with reduced respiratory variability; 7) increased IVS/posterior left ventricular (LV) wall ratio (>1); 8) increased RV end-diastolic volume index; 9) increased RV endsystolic volume index, and 10) decreased RV ejection fraction [58] [59] [60]. 11). right ventricular enlargement with tricuspid regurgitation, small left ventricle with an asymmetric hypetrophic wall, with ventricular stiffness and diastolic incompetence [61]. Methods used to determine PAP by echocardiography include: measure‐ ment of the tricuspid annular plane systolic excursion (TAPSE), two-dimensional strain, tissue

ing and TCW in patients with IPAH [56].

210 Pulmonary Hypertension

#### *6.1.1. Right heart catheterization*

Right heart catheterization is considered the gold standard for measuring PAP. Evidence of significant RV dysfunction should prompt reevaluation of the need for surgery [68]. All attempts to lower PAP should be done preoperatively. Treatment options include oxygen, bronchodilators, vasodilators and inotropes. In addition to the careful evaluation of the patient's current therapeutic regimen for pulmonary hypertension, all other medications should be reviewed for possible drug-drug interactions. Likewise, it is important to maintain the patient's current therapeutic regimen as discontinuation of medications can potentially lead to rebound or even worsened PH and RV dysfunction. Although medications such as inhaled prostacyclin (epoprostenol or Flolan) are associated with impaired platelet aggrega‐ tion, they have not been implicated in clinically significant bleeding. Due to the short half-life of this medication, epoprostenol should not be stopped at any time in the perioperative period. The anesthesiologist must ensure preoperative maximization of the patient's therapeutic options being accomplished and coordinated, if needed, a perioperative strategy for continu‐ ance of chronic PH therapy [69].

ments for the detection of mPAP [greater than or equal to] 25 mmHg was assessed using Fisher's exact test and receiver operating characteristic (ROC) analysis. Ventricular mass index (VMI) was the MRI measurement with the strongest correlation with mPAP (r=0.78) and the highest diagnostic accuracy for the diagnosis of PH (area under the ROC curve of 0.91) compared to an ROC of 0.88 for mPAP measured by echocardiography. Using late gadolinium enhancement, VMI [greater than or equal to] 0.4, retrograde flow [greater than or equal to] 0.3 L/min/m2 and PA relative area change [less than or equal to] 15% predicted the presence of PH with a high degree of diagnostic certainty with a positive predictive value of 98%, 97%, 95% and 94% respectively. No single MRI parameter could definitely exclude the presence of PH. Thus they concluded that MRI is a useful alternative to echocardiography in the evaluation of suspected PH. They support the routine measurement of ventricular mass index, late gadolinium enhancement and the use of phase contrast imaging in addition to right heart functional indices in patients undergoing diagnostic MRI evaluation for suspected pulmonary

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Frantz *et al* used N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a biomarker of the disease severity in patients with PAH. They aimed to determine whether baseline NT-proBNP levels correlate with improvement in 6MWD in the pivotal randomized, placebo-controlled, double-blind study of the addition of inhaled treprostinil to oral therapy for PH. They found that baseline NT-proBNP levels demonstrated a strong correlation with treatment in predicting change from baseline for 6MWD (p < 0.01), indicating that in the upper quartile (≥1,513.5 pg/ ml), patients on inhaled treprostinil had a better response (+64 versus +32 m), whereas patients on placebo fared worse (-13 versus +20 m) when compared with the lower 3 quartiles (<1,513.5 pg/ml). Furthermore, least-squares mean difference in 6MWD between active and placebo groups was +67 and +16 m for the upper and lower 3 quartiles of NT-proBNP, respectively. The investigators concluded that greater improvement in 6MWD in actively treated patients with high levels of NT-proBNP predicts better clinical response to inhaled treprostinil in more advanced disease [73]. Diller *et al* followed up 181 patients (mean follow-up period is 3.3 years, 7 patients with Down syndrome) with 20 deaths. Their results showed that higher BNP concentrations were predictive of all cause mortality on univariate analysis in patients with or without Down syndrome. On multivariable Cox proportional hazard analysis, BNP predicted survival independently of renal function, Down syndrome, or 6MWD (p=0.004). Temporal increases in BNP concentration also predicted mortality in patients with concurrent Eisen‐ menger syndrome patients. Treatment with disease targeting therapies was associated with a

**Perioperative Risks of PH:** The patient with PH is at elevated risk for morbidity and mortality in the perioperative period [5], [76], [77], [78]. There is a relative paucity of literature studying outcomes in this patient population presenting for noncardiac surgery, however, the evidence that does exist points to significantly increased potential for complications in the perioperative period. Ramakrishna *et al* presented the results from an overview of 145 patients with PH presenting for noncardiac surgery. A 42% rate of early (<30 days) morbidity (congestive heart

hypertension [72].

*6.1.4. N-Terminal pro-B-type Natriuretic Peptide (NT-proBNP)*

significant reduction in BNP concentrations [74].

#### *6.1.2. Pulmonary function tests, ventilation/perfusion (V/Q) scanning and pulmonary angiography*

Pulmonayfunctiontest(PFT)hasbeenusedfortheassessmentoftheoverallpulmonaryfunction. PFT can help determine patient's tolerability to certain surgical procedures. He *et al* conducted V/Q scanning and computed tomography pulmonary angiography (CTPA) for a total of 114 consecutivepatients(49menand65women,averageage43.3years)suspectedofhavingCTEPH. InterpretationofV/Qimages was basedonthe refinedPulmonaryEmbolismDiagnosis criteria. For threshold 1, high-probability and intermediate-probability V/Q scan findings were considered to be positive, and low-probability/normal V/Q scan findings were negative. For threshold 2, only a high-probability V/Q scan finding was considered to be positive. And intermediate-probability and low-probability/normal V/Q scan findings were considered to be negative. Their results indicated that 51 patients (44.7%) had a final diagnosis of CTEPH. V/Q scan showed high probability (52 patients), intermediate probability (2 patients), and low probability/normal scan (59 patients) respectively. CTPA revealed 50 patients with CTEPH and 64 patients without CTEPH. The sensitivity, specificity, and accuracy of the V/Q scan were 100, 93.7, and 96.5%, respectively, with threshold 1, and 96.1, 95.2, and 95.6%, respectively, with threshold 2; similarly, the sensitivity, specificity, and accuracy of CTPA were 92.2, 95.2, and 93.9%, respectively. They therefore concluded that both V/Q scanning and CTPA are accurate methods for the detection of CTEPH with excellent diagnostic efficacy [70].

