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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery

      Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

      KEYWORDS

      Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. Successful management of the perioperative patient with PH is complex. It requires a thorough understanding of the pathophysiology of PH and right ventricular (RV) failure, as well as building a safety net preoperatively to mitigate the risks of surgery and improve outcomes. This approach includes ensuring accurate diagnostic classification of PH based upon the World Health Organization (WHO) clinical and hemodynamic classification of PH
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      (Figure 1), assessment of the patient's functional status and disease severity, evaluation of the risks vs benefits of anesthesia and surgery, development of a perioperative plan with a multidisciplinary team, preoperative hemodynamic optimization, and vigilant postoperative monitoring for the early recognition and treatment of any postoperative complications (Figure 2). Additionally, determination of the best location for surgery to occur (particularly for non-cardiac surgery) is important given data that suggests patients with WHO Group 1 pulmonary arterial hypertension (PAH) benefit from having surgery in a center with experienced PH providers
      • Meyer S
      • McLaughlin VV
      • Seyfarth H-J
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      –an approach that has been advocated in recent guidelines.
      • Taichman DB
      • Ornelas J
      • Chung L
      • et al.
      Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report.
      Figure 1
      Figure 1Hemodynamic and clinical classifications of PH. Abbreviations: mPAP, mean pulmonary artery pressure ; PCWP, pulmonary capillary wedge pressure ; PVR, pulmonary vascular resistance.
      Figure 2
      Figure 2Recipe for successful perioperative outcome.
      In the absence of robust literature to form clinical practice guidelines, this statement represents the consensus of international experts in the field on the perioperative evaluation and management for patients with a spectrum of PH etiologies undergoing various types of surgeries and procedures, including non-cardiac and cardiac surgeries, cardiothoracic and abdominal organ transplantation, surgery for acute and chronic pulmonary embolism, and procedures in children and adult congenital heart disease patients with PH. It is meant to serve as a guide for physicians, surgeons, anesthesiologists, and other providers who manage these patients.