#### *6.1.3. Cardiac Magnetic Resonance Imaging (MRI)*

Cardiac magnetic resonance imaging (MRI) has prognostic value in patients with IPAH before starting intravenous prostacyclin [71]. Swift *et al* studied the diagnostic accuracy of MRI derived RV measurements for the detection of pulmonary hypertension (PH) in the assessment of patients with suspected PH. They retrospectively reviewed 233 treatment-naïve patients with suspected PH including 39 patients with no PH who underwent MRI and right heart catheterization (RHC) within 48 hours. The diagnostic accuracy of multiple MRI measure‐ ments for the detection of mPAP [greater than or equal to] 25 mmHg was assessed using Fisher's exact test and receiver operating characteristic (ROC) analysis. Ventricular mass index (VMI) was the MRI measurement with the strongest correlation with mPAP (r=0.78) and the highest diagnostic accuracy for the diagnosis of PH (area under the ROC curve of 0.91) compared to an ROC of 0.88 for mPAP measured by echocardiography. Using late gadolinium enhancement, VMI [greater than or equal to] 0.4, retrograde flow [greater than or equal to] 0.3 L/min/m2 and PA relative area change [less than or equal to] 15% predicted the presence of PH with a high degree of diagnostic certainty with a positive predictive value of 98%, 97%, 95% and 94% respectively. No single MRI parameter could definitely exclude the presence of PH. Thus they concluded that MRI is a useful alternative to echocardiography in the evaluation of suspected PH. They support the routine measurement of ventricular mass index, late gadolinium enhancement and the use of phase contrast imaging in addition to right heart functional indices in patients undergoing diagnostic MRI evaluation for suspected pulmonary hypertension [72].

#### *6.1.4. N-Terminal pro-B-type Natriuretic Peptide (NT-proBNP)*

*6.1.1. Right heart catheterization*

212 Pulmonary Hypertension

ance of chronic PH therapy [69].

Right heart catheterization is considered the gold standard for measuring PAP. Evidence of significant RV dysfunction should prompt reevaluation of the need for surgery [68]. All attempts to lower PAP should be done preoperatively. Treatment options include oxygen, bronchodilators, vasodilators and inotropes. In addition to the careful evaluation of the patient's current therapeutic regimen for pulmonary hypertension, all other medications should be reviewed for possible drug-drug interactions. Likewise, it is important to maintain the patient's current therapeutic regimen as discontinuation of medications can potentially lead to rebound or even worsened PH and RV dysfunction. Although medications such as inhaled prostacyclin (epoprostenol or Flolan) are associated with impaired platelet aggrega‐ tion, they have not been implicated in clinically significant bleeding. Due to the short half-life of this medication, epoprostenol should not be stopped at any time in the perioperative period. The anesthesiologist must ensure preoperative maximization of the patient's therapeutic options being accomplished and coordinated, if needed, a perioperative strategy for continu‐

*6.1.2. Pulmonary function tests, ventilation/perfusion (V/Q) scanning and pulmonary angiography*

Pulmonayfunctiontest(PFT)hasbeenusedfortheassessmentoftheoverallpulmonaryfunction. PFT can help determine patient's tolerability to certain surgical procedures. He *et al* conducted V/Q scanning and computed tomography pulmonary angiography (CTPA) for a total of 114 consecutivepatients(49menand65women,averageage43.3years)suspectedofhavingCTEPH. InterpretationofV/Qimages was basedonthe refinedPulmonaryEmbolismDiagnosis criteria. For threshold 1, high-probability and intermediate-probability V/Q scan findings were considered to be positive, and low-probability/normal V/Q scan findings were negative. For threshold 2, only a high-probability V/Q scan finding was considered to be positive. And intermediate-probability and low-probability/normal V/Q scan findings were considered to be negative. Their results indicated that 51 patients (44.7%) had a final diagnosis of CTEPH. V/Q scan showed high probability (52 patients), intermediate probability (2 patients), and low probability/normal scan (59 patients) respectively. CTPA revealed 50 patients with CTEPH and 64 patients without CTEPH. The sensitivity, specificity, and accuracy of the V/Q scan were 100, 93.7, and 96.5%, respectively, with threshold 1, and 96.1, 95.2, and 95.6%, respectively, with threshold 2; similarly, the sensitivity, specificity, and accuracy of CTPA were 92.2, 95.2, and 93.9%, respectively. They therefore concluded that both V/Q scanning and CTPA are accurate

methods for the detection of CTEPH with excellent diagnostic efficacy [70].

Cardiac magnetic resonance imaging (MRI) has prognostic value in patients with IPAH before starting intravenous prostacyclin [71]. Swift *et al* studied the diagnostic accuracy of MRI derived RV measurements for the detection of pulmonary hypertension (PH) in the assessment of patients with suspected PH. They retrospectively reviewed 233 treatment-naïve patients with suspected PH including 39 patients with no PH who underwent MRI and right heart catheterization (RHC) within 48 hours. The diagnostic accuracy of multiple MRI measure‐

*6.1.3. Cardiac Magnetic Resonance Imaging (MRI)*

Frantz *et al* used N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a biomarker of the disease severity in patients with PAH. They aimed to determine whether baseline NT-proBNP levels correlate with improvement in 6MWD in the pivotal randomized, placebo-controlled, double-blind study of the addition of inhaled treprostinil to oral therapy for PH. They found that baseline NT-proBNP levels demonstrated a strong correlation with treatment in predicting change from baseline for 6MWD (p < 0.01), indicating that in the upper quartile (≥1,513.5 pg/ ml), patients on inhaled treprostinil had a better response (+64 versus +32 m), whereas patients on placebo fared worse (-13 versus +20 m) when compared with the lower 3 quartiles (<1,513.5 pg/ml). Furthermore, least-squares mean difference in 6MWD between active and placebo groups was +67 and +16 m for the upper and lower 3 quartiles of NT-proBNP, respectively. The investigators concluded that greater improvement in 6MWD in actively treated patients with high levels of NT-proBNP predicts better clinical response to inhaled treprostinil in more advanced disease [73]. Diller *et al* followed up 181 patients (mean follow-up period is 3.3 years, 7 patients with Down syndrome) with 20 deaths. Their results showed that higher BNP concentrations were predictive of all cause mortality on univariate analysis in patients with or without Down syndrome. On multivariable Cox proportional hazard analysis, BNP predicted survival independently of renal function, Down syndrome, or 6MWD (p=0.004). Temporal increases in BNP concentration also predicted mortality in patients with concurrent Eisen‐ menger syndrome patients. Treatment with disease targeting therapies was associated with a significant reduction in BNP concentrations [74].

**Perioperative Risks of PH:** The patient with PH is at elevated risk for morbidity and mortality in the perioperative period [5], [76], [77], [78]. There is a relative paucity of literature studying outcomes in this patient population presenting for noncardiac surgery, however, the evidence that does exist points to significantly increased potential for complications in the perioperative period. Ramakrishna *et al* presented the results from an overview of 145 patients with PH presenting for noncardiac surgery. A 42% rate of early (<30 days) morbidity (congestive heart failure, cardiac ischemic event, stroke, respiratory failure, hepatic or renal disfunction, cardiac dysrhythmia) and a 9.7% rate of early mortality in this population have been reported [47]. Ramakrishna *et al* summarized the clinical characteristics associated with early morbidity and mortality in Table-5.

**1.** Arterial line for the continuous monitoring of arterial pressure. By using arterial pressure monitoring we can ensure adequate perfusion pressures for all vital organs including heart, lungs and brain. Arterial line can also be used for frequent blood gas analysis.

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**2.** Pulmonary artery catheterization (PAC): PAC can be used for the monitoring of pulmo‐ nary artery pressure, for the measurement of CO and for the measurement of mixed venous oxygen saturation. By measuring PCWP, PAC can help determine left ventricular preload in pulmonary hypertensive patients whose cardiac output is limited by right ventricular function. PAP measurement is also critical in determining PH severity, and choice and dosing of therapeutic agents. However, intraoperative PAC placement is controversial in patients with PH because of the potential complications due to PAC placement. Hoeper *et al* performed a multicenter 5-year retrospective and 6-month prospective evaluation of serious adverse events related to right heart catheter procedures in patients with pulmonary hypertension, as defined by a mean pulmonary artery pressure >25 mm Hg. Out of total 7218 PAC procedures, they found the overall number of serious adverse events was 76 (1.1%). The most frequent complications were related to venous access (e.g., hematoma, pneumothorax), followed by arrhythmias and hypoten‐ sive episodes related to vagal reactions or pulmonary vasoreactivity testing. The vast majority of these complications were mild to moderate in intensity and resolved either spontaneously or after appropriate intervention. Four fatal events were recorded in association with any of the catheter procedures, resulting in an overall procedure-related mortality of 0.055%. Thus they believe that in experienced centers, right heart catheter procedures in patients with pulmonary hypertension are still safe, only associated with

**3.** Central venous pressure (CVP) may be a more accurate guide for volume administration. Care should be taken in placing PAC and/or CVP catheters as these patients are reliant on sequential atrial-ventricular contraction for adequate preload and cardiac output. Arrhythmias associated with catheter insertion may not be well tolerated by these

**4.** Non-invasive or minimally invasive CO measurement techniques may also be useful in

**5.** Bispectral index score (BIS) monitoring helps maintain appropriate depth of anesthesia.

**6.** Transesophageal echocardiography (TEE): Transesophageal echocardiography can be very useful in assessing the preload, contractility, anatomical irregularities and valvular abnormalities of both right-side and left-side of the heart. TEE can also help evaluate the

There are multiple methods available to control the increased PAP intraoperatively. These strategies can be categorized into pharmacological and non-pharmacological measures.

Pharmacological management of intraoperative hypertension includes the following:

PH patients undergoing surgical procedures and labor and delivery [81].

result of cardiopulmonary surgical procedures [82] [83].

**6.3. Strategies of controlling pulmonary arterial pressure**

low morbidity and mortality rates [80].

patients.


**Table 5.** Clinical characteristics associated with increased morbility and mortality in PA patients. Modified from reference [47].

Lai *et al*. performed a case-control study examining 67 patients with pulmonary systolic pressures greater than 70 mmHg compared to controls with normal pulmonary pressures [8]. As shown in Table-4, the pulmonary hypertension group developed postoperative heart failure more frequently (9.7 vs. 0%, p =.028), delayed tracheal extubation (21 vs. 0%, p =.004) and greater in hospital mortality (9.7 vs. 0%, p = 0.004). A review of a large U.S. database by Memtsoudis *et al*. estimated the mortality rate in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) [7]. The authors identified 1359 THA and 2184 TKA patients with the diagnosis of PH. In comparison to a matched sample without PH, the THA patients had a 4-fold increased adjusted risk of in-hospital mortality and the TKA patients had a 4.5-fold increase (p< 0.001) [7]. Patients with PH are at considerably increased risk in the perioperative period morbidity and mortality. [8].

#### **6.2. Intraoperative considerations**

Dependent upon the nature of the scheduled surgical procedure, various anesthesia techniques including general anesthesia, neuraxial anesthesia, peripheral nerve blockade and monitored anesthesia care (MAC) have been reported to be success in the management of patients with PH [45] [79]. Except for few case reports, very little literature exists evaluating the differences of these management strategies for intraoperative and postoperative management of the patient with PH. Furthermore the choice of technique is less important as the ability to adhere to the goals of avoiding elevations in PVR and RHF.

For major procedures in patients with PH, routine ASA standard monitoring should be utilized. The following additional strategies are potentially critical for the appropriate perioperative management of patients with PH:

**1.** Arterial line for the continuous monitoring of arterial pressure. By using arterial pressure monitoring we can ensure adequate perfusion pressures for all vital organs including heart, lungs and brain. Arterial line can also be used for frequent blood gas analysis.

failure, cardiac ischemic event, stroke, respiratory failure, hepatic or renal disfunction, cardiac dysrhythmia) and a 9.7% rate of early mortality in this population have been reported [47]. Ramakrishna *et al* summarized the clinical characteristics associated with early morbidity and

**Clinical characteristics prone to early mortality Clinical characteristics prone to early morbidity**

NYHA=New York Heart Association, RVSP=right ventricular systolic pressure, SBP=systolic blood pressure.