      Preoperative evaluation and management of patients with PH

      Risk assessment

      A fundamental risk for patients with PH during and after surgery and anesthesia is the inability of a dysfunctional RV to accommodate to rapid changes in ventricular preload, afterload and contractility to provide adequate left ventricular preload and meet systemic oxygen demands. Volume shifts, anesthetic agents, mechanical ventilation, and changes in sympathetic tone can precipitate worsening PH, RV ischemia, or RV dysfunction
      • Fox DL
      • Stream AR
      • Bull T
      Perioperative management of the patient with pulmonary hypertension.
      • Olsson KM
      • Halank M
      • Egenlauf B
      • et al.
      Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
      • Tonelli AR
      • Minai OA
      Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: perioperative management in patients with pulmonary hypertension.
      and lead to a cascade of hypotension, arrhythmias, metabolic acidosis, multiorgan failure, and death. These events often occur within the first 48 to 72 hours after surgery.
      Risks vary with different surgeries, etiologies of PH, comorbidities, and the spectrum of clinical status among patients with PH. Risk assessment therefore demands a comprehensive approach to the preoperative evaluation of patients in order to prevent excessive peri-procedural morbidity and mortality. We strongly recommend a systematic preoperative risk assessment be performed and that an individualized perioperative plan be developed by a multidisciplinary team for all patients with WHO Groups 1 (PAH) and 4 (chronic thromboembolic pulmonary hypertension [CTEPH]) PH as well as other etiologies of PH when the PH is significant and RV dysfunction present. Even minor procedures requiring conscious sedation should be approached cautiously in patients with severe PAH and efforts to mitigate risk enacted.
      Preoperative risk assessment should start with well-established general cardiac/non-cardiac perioperative risk assessment algorithms, and consider several factors that are germane to patients with PH, including the type and urgency of surgery, patient's functional status, etiology and severity of PH, RV function, and patient comorbidities. Unless the surgery is urgently needed, patients with previously undiagnosed PH should have an expedited evaluation to establish the pathologic etiology of PH (i.e., WHO clinical classification), assess disease severity, and guide treatment for PH following evidence-based PH guidelines.
      • Galie N
      • Channick RN
      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      Emergency procedures,
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      ,
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      American society of anesthesiologists class ≥ 2,
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      intermediate or high risk surgery,
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      ,
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      ,
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      longer duration of surgery and anesthesia (>3 hours),
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      ,
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      coronary artery disease,
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      ,
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      chronic renal insufficiency,
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      history of pulmonary embolism,
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      NYHA Functional Class ≥ 2,
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      RV dysfunction,
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      and hemodynamic derangement
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      ,
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      are established risk factors for perioperative morbidity/mortality in patients with PH undergoing general surgery. Intermediate to high-risk procedures in patients with PH are those that involve general anesthesia and/or the potential for rapid blood loss (e.g., organ transplantation, vascular surgery), significant perioperative systemic inflammatory response (e.g., cardiopulmonary bypass), venous air embolism, carbon dioxide (CO2) (e.g., laparoscopic surgery), fat or cement emboli (e.g., orthopedic surgery), and reduction in the pulmonary vasculature (e.g., lung resection). Table 1.
      Table 1Surgery Specific Risks
      Lowest Risk Procedures
      Procedures with local anesthesia for minor procedures
      Dermatologic surgeries
      Low Risk Surgeries
      Dermatologic surgeries
      Endoscopic procedures
      Cataract surgery
      Breast surgery
      Intermediate Risk Surgeries
      Carotid endarterectomy
      Head and neck surgery
      Gynecologic surgery
      GI/abdominal surgery
      Orthopedic surgery
      Prostate surgery
      High Risk Surgeries
      Emergent major surgery
      Cardiovascular surgery
      Liver transplantation
      Any operation with anticipated large fluid shifts and/or blood loss
      The preoperative evaluation (Figure 3) should include a detailed history, including elicitation of PH related symptoms of exertional dyspnea, chest discomfort, and/or pre-syncope/syncope to determine functional status. A thorough physical examination with particular attention to signs of RV failure (RVF) is required. Preoperative testing in patients with PH should be done within 2 weeks of elective surgery and include natriuretic peptide level (correlates with severity of disease in PAH and heart failure) along with basic chemistry (especially renal function), coagulation panel, chest X-ray, ECG, 6 minute walk test, and an echocardiogram with detailed attention to the right ventricle. Measures of RV size and function, including tricuspid annular plane systolic excursion (TAPSE) and RV S’, degree of interventricular septal flattening from RV volume and pressure overload, and an estimate of the pulmonary artery systolic pressure (PASP) by echocardiography are helpful to identify patients with more severe PH and RV dysfunction who may be at greater risk. An estimate of physiological reserve can also inform risk. Patients with PAH and a 6-minute walk distance <399 m at the last preoperative assessment are at higher risk of major postoperative complications.