**Table 5.** Clinical characteristics associated with increased morbility and mortality in PA patients. Modified from

Lai *et al*. performed a case-control study examining 67 patients with pulmonary systolic pressures greater than 70 mmHg compared to controls with normal pulmonary pressures [8]. As shown in Table-4, the pulmonary hypertension group developed postoperative heart failure more frequently (9.7 vs. 0%, p =.028), delayed tracheal extubation (21 vs. 0%, p =.004) and greater in hospital mortality (9.7 vs. 0%, p = 0.004). A review of a large U.S. database by Memtsoudis *et al*. estimated the mortality rate in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) [7]. The authors identified 1359 THA and 2184 TKA patients with the diagnosis of PH. In comparison to a matched sample without PH, the THA patients had a 4-fold increased adjusted risk of in-hospital mortality and the TKA patients had a 4.5-fold increase (p< 0.001) [7]. Patients with PH are at considerably increased risk in the

Dependent upon the nature of the scheduled surgical procedure, various anesthesia techniques including general anesthesia, neuraxial anesthesia, peripheral nerve blockade and monitored anesthesia care (MAC) have been reported to be success in the management of patients with PH [45] [79]. Except for few case reports, very little literature exists evaluating the differences of these management strategies for intraoperative and postoperative management of the patient with PH. Furthermore the choice of technique is less important as the ability to adhere

For major procedures in patients with PH, routine ASA standard monitoring should be utilized. The following additional strategies are potentially critical for the appropriate

1. NYHA class 2 or higher 2. History of pulmonary embolism 3. Obstructive sleep apnea 4. High-risk surgery

5. Anesthesia duration 3 hours or longer

6. Intraoperative use of epinephrine or dopamine

mortality in Table-5.

214 Pulmonary Hypertension

1. Right axis deviation (RAD)

3. RVSP/SBP ratio above 0.6

reference [47].

2. Right ventricular hypertrophy (RVH)

4. Intraoperative use of epinephrine or dopamine

perioperative period morbidity and mortality. [8].

to the goals of avoiding elevations in PVR and RHF.

perioperative management of patients with PH:

**6.2. Intraoperative considerations**


#### **6.3. Strategies of controlling pulmonary arterial pressure**

There are multiple methods available to control the increased PAP intraoperatively. These strategies can be categorized into pharmacological and non-pharmacological measures.

Pharmacological management of intraoperative hypertension includes the following:

**1.** Inhaled nitric oxide: Inhaled nitric oxide (INO) is one of the most potent medications commonly used perioperatively. The usual dose is 20–80 ppm (parts per million). The delivery system is shown in Figure-3. The INO delivery system includes a circuit and a control panel and related tank and tubing. INO can diffuse from the alveoli to the pulmonary capillaries and stimulates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) which leads to vasodilation. INO does not produce systemic vasodilatation because nitric oxide is inactivated when bound to hemoglobin. It also has the benefit of improving ventilation– perfusion matching by increasing perfusion to areas of the lung that are well ventilated. If the clinical picture is of pulmonary hypertension with systemic hypotension, IV vasodilators may cause worsening of systemic blood pressure, subsequent RV hypoperfusion, ischemia and failure. In this situation, the patient may benefit from therapy selective for the pulmonary vasculature such as inhaled nitric oxide (INO) or prostacyclin. INO has also been shown to improve PH in cardiopulmonary bypass settings [84] [85].

**Figure 3.** Inhaled nitric oxide delivery system Left: Inhaled nitric oxide delivery system control panel. Right: Inhaled nitric oxide delivery circuit, the arrow indicates the inspiratory limb. (Copyright owned by Henry Liu, MD)


41

mole augments and prolongs the pulmonary vasodilator effects of INO in CHF patients

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217

**4.** Inhaled prostacyclin: Continuous intravenous administration of prostacyclin 50 ng/kg/min after reconstituting prostacyclin in sterile glycine diluent to 30,000 ng/ml (1.5mg of prostacyclin in 50 ml of diluent). For an 80 kg patient, 50 ng/kg/min is 8 ml of this solution per hour. It is nebulized into the inspiratory side of the ventilator circuit; an example of a prostacyclin nebulized delivery system that can be integrated into the anesthesia circuit is shown in Figure-4. Iloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4*S* isomer substantially more potent than the 4*R* isomer. Prostacyclin, available in inhaled and intravenous forms, stimulates adenylate cyclase and increases cAMP and release of endothelial NO leading to decreases in PAP, RAP, and increased cardiac output [88]. Combination therapy, with both INO and prostacyclin, has synergistic effects compared to monotherapy [89] [90]. Due to the extremely short half-life of these medications, one should ensure that the medication is delivered continuously without interruption to minimize the risk of rebound PH. Weaning from these medications should be performed gradually with frequent assessment of PAP and RV function. A disadvantage of INO compared to inhaled prostacyclin is its high cost. A recent analysis revealed that INO is approximately 20 times more expensive than prostacyclin (\$3000/day vs. \$150/day) [91]. Table-6 lists the medical management options, including common doses and common side effects, for intraopera‐ tive management of pulmonary hypertension. Lastly, in patients refractory to the above

therapies, right ventricular assist device implantation should be considered.

**Figure 4.** Inhaled prostacyclin delivery system Figure-6: Inhaled prostacyclin delivery system. Reconstituted prostacy‐ clin is delivered by a Lo-Flo Mini Heart nebulizer (a), which is driven by a separate oxygen source at 2 L/min (b). The nebulizer output is 8 mL/h, which allows for 1–3 h of continuous nebulization. The nebulizer should be supported by an IV pole or ventilator side arm to prevent spillage. An IV port (c) allows the chamber to be refilled without discon‐ necting from the anesthetic circuit. Prostacyclin is photosensitive and requires the nebulizing chamber to be covered

with severe PH [87].

from ambient light (d) [88].

mole augments and prolongs the pulmonary vasodilator effects of INO in CHF patients with severe PH [87].

**1.** Inhaled nitric oxide: Inhaled nitric oxide (INO) is one of the most potent medications commonly used perioperatively. The usual dose is 20–80 ppm (parts per million). The delivery system is shown in Figure-3. The INO delivery system includes a circuit and a control panel and related tank and tubing. INO can diffuse from the alveoli to the pulmonary capillaries and stimulates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) which leads to vasodilation. INO does not produce systemic vasodilatation because nitric oxide is inactivated when bound to hemoglobin. It also has the benefit of improving ventilation– perfusion matching by increasing perfusion to areas of the lung that are well ventilated. If the clinical picture is of pulmonary hypertension with systemic hypotension, IV vasodilators may cause worsening of systemic blood pressure, subsequent RV hypoperfusion, ischemia and failure. In this situation, the patient may benefit from therapy selective for the pulmonary vasculature such as inhaled nitric oxide (INO) or prostacyclin. INO has also been shown to improve PH in cardiopulmonary

**Figure 3.** Inhaled nitric oxide delivery system Left: Inhaled nitric oxide delivery system control panel. Right: Inhaled

**2.** Milrinone: Milrinone is a phosphodiesterase-3 inhibitor and prevents the breakdown of cyclic adenosine monophosphate (cAMP). It has shown to reduce both PVR and SVR in addition to causing increases in myocardial contractility [86]. The usual dose of milrinone

**3.** Thromboxane synthase inhibitor: Dipyridamole (tradename: Persantine) can be used intraoperatively in managing PH; its usual dose is 0.2–0.6 mg/kg i.v. over 15 minutes, and it may be repeated after 12 hours. Lepore et al used intravenous dipyridamole combined with INO in 9 patients with congestive heart failure (CHF) and severe PH who were breathing 100% oxygen during right heart catheterization, we administered inhaled NO (80 ppm) alone and in combination with intravenous dipyridamole (0.2-mg/ kg bolus, with an infusion of 0.0375 mg/kg/min), and found that Intravenous dipyrida‐

nitric oxide delivery circuit, the arrow indicates the inspiratory limb. (Copyright owned by Henry Liu, MD)

is 50 mg/kg loading, then 0.5–0.75mg/kg/min for the maintenance.

41

bypass settings [84] [85].

216 Pulmonary Hypertension

**4.** Inhaled prostacyclin: Continuous intravenous administration of prostacyclin 50 ng/kg/min after reconstituting prostacyclin in sterile glycine diluent to 30,000 ng/ml (1.5mg of prostacyclin in 50 ml of diluent). For an 80 kg patient, 50 ng/kg/min is 8 ml of this solution per hour. It is nebulized into the inspiratory side of the ventilator circuit; an example of a prostacyclin nebulized delivery system that can be integrated into the anesthesia circuit is shown in Figure-4. Iloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4*S* isomer substantially more potent than the 4*R* isomer. Prostacyclin, available in inhaled and intravenous forms, stimulates adenylate cyclase and increases cAMP and release of endothelial NO leading to decreases in PAP, RAP, and increased cardiac output [88]. Combination therapy, with both INO and prostacyclin, has synergistic effects compared to monotherapy [89] [90]. Due to the extremely short half-life of these medications, one should ensure that the medication is delivered continuously without interruption to minimize the risk of rebound PH. Weaning from these medications should be performed gradually with frequent assessment of PAP and RV function. A disadvantage of INO compared to inhaled prostacyclin is its high cost. A recent analysis revealed that INO is approximately 20 times more expensive than prostacyclin (\$3000/day vs. \$150/day) [91]. Table-6 lists the medical management options, including common doses and common side effects, for intraopera‐ tive management of pulmonary hypertension. Lastly, in patients refractory to the above therapies, right ventricular assist device implantation should be considered.

**Figure 4.** Inhaled prostacyclin delivery system Figure-6: Inhaled prostacyclin delivery system. Reconstituted prostacy‐ clin is delivered by a Lo-Flo Mini Heart nebulizer (a), which is driven by a separate oxygen source at 2 L/min (b). The nebulizer output is 8 mL/h, which allows for 1–3 h of continuous nebulization. The nebulizer should be supported by an IV pole or ventilator side arm to prevent spillage. An IV port (c) allows the chamber to be refilled without discon‐ necting from the anesthetic circuit. Prostacyclin is photosensitive and requires the nebulizing chamber to be covered from ambient light (d) [88].


**6.4. General anesthesia**

(Copyright owned by Henry Liu, MD)

Prostaglandins Epoprostenol

Phosphodiesterase Type-5 inhibitors

Endothelin receptor

antagonist

(Tradename:Flolan)

Anbrisentan (Letairis in USA, Volibris in EU) Bosentan(Tracleer)

Without any doubt, every effort should be made to have a smooth induction of anesthesia and endotracheal intubation which will minimize the hemodynamic instability in highly suscep‐ tible patients. Commonly used intravenous anesthetics such as propofol and thiopental are associated with hypotension and myocardial depression. Their use should be very judicious. Etomidate has much fewer effects on SVR, PVR and myocardial contractility and may be a more useful hypnotic for patient with severe PH. Use of volatile anesthetics is associated with decreased SVR, myocardial contractility and potential arrhythmias, all of which can impair right ventricular myocardial perfusion and also right ventricular cardiac output. A balanced technique utilizing high dose narcotics to blunt the sympathetically mediated cardiovascular response to surgical stimulation and minimal volatile anesthetics can limit these adverse effects. Additionally, the anesthesiologist should strive to use basic physiology to her/his advantage. These principles include utilization of 100% oxygen for its pulmonary vasodilator

**Drug category Drug name Delivery pathway/dose Common side effects**

Treprostinil (Tyvaso) Inhaled, follow doctor's

instraction

Nitric oxide Inhaled nitric oxide Inhaled, 20-50ppm Methemoglobinemia, Lung

maintenance

0.25-0.75 mcg/kg/min

Sildenafil Oral, 50 mg preoperatively hypotension

62.5mg twice daily, oral for 4

Milrinone Intravenous, 50mcg/kg loading,

weeks

Nitrovasodilator Nitroglycerin Intravenous, 0.5 g/kg/min, Hypotension, headache Calcium channel blockers Diltiazem High oral dose:720mg/day Constipation, dizziness,

Nifedipine Oral 240mg/day

**Table 6.** Pharmacological treatment for pulmonary hypertension [94] [95] [96] [97].

Inhaled 31mcg/kg/min Occupational health concern

Perioperative Considerations of Patients with Pulmonary Hypertension

lighheatedness,

toxicity,

tachycardia,

Hepatotoxicity Birth defects Anemia

flushing, headache

giddiness

Constipation, cough, flushing,

Cough, headache, throat irritation, pain, flushing

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219

Ventricular dysrhythmia,

Iloprost (Ventavis) Inhaled, 6-9 times/day Dizziness, headache, flushing,

2.5-10mg/day, oral Birth defects

Non-pharmacological management of pulmonary hypertension is listed in Table-7.