      • Meyer S
      • McLaughlin VV
      • Seyfarth HJ
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      Preoperative right heart catheterization (RHC) should be considered in patients with clinical evidence of severe PH and RV dysfunction and/or planned high risk operation. Table 2.
      Table 2PH Specific Risk Assessment Tools
      Low riskHigh risk
      Clinical symptoms/signs
       RHFNonePresent
       Functional classI/IIIII/IV
      Exercise capacity
       6 mwd> 400 meters< 165 meters
       CPETPeak VO2 > 15 ml/min/kg-1 VE/VCO2 slope < 36.0Peak VO2 < 11 ml/min/kg-1 VE/VCO2 slope > 45.0
      Imaging
       (echo, MRI)Normal RV size & function Normal RA sizeMarkedly dilated RV, RV dysfunction Severe RAE, pericardial effusion
       HemodynamicsRAP < 8, CI > 2.5, SvO2 > 65%, RVSP/SBP < 0.33RAP > 14, CI < 2.0, SvO2 < 60%, mPAP > 35 mm Hg, RVSP/SBP > 0.66
       Biomarkers (ng/liter)BNP < 50, NT-pro BNP < 300BNP > 300, NT-pro BNP > 400
       PAH risk scoreLow riskHigh risk
      BNP, brain type natriuretic peptide; CI, cardiac index; mPAP, mean pulmonary artery pressure; RA, right atrium; RAE, right atrial enlargement; RAP, right atrial pressure; RV, right ventricle; RVSP, right ventricular systolic pressure; SBP, systolic blood pressure; SvO2, systemic venous O2 saturation; VE/VCO2, minute ventilation/carbon dioxide production; VO2, maximal oxygen consumption; .
      The prognostic scoring systems for PAH from the European Respiratory and European Cardiology Society and the United States Registry to Evaluate Early And Long-term PAH Disease Management, may also be helpful to generally assess disease severity in patients with WHO Group 1 PAH,
      • Hoeper MM
      • Kramer T
      • Pan Z
      • et al.
      Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model.
      • Benza RL
      • Miller DP
      • Foreman AJ
      • et al.
      Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) analysis.
      • Kylhammar D
      • Kjellstrom B
      • Hjalmarsson C
      • et al.
      A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension.
      however their perioperative utility has not been assessed nor have they been validated in patients with non-WHO Group 1 PH.
      In high perioperative risk situations, surgery should be performed at a center with the expertise (PH specialists, CV anesthesiologists, intensivists) and resources (inhaled nitric oxide, extracorporeal membrane oxygenation [ECMO]) to effectively manage the patient postoperatively should complications arise. This may entail transfer to a tertiary care center, and if this is not feasible then urgent consultation with a PH expert center for management recommendations can be helpful. If time permits, medical and hemodynamic optimization should be attempted prior to surgery in patients with evidence of decompensated disease.
      Very low risk procedures that involve minimal sedation and analgesia, such as cataract and dental surgeries, do not generally require a full reassessment of PH disease severity. However, for patients with advanced PH, recommendations to avoid nitrous oxide (reports suggest it can increase PVR) and epinephrine (may be proarrhythmic) along with minimizing oral sedation usually suffice.
      Endoscopic procedures require sedation, which can cause hemodynamic and respiratory compromise if not approached with caution. Upper endoscopy is generally well tolerated and can often performed at the local facility. Recommendations for this procedure typically include administration of minimal sedation and close hemodynamic and respiratory monitoring. In urgent, higher risk cases (e.g., active GI bleeding in a patient with uncontrolled PH and RV/respiratory failure or Eisenmenger Syndrome), an anesthesiologist should be involved. Colonoscopy involves deeper sedation and therefore greater risk of cardiorespiratory compromise. Thus, in very high-risk PH patients, especially those with baseline severe PH/RV and respiratory failure, performing the procedure at a tertiary care center with anesthesia and PH expertise is most prudent. In some cases, the risks of the procedure may outweigh its potential benefits.
      Absolute contraindications for surgery in patients with PH cannot be provided since the balance of relative risks vs benefits always needs to be considered, and ultimately the decision to proceed will be informed by the urgency of the procedure, prognosis of PH relative to the condition being addressed surgically (e.g., cancer), capability of altering risk by optimizing their PH and RV function, and patient preferences.
      Table 3 lists key perioperative questions to answer preoperatively.
      Table 3Key Perioperative Questions to Answer
      • Do the benefits of the surgery outweigh the patient specific and surgery associated risks of the procedure?
      • Is the patient medically optimized or are additional procedures and treatment needed?
      • What is the urgency of surgery (e.g., is there time for optimization of PH/RV function)?
      • Should the procedure be moved from its usual location to a tertiary location (e.g., available CV anesthesia, PH expertise, PAH meds, ECMO capabilities)?
      • What is the intra- and postoperative monitoring plan?
      • How should anesthesia staffing be allocated (CV vs general anesthesiology)?
      • Is the patient a candidate for ECMO?
      • What is the optimal postoperative disposition (e.g., postoperative recovery in ICU for 48 hours or more)?
      • What is the plan for managing chronic PAH therapies?