**Table 6.** Pharmacological treatment for pulmonary hypertension [94] [95] [96] [97].

#### **6.4. General anesthesia**

**5.** Intravenous prostacyclin (if inhaled is not available) is 4–10 ng/kg/min. In the U.S., iloprost is inhaled specifically using the I-Neb AAD or Prodose AAD delivery systems. Ventavis is supplied in 1 mL single-use glass ampules containing either 10 mcg/mL or 20 mcg/mL. The 20 mcg/mL concentration is intended for patients who are maintained at the 5 mcg dose and who have repeatedly experienced extended treatment times which could result in incomplete dosing. Transitioning patients to the 20 mcg/mL concentration using the Ineb AAD System will decrease treatment times to help maintain patient compliance. The approved dosing regimen for iloprost is 6 to 9 times daily (no more than every 2 hours)

**6.** Systemic hypotension should be treated according to the potential causes. Phenylephrine and norepinephrine have been used to treat persistent systemic hypotension. Norepi‐ nephrine has the advantage of being both a vasoconstrictor and positive inotropic agent.

**7.** Sildenafil produced significant pulmonary vasodilatory effect relative to placebo in anesthetized cardiac surgical patients with pulmonary hypertension. With respect to the predominant selectivity of sildenafil to pulmonary vasculature shown in this study and other potentially beneficial effects such as myocardial protection, use of sildenafil in the intraoperative period in cardiac surgical patients with pulmonary hypertension should be considered [93]. Sildenafil citrate (INN sildenafil) is a selective phosphodiesterase type 5 inhibitor that is being increasingly recognized as a treatment modality for pulmonary

**8.** Calcium channel blockers have been shown to inhibit the contraction of pulmonary artery smooth muscle cells, reduce right ventricular hypertrophy and improve long-term hemodynamics in PH in a small subset of patients who also show an acute hemodynamic response to calcium channel blockers. An interesting study demonstrated that survival was greatly improved in patients who showed a long-term response to calcium channel blockers; however, in patients that failed on long-term calcium channel blocker therapy, the 5-year survival rate was only 48% [94]. Calcium channel blockers are now only recommended for patients with a positive response during acute vasoreactivity testing and who show sustained hemodynamic improvement [94]. Calcium channel blockers are the only systemic antihypertensive drugs that have been shown to benefit patients with PH. By blocking calcium entry into cells of the pulmonary arterial vasculature, calcium channel blockers can induce vasodilation (or at least prevent vasoconstriction) of pulmo‐ nary arteries. In an initial trial in patients who demonstrated a response to calcium channel blockers during acute testing, use of calcium channel blockers led to a significant reduction in mPAP and PVR after 24 hours of treatment. Continued use over 1 year was associated

Non-pharmacological management of pulmonary hypertension is listed in Table-7.

Vasopressin has also been advocated for treatment of hypotension [68] [92]

during waking hours, according to individual need and tolerability.

hypertension.

218 Pulmonary Hypertension

with improvements in symptoms [94].

Without any doubt, every effort should be made to have a smooth induction of anesthesia and endotracheal intubation which will minimize the hemodynamic instability in highly suscep‐ tible patients. Commonly used intravenous anesthetics such as propofol and thiopental are associated with hypotension and myocardial depression. Their use should be very judicious. Etomidate has much fewer effects on SVR, PVR and myocardial contractility and may be a more useful hypnotic for patient with severe PH. Use of volatile anesthetics is associated with decreased SVR, myocardial contractility and potential arrhythmias, all of which can impair right ventricular myocardial perfusion and also right ventricular cardiac output. A balanced technique utilizing high dose narcotics to blunt the sympathetically mediated cardiovascular response to surgical stimulation and minimal volatile anesthetics can limit these adverse effects. Additionally, the anesthesiologist should strive to use basic physiology to her/his advantage. These principles include utilization of 100% oxygen for its pulmonary vasodilator 1. Ensure adequate oxygenation; avoid hypercarbia;

2. Avoidance of acidosis;

3. Avoidance of hypothermia;

4. Whatever medication is used to control PH, wean the medication slowly to prevent rebound pulmonary hypertension;

5. Neuraxial anesthesia, peripheral nerve blockade, and lumbar plexus block can all be used to provide surgical anesthesia for scheduled procedures. But the loading dose should be slow and adjusted according to patient's condition. Epidural anesthesia should be induced slowly. Mixtures of local anesthetics and opioids should be given to reduce the dose of local anesthetics and hypotension;

**6.5. Regional anesthesia**

Regional anesthetic techniques, including neuraxial blockade (epidural, spinal anesthesia, or combined epidural and spinal anesthesia) and peripheral nerve blockade (cervical plexus, auxillary plexus, sciatic nerve, femoral, etc), have all been successfully used in surgical procedures in patients with severe pulmonary hypertension [100]. Among the benefits of regional anesthesia are potential minimization of the stimulation-related (direct laryngoscopy, endotracheal intubation, etc) sympathetic activation. Even with adequate intravenous anesthetic induction agents, opioids and neuromuscular blockade, it is difficult to avoid increases in sympathetic nervous system activity due to laryngoscopy and induction. These sympathetic responses include tachycardia, systemic hypertension and increased myocardial oxygen consumption, which could lead to increases in PVR and potential acute right heart failure. During surgery and general anesthesia, due to various surgery-related (incision, surgical dissection, blood loss etc) or other surgical environment-related stimulations (hypo‐ thermia, psychological stress etc), the anesthesiologist has to continually balance excessive sympathetic outflow, increased PVR and potential acute right heart failure on one hand and excessive depth of anesthesia, low cardiac output, low coronary perfusion and cardiovascular collapse on the other hand [101]. A healthier patient tolerates these variations well, but the patient with severe PH has limited reserve to compensate for acute increases in PVR or decreased coronary perfusion. A peripheral nerve block technique could potentially limit anesthesia to the specific location of the surgery and avoid the need for the stimulation of intubation and reduced likelihood of sympathectomy and low blood pressure as one would achieve with general anesthesia. An important distinction is that a sympathectomy is still possible when utilizing a regional anesthesia technique such as epidural or spinal anesthesia. This may lead to arterial and venous dilatation and reduced preload and cardiac output compromising coronary perfusion. When utilizing neuraxial or peripheral nerve block techniques, it is important to ensure adequate ventilation and oxygenation to prevent increases in PVR due to hypoxemia. For example, sedation provided to allow the patient to tolerate placement of a peripheral nerve block or to tolerate lying on the narrow, stiff operating table may lead to hypoxemia and hypercarbia secondary to hypoventilation. On the other hand, lack of adequate sedation can promote anxiety, pain and sympathetic stimulation. Achieving

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221

the delicate balance can be a daunting task for anesthesia providers.

vasoconstriction and elevated PAP.

**6.6. Postoperative management**

For those patients with PH to undergo minor surgical procedures with only monitored anesthesia care (MAC), special attention should be paid to provide adequate sedation to minimize patients' anxiety, which can be harmful because it may lead to increased sympathetic outflow as we discussed previously. Over-sedation should be avoided to prevent respiratory suppression and subsequent hypoventilation and hypoxemia which may induce hypoxic

These patients with moderate to severe PH warrant intensive care monitoring in the postop‐ erative period by experienced critical care personnel. As the analgesic and sympathetic nervous system effects of opioids, volatile anesthetics, and regional anesthetics disappear, the

6. Avoidance of elevating intrapleural pressure which will potentially be transmitted to increased pulmonary arterial pressure.

(Copyright by Henry Liu, MD)

**Table 7.** Non-Pharmacological management of pulmonary hypertension

effects, and aggressive treatment of hypercarbia, acidosis, and hypothermia as these may cause pulmonary vasoconstriction. Certain anesthetic agents such as nitrous oxide and ketamine have been associated with increases in PVR and should be used with caution [98] [99]. Uncompensated vasodilatation or myocardial depression induced by anesthetics and me‐ chanical ventilation may be responsible for acute RV dysfunction associated with low systemic blood pressure. Cardiovascular collapse can develop after institution of one-lung ventilation and pulmonary artery clamping during thoracotomy. An acute increase in pulmonary pressure results in a decrease in RV ejection fraction and then acute RV failure. Interdepend‐ ence of the right and left ventricles occurs such that RV function can alter LV function. Early detection of impending circulatory and/or respiratory deterioration is warranted to prevent an irreversible decline in cardiac output. Inhaled nitric oxide represents the first choice for treatment of PH and RV failure associated with systemic hypotension during lung transplan‐ tation. Intraoperative situations requiring CPB must be identified before development of systemic shock, which represents a late ominous sign of RV failure [61].

The anesthetic goals of intraoperative management include optimizing PAP, RV preload and avoiding RV ischemia and failure. Intraoperatively, often times there are significant alterations in all above parameters and appropriate vigilance and monitoring are paramount. Intraoper‐ ative management of the RV can be made on the presence of RV failure and the presence of systemic hyper- or hypotension. Initially, one should ensure that oxygenation, ventilation, and acid/base status are optimized. Treatment options for PH include both intravenous and inhaled agents. Intravenous vasodilators, such as nitroglycerin, sodium nitroprusside, beta blockers, calcium channel blockers, and certain prostaglandin preparations will cause dilation of both the pulmonary and systemic vascular beds and can be useful in the setting of PH with systemic hypertension. The advantages to intravenous preparations are the relative decreased cost, easier availability of medications, and longer duration of action and ease of administration in comparison to inhaled agents.

#### **6.5. Regional anesthesia**

effects, and aggressive treatment of hypercarbia, acidosis, and hypothermia as these may cause pulmonary vasoconstriction. Certain anesthetic agents such as nitrous oxide and ketamine have been associated with increases in PVR and should be used with caution [98] [99]. Uncompensated vasodilatation or myocardial depression induced by anesthetics and me‐ chanical ventilation may be responsible for acute RV dysfunction associated with low systemic blood pressure. Cardiovascular collapse can develop after institution of one-lung ventilation and pulmonary artery clamping during thoracotomy. An acute increase in pulmonary pressure results in a decrease in RV ejection fraction and then acute RV failure. Interdepend‐ ence of the right and left ventricles occurs such that RV function can alter LV function. Early detection of impending circulatory and/or respiratory deterioration is warranted to prevent an irreversible decline in cardiac output. Inhaled nitric oxide represents the first choice for treatment of PH and RV failure associated with systemic hypotension during lung transplan‐ tation. Intraoperative situations requiring CPB must be identified before development of

4. Whatever medication is used to control PH, wean the medication slowly to prevent rebound pulmonary

5. Neuraxial anesthesia, peripheral nerve blockade, and lumbar plexus block can all be used to provide surgical anesthesia for scheduled procedures. But the loading dose should be slow and adjusted according to patient's condition. Epidural anesthesia should be induced slowly. Mixtures of local anesthetics and opioids should be given to

6. Avoidance of elevating intrapleural pressure which will potentially be transmitted to increased pulmonary arterial

The anesthetic goals of intraoperative management include optimizing PAP, RV preload and avoiding RV ischemia and failure. Intraoperatively, often times there are significant alterations in all above parameters and appropriate vigilance and monitoring are paramount. Intraoper‐ ative management of the RV can be made on the presence of RV failure and the presence of systemic hyper- or hypotension. Initially, one should ensure that oxygenation, ventilation, and acid/base status are optimized. Treatment options for PH include both intravenous and inhaled agents. Intravenous vasodilators, such as nitroglycerin, sodium nitroprusside, beta blockers, calcium channel blockers, and certain prostaglandin preparations will cause dilation of both the pulmonary and systemic vascular beds and can be useful in the setting of PH with systemic hypertension. The advantages to intravenous preparations are the relative decreased cost, easier availability of medications, and longer duration of action and ease of administration in

systemic shock, which represents a late ominous sign of RV failure [61].

comparison to inhaled agents.

1. Ensure adequate oxygenation; avoid hypercarbia;

reduce the dose of local anesthetics and hypotension;

**Table 7.** Non-Pharmacological management of pulmonary hypertension

2. Avoidance of acidosis; 3. Avoidance of hypothermia;

220 Pulmonary Hypertension

(Copyright by Henry Liu, MD)

hypertension;

pressure.