      Multidisciplinary planning for the PH patient undergoing surgery

      Carefully planned non-emergency surgery has better outcomes in patients with PH.
      • Fox DL
      • Stream AR
      • Bull T
      Perioperative management of the patient with pulmonary hypertension.
      • Olsson KM
      • Halank M
      • Egenlauf B
      • et al.
      Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
      • Tonelli AR
      • Minai OA
      Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: perioperative management in patients with pulmonary hypertension.
      In order to achieve the best outcomes, the management team must be organized, proficient with knowledge and skills, and effective in communication. The PH specialist, anesthesiologist, and surgeon are at the core of the multidisciplinary group to develop an individualized perioperative plan and ensure clear communication of the plan with the respective team members (Figure 4).
      Figure 4
      Figure 4Preoperative multidisciplinary communications and planning: the core team.

      Multidisciplinary team

      PH specialist

      The role of the PH specialist is to perform a thorough preoperative evaluation for disease phenotyping and risk assessment, help weigh the risks vs benefits of surgery, provide timely and effective communication with the surgeon and anesthesiologist to determine the urgency and best location for surgery, discuss intraoperative monitoring and medical management considerations with the anesthesiologist, consider potential need and patient candidacy for ECMO and communicate with the appropriate teams, optimize the patient's clinical and hemodynamic status preoperatively, and participate in the postoperative care and management based on institutional practices.
      Importantly, preoperative plans for the perioperative administration of chronic PAH specific therapies for patients with PAH and CTEPH should be discussed with the anesthesiologist and intensive care unit (ICU) team, including the logistics of continuing chronic infused and inhaled prostacyclin analogues as well as options for non-enteral PAH drug administration while NPO.

      Anesthesiologist

      The anesthesiologist assesses patient and surgical/anesthesia risk, taking into account the severity of PH and RV dysfunction. The anesthesiologist, along with input from the PH specialist and surgeon determine appropriate intraoperative anesthesia plans including who should be present (institutions may have gradations of general, cardiac or intensivist anesthesiologists), preferred anesthetic modality, monitoring, fluid administration, ventilation strategy, additive pulmonary vasodilators (e.g., iNO and/or chronic infused prostacyclin analogues) and preferred inopressor use tailored to the patient's PH phenotype and hemodynamics. The anesthesiologist in concert with the surgical team should give a in-person sign over to the intensivist and/or PH specialist immediately after surgery to report intraoperative events that could affect the postoperative course.

      Surgeon

      The surgeon determines the need and urgency for surgery. Along with the anesthesiologist and PH specialist, the surgeon assesses the balance of anticipated benefits vs associated risks of surgery and determines the best location for surgery (this may be at a tertiary care center with CV anesthesia and PH expertise availability requiring a change in surgeon). The surgeon decides the surgical approach, along with input from the anesthesiologist in some cases (e.g., laparoscopic, robotic, minimally invasive or open procedures), and coordinates with the PH specialist on the timing of surgery in elective cases.

      Intensivist

      The risk of death from acute decompensated RV failure (ADRVF) in patients with PAH is highest within 48 to 72 hours of the procedure.
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      ,
      • Meyer S
      • McLaughlin VV
      • Seyfarth HJ
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      If the preoperative evaluation revealed intermediate to high PH-related morbidity/mortality risk, or if the surgery is emergent or prolonged, planned postoperative recovery in the ICU for 24 to 72 hours is advised. The role of the intensivist is to be vigilant for signs of worsened PH and/or decompensated RV, rapidly treat precipitating factors
      • Olsson KM
      • Halank M
      • Egenlauf B
      • et al.
      Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
      ,
      • Lahm T
      • McCaslin CA
      • Wozniak TC
      • et al.
      Medical and surgical treatment of acute right ventricular failure.
      and activate the multidisciplinary team if cardiogenic shock occurs. Close communication with the PH specialist is essential, particularly before changing or stopping PAH medications, and provide input into decision to use pharmacological or mechanical rescue strategies. The intensivist should be familiar with PAH therapies if managing WHO Group 1 PH patients. The half-life of agents varies, but typically is minutes to hours for prostanoids. A potential for rebound pulmonary vasoconstriction and PH crisis can occur after abrupt discontinuation, thus underscoring the importance of avoiding any interruption.
      • Olsson KM
      • Halank M
      • Egenlauf B
      • et al.
      Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
      • Tonelli AR
      • Minai OA
      Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: perioperative management in patients with pulmonary hypertension.
      • Galie N
      • Channick RN
      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.

      Pharmacists

      Pharmacists play a vital role in the care of the PH population (particularly for patients with PAH) during the postoperative period.
      • Bedouch P
      • Roustit M
      • Quetant S
      • et al.
      Development of a pharmacist collaborative care program for pulmonary arterial hypertension.
      The PH pharmacy specialist may serve as a liaison to communicate the plan of care, concerns and recommendations among specialists. Further, they alert the PH specialist if the patient is unable to take oral PAH medications and alternatives need to be identified. The complexity of parenteral prostanoids leads to particularly high risk with medication errors, including accidental flushing of the dedicated line, incorrect dosing (calculation, compounding, or ordering errors), and pump-related errors, all of which can be fatal.
      • Kingman MS
      • Tankersley MA
      • Lombardi S
      • et al.
      Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey.
      Medication reconciliation, reviewing and checking dosages, drug infusion preparation, are important roles. Hospital pharmacists also play a key role in monitoring adverse event reports and assure adherence to institutional compliance protocols.

      Nurses

      A PH nurse specialist plays a key role in navigating a PAH patient through the evaluation and perioperative phases. They should be invested in the education of the patient and family regarding risks and goals of treatment. They are integral to preoperative optimization of therapy–in particular optimization of fluid status. They are in a key position to advocate for the patient and work with the various teams to ensure continuity of care and realization of the treatment plan.
      Only bedside nurses with training and proficiency in managing inhaled and infused pulmonary vasodilator therapies should care for patients with PAH in the postoperative setting. They play a vital role in the safe administration and adjustment of these therapies to PAH patients, and this is a key reason why WHO Group 1 and 4 PH patients should have surgery performed at a PH expert center.