Regional anesthetic techniques, including neuraxial blockade (epidural, spinal anesthesia, or combined epidural and spinal anesthesia) and peripheral nerve blockade (cervical plexus, auxillary plexus, sciatic nerve, femoral, etc), have all been successfully used in surgical procedures in patients with severe pulmonary hypertension [100]. Among the benefits of regional anesthesia are potential minimization of the stimulation-related (direct laryngoscopy, endotracheal intubation, etc) sympathetic activation. Even with adequate intravenous anesthetic induction agents, opioids and neuromuscular blockade, it is difficult to avoid increases in sympathetic nervous system activity due to laryngoscopy and induction. These sympathetic responses include tachycardia, systemic hypertension and increased myocardial oxygen consumption, which could lead to increases in PVR and potential acute right heart failure. During surgery and general anesthesia, due to various surgery-related (incision, surgical dissection, blood loss etc) or other surgical environment-related stimulations (hypo‐ thermia, psychological stress etc), the anesthesiologist has to continually balance excessive sympathetic outflow, increased PVR and potential acute right heart failure on one hand and excessive depth of anesthesia, low cardiac output, low coronary perfusion and cardiovascular collapse on the other hand [101]. A healthier patient tolerates these variations well, but the patient with severe PH has limited reserve to compensate for acute increases in PVR or decreased coronary perfusion. A peripheral nerve block technique could potentially limit anesthesia to the specific location of the surgery and avoid the need for the stimulation of intubation and reduced likelihood of sympathectomy and low blood pressure as one would achieve with general anesthesia. An important distinction is that a sympathectomy is still possible when utilizing a regional anesthesia technique such as epidural or spinal anesthesia. This may lead to arterial and venous dilatation and reduced preload and cardiac output compromising coronary perfusion. When utilizing neuraxial or peripheral nerve block techniques, it is important to ensure adequate ventilation and oxygenation to prevent increases in PVR due to hypoxemia. For example, sedation provided to allow the patient to tolerate placement of a peripheral nerve block or to tolerate lying on the narrow, stiff operating table may lead to hypoxemia and hypercarbia secondary to hypoventilation. On the other hand, lack of adequate sedation can promote anxiety, pain and sympathetic stimulation. Achieving the delicate balance can be a daunting task for anesthesia providers.

For those patients with PH to undergo minor surgical procedures with only monitored anesthesia care (MAC), special attention should be paid to provide adequate sedation to minimize patients' anxiety, which can be harmful because it may lead to increased sympathetic outflow as we discussed previously. Over-sedation should be avoided to prevent respiratory suppression and subsequent hypoventilation and hypoxemia which may induce hypoxic vasoconstriction and elevated PAP.

#### **6.6. Postoperative management**

These patients with moderate to severe PH warrant intensive care monitoring in the postop‐ erative period by experienced critical care personnel. As the analgesic and sympathetic nervous system effects of opioids, volatile anesthetics, and regional anesthetics disappear, the patient can develop sudden worsening of PH and RV ischemia. Thus weaning from the ventilatory support and endotracheal extubation should be done gradually with close attention to adequate oxygenation, ventilation and analgesia. Even routine events such as bucking on the ventilator due to tracheal stimulation, while tolerated by the average patient, can lead to acute rises in PVR and RV failure in patient with severe PH [78]. Postoperative pain manage‐ ment of patients with PH warrants special attention, because in clinical practice, the most commonly used analgesic agents are opioids which are potent respiratory depressants also. Depression of respiratory drive will likely cause hypoventilation which leads to increased PAP. Thus using multimodal analgesic strategy is critical in minimizing the side effect of respiratory inhibition by opioids and avoiding hypoventilation-associated increase of PAP.

pulmonary hypertensive crisis [103]. Management of pediatric patients with PH poses unique challenges to pediatric anesthesiologists: PAC may not be available for many smaller pediatric patients due to the small sizes of their cardiac chamber and blood vessels. TEE may not be available to some pediatric patients due to lack of suitable size of TEE probe. So transthoracic or epicardial echocardiography will play a much more important role for those pediatric patients without TEE and PAC. Minimally invasive/non-invasive monitoring of MAP, CO/CI, SVV may play some role intraoperatively, however these current technologies may not work as well in children as in adults [104]. And information from randomized controlled clinical studies on the treatment of pediatric PH is currently very limited, unanimous opinions are to refer to the guidelines and treatment strategies for the treatment of adult PH. Therefore, the recommended treatment for children is only grade IIa with the level of evidence class C.

Perioperative Considerations of Patients with Pulmonary Hypertension

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Curry *et al* reported two maternal deaths out of 12 pregnancies in 9 patients. One of the two deaths was related to pre-eclampsia and the other related to cardiac arrhythmia. Maternal morbidity included postpartum hemorrhage (five cases), and one post-caesarean evacuation of a wound hematoma. There were no perinatal death, nine live births and three first-trimester miscarriages. Mean birthweight was 2197 grams, mean gestational age was 34 weeks (range 26-39), and mean birthweight percentile was 36 (range 5-60). Five babies required admission to the neonatal intensive care unit, but were all eventually discharged home. All women were delivered by caesarean section (seven elective and two emergency deliveries), under general anesthesia except for one emergency and one elective caesarean performed under regional block [105]. Maternal and fetal outcomes for women with PH has improved; however, the risk of maternal mortality remains significant, so that early and effective counseling about contraceptive options and pregnancy risks should continue to play a major role in the man‐

We have gained better understanding of PH and have significantly more sophisticated management strategies now compared with two decades ago. PH can develop due to pulmo‐ nary vascular remodeling (cellular proliferation), abnormal vasoconstriction, mechanical obstruction (chronic thromboembolic events, interstitial lung diseases) or left-side heart diseases. Thorough preoperative evaluation is mandatory. A clear understanding of the etiology of pulmonary hypertension is extremely important to understand how to optimally manage these patients in the operating room. Echocardiography plays a key role in preliminary screening, monitoring the progress and evolution of PH, and intraoperative monitoring and treatment. Right heart catheterization remains the gold standard for the diagnosis of PH. Evaluation of the overall pulmonary functional status is also important in assessing patients' tolerability to the planned surgical procedure. Perioperatively these patients can present very challenging clinical scenarios due to the complexity of their PH and increased risks for significant complications with elevated morbidity and mortality. Several clinical characteris‐

agement of such women when they reach reproductive maturity.

**7.2. Obstetrics**

**8. Summary**