      Preoperative hemodynamic optimization

      All attempts to lower PVR and improve RV function should be done prior to surgery (Figure 5). Patients with uncontrolled or decompensated cardiovascular disease have increased perioperative morbidity and mortality. Dyspnea at rest, syncope, severe RVF (low CO and central venous pressure [CVP] > 15 mm Hg), metabolic acidosis and marked hypoxemia signal advanced, unstable PH disease, and in such cases the surgery should be cancelled or postponed until improvement and stabilization can be achieved, if possible.
      • Fox DL
      • Stream AR
      • Bull T
      Perioperative management of the patient with pulmonary hypertension.
      • Olsson KM
      • Halank M
      • Egenlauf B
      • et al.
      Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
      • Tonelli AR
      • Minai OA
      Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: perioperative management in patients with pulmonary hypertension.
      ,
      • Lahm T
      • McCaslin CA
      • Wozniak TC
      • et al.
      Medical and surgical treatment of acute right ventricular failure.
      Preoperative optimization, whether guided clinically or by invasive assessment, mainly involves optimizing RV loading conditions with diuretic adjustment to improve or normalize ventricular filling pressures, maximizing evidence-based medical therapy for PH/PAH and heart failure, and identify conditions that may cause acute deterioration. Examples include the initiation or augmentation of PAH specific therapies for patients with WHO Group I PAH; administration of oxygen, bronchodilators, antibiotics, and steroids for patients with chronic obstructive pulmonary disease; use of BIPAP for patients with obstructive sleep apnea (OSA); and systemic vasodilators and other appropriate HF therapies for patients with WHO Group 2 PH. Additionally, pulmonary balloon angioplasty has been successfully performed preoperatively for CTEPH prior to non-cardiac surgery to reduce perioperative risk.
      • Watanabe K
      • Ito N
      • Ohata T
      • Kariya T
      • Inui H
      • Yamada Y
      Preoperative balloon pulmonary angioplasty enabled noncardiac surgery of a patient with chronic thromboembolic pulmonary hypertension (CTEPH): a case report.
      In moderate to high-risk cases (e.g., high risk patient and/or operation), consideration should be given to preoperative invasive hemodynamic assessment of disease severity in order to guide optimization and decision making regarding intraoperative monitoring and postoperative location. Depending on the urgency of surgery, the assessment can be done several weeks in advance of surgery so that PAH therapies in appropriate patients can be initiated or escalated. For example, patients with idiopathic or associated PAH may benefit from preoperative RHC followed by the initiation of intravenous prostanoid therapy if poor prognostic findings are demonstrated (e.g., high right atrial pressure [RAP], low cardiac index [CI], severely elevated pulmonary vascular resistance [PVR], reduced central venous saturation). Patients with severe post-capillary PH may be optimized with appropriate diuresis, systemic vasodilators, and perhaps inodilators. In some cases a RHC may be done within days of surgery with anticipation of retaining the pulmonary artery catheter (PAC) depending on the hemodynamics and perioperative monitoring plan.
      Although few randomized studies have been performed to determine optimal management practices, principles of management are commonly based on experience and consensus. Table 4 outlines reasonable hemodynamic goals that can be used to guide management throughout the perioperative period. These values may not be achievable in all cases, especially depending on underlying PH type/etiology, but are meant to serve as a target.
      Table 4Optimal Perioperative Hemodynamic Goals
      • MAP > 60-65 mm Hg
      • SBP > 90 mm Hg
      • SpO2 > 92%
      • RAP 5-10 mm Hg
      • Mean PAP < 35 mm Hg
        Not all of these hemodynamics are achievable in patients with pulmonary hypertension; however, they represent goals for the medical management of patients during the perioperative period.
      • PVR/SVR ratio < 0.5
        Not all of these hemodynamics are achievable in patients with pulmonary hypertension; however, they represent goals for the medical management of patients during the perioperative period.
      • PCWP < 18 (for WHO Group 2 PH)
      • CI > 2.2 liter/min/m2
        Thermodilution or direct Fick CO methodologies.
      CI, cardiac index; MAP, mean arterial pressure; MPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; SBP, systolic blood pressure; SpO2, systemic pulse arterial oxygen saturation; RAP, right atrial pressure; SVR, systemic vascular resistance.
      This table summarizes optimal perioperative hemodynamic conditions.
      a Not all of these hemodynamics are achievable in patients with pulmonary hypertension; however, they represent goals for the medical management of patients during the perioperative period.
      b Thermodilution or direct Fick CO methodologies.

      Emergency surgery

      Emergency surgery is associated with worse perioperative outcomes. In non-cardiac surgery in patients with PH, emergency surgery is an independent risk factor for perioperative mortality (mortality 15%-50%), which is significantly higher than reported for non-emergent surgeries in PH cohorts.
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      ,
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      ,
      • Meyer S
      • McLaughlin VV
      • Seyfarth HJ
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      There is little time to complete a preoperative risk assessment and optimize the patient before emergency surgery. Figure 6 provides a schematic for preoperative assessment in emergent and elective surgery. Emergency surgery typically cannot be postponed even in the face of a high surgical risk. In these instances, intraoperative and postoperative monitoring and management become the major focus. Emergency echocardiography should be arranged, and the information shared among the PH specialist, anesthesiologist, surgeon, and intensivist. Plans for the anesthetic approach and management of PH specific medications should be quickly established and communicated. If the patient is at very high perioperative mortality based on advanced PH disease and intermediate to high-risk surgery, urgent transfer to a PH center with ECMO capabilities should be discussed, depending on patient stability for transfer and candidacy for ECMO support. Patient selection for ECMO support in this situation depends heavily on the patient's age, likelihood of recovery, and transplant candidacy.
      Figure 6
      Figure 6Schematic for preoperative assessment.

      Key Points

      Tabled 1
      1. A systematic preoperative risk assessment should be performed and an individualized perioperative plan developed by a multidisciplinary team for all patients with WHO Groups 1 (PAH) and 4 (CTEPH) PH as well as other etiologies of PH when the PH is significant and RV dysfunction present. Even minor procedures requiring conscious sedation should be approached cautiously in patients with severe PAH and efforts to mitigate risk enacted.
      2. Patients with WHO Group 1 PAH should have surgery performed at a PH expert center
      3. Preoperative risk assessment should start with well-established general cardiac/non-cardiac perioperative risk assessment algorithms, and also consider the type and urgency of surgery, etiology and severity of PH, RV function, patient's functional status, and comorbidities.
      4. In moderate to high-risk cases (e.g., high risk patient and/or operation), consideration should be given to preoperative invasive hemodynamic assessment of disease severity in order to guide optimization and decision making regarding intraoperative monitoring and postoperative recovery location.
      5. If time permits, medical and hemodynamic optimization should be attempted prior to surgery in patients with evidence of decompensated PH/RVF
      6. Unless surgery is urgently needed, patients with previously undiagnosed PH should have an expedited evaluation to establish the pathologic etiology of PH (i.e., WHO clinical classification), assess disease severity, and guide treatment for PH according to evidence-based PH guidelines

      Intraoperative considerations in patients with PH

      The overarching goals in PH patients receiving anesthesia are to support RV function by maintaining adequate preload in addition to preventing increases in RV afterload or reduced contractility that may precipitate acute RVF. The general principles and fundamentals of intraoperative management have been reviewed in detail.
      • McGlothlin D
      • Ivascu N
      • Heerdt PM
      Anesthesia and pulmonary hypertension.
      One of the most important fundamental goals is to avoid systemic arterial hypotension that can promote RV ischemia in the setting of a pressure and volume overloaded RV with altered right coronary artery perfusion. Periods of transient hypotension are common and may be due to the direct cardiovascular of anesthetic drugs, impact of withdrawing sympathetic tone, effects of mechanical ventilation, intraoperative fluid shifts, and / or manipulation of the heart and great vessels. Therefore, these events must be anticipated and effectively managed.
      Regardless of anesthetic technique and agents, appropriate use of supplemental oxygen (a potent pulmonary vasodilator) should be used to avoid hypoxemia, and intravenous lines and syringes must be meticulously de-aired to prevent even small amounts of air embolism that could be detrimental to the hypertensive pulmonary circulation or pass through a patent foramen ovale into the systemic circulation. Additionally, warming blankets, heat and moisture exchangers in the breathing circuit, and warmed IV fluids can help prevent hypothermia, which can inhibit physiologic hypoxic pulmonary vasoconstriction (HPV) and ventilation-perfusion (V/Q) mismatching.
      Additionally, if significant postoperative pain is anticipated, consideration should be given to insertion of an epidural catheter for postoperative analgesia administration to mitigate the deleterious effects of systemic opioid use (hypoventilation, hypoxemia, hypercarbia).

      Anesthesia and anesthetic management

      The decision about the anesthetic method (e.g., general, regional, neuraxial) is determined by a combination of the planned surgery, severity of pulmonary vascular disease/RVF and other comorbidities, as well as patient preference. For instance, choosing an anesthetic technique that optimizes airway patency and gas exchange is essential in patients with co-morbid respiratory conditions such as chronic hypoxia from intrinsic lung disease, obesity, or OSA. We highly recommend avoiding general anesthesia (GA) in patients with significant PAH when adequate alternative anesthetic methods exist due to the hemodynamic risks related to mechanical ventilation and anesthetic agents. However, this must be balanced with the potential risk of hypoxemia and/or hypercarbia or oxygen supply/demand issues related to conscious sedation or insufficient pain control.

      General anesthesia

      The period of induction is high risk for hemodynamic compromise and collapse. There are many different approaches to achieve a stable induction, and the safest path is for the anesthesiologist to use medications and techniques they are comfortable with. Vasopressors should be readily available, and it may be wise to start infusion at the time of induction to prevent systemic hypotension rather than chase it.
      The effects of common general anesthetic agents on the systemic and pulmonary vasculature as well as inotropy have been reviewed.
      • Reimer CG
      J. Pharmacology of the Pulmonary Circulation.
      • Pilkington SA
      • Taboada D
      • Martinez G
      Pulmonary hypertension and its management in patients undergoing non-cardiac surgery.
      • Steppan J
      • Diaz-Rodriguez N
      • Barodka VM
      • et al.
      Focused review of perioperative care of patients with pulmonary hypertension and proposal of a perioperative pathway.
      Most agents cause some degree of systemic hypotension and variable effects on the pulmonary arterial system and inotropy. For example, propofol has been shown to cause both vasoconstriction
      • Kondo U
      • Kim SO
      • Nakayama M
      • Murray PA
      Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic alpha- and beta-adrenoreceptor activation.
      and vasodilation of pulmonary arteries.
      • Ouedraogo N
      • Mounkaila B
      • Crevel H
      • Marthan R
      • Roux E
      Effect of propofol and etomidate on normoxic and chronically hypoxic pulmonary artery.
      It also has myocardial depressant effects and predictably decreases systemic vascular resistance (SVR),
      • Pensado A
      • Molins N
      • Alvarez J
      Effects of propofol on mean arterial pressure and systemic vascular resistance during cardiopulmonary bypass.
      mean arterial pressure and venous return to the right heart.
      • Green DW
      Cardiac output decrease and propofol: what is the mechanism?.
      This makes propofol a less than ideal isolated agent to use in the setting of PH, especially without concomitant vasopressor/inotrope support. The use of ketamine has been controversial, as early studies demonstrated increases in PAP, PVR
      • Tweed WA
      • Minuck M
      • Mymin D
      Circulatory responses to ketamine anesthesia.
      ,
      • Gooding JM
      • Dimick AR
      • Tavakoli M
      • Corssen G
      A physiologic analysis of cardiopulmonary responses to ketamine anesthesia in noncardiac patients.
      and myocardial oxygen consumption. Subsequent studies in patients with PH have shown negligible increases in pulmonary indices and maintenance of SVR superior to other drugs.
      • Williams GD
      • Philip BM
      • Chu LF
      • et al.
      Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation.
      • Friesen RH
      • Twite MD
      • Nichols CS
      • et al.
      Hemodynamic response to ketamine in children with pulmonary hypertension.
      • Heller AR
      • Litz RJ
      • Koch T
      A fine balance–one-lung ventilation in a patient with Eisenmenger syndrome.
      • Rees DI
      • Gaines 3rd, GY
      One-lung anesthesia–a comparison of pulmonary gas exchange during anesthesia with ketamine or enflurane.
      • Burbridge MA
      • Brodt J
      • Jaffe RA
      Ventriculoperitoneal shunt insertion under monitored anesthesia care in a patient with severe pulmonary hypertension.
      Etomidate causes minimal systemic hemodynamic changes
      • Colvin MP
      • Savege TM
      • Newland PE
      • et al.
      Cardiorespiratory changes following induction of anaesthesia with etomidate in patients with cardiac disease.
      and has been shown to relax the pulmonary arteries,
      • Ouedraogo N
      • Mounkaila B
      • Crevel H
      • Marthan R
      • Roux E
      Effect of propofol and etomidate on normoxic and chronically hypoxic pulmonary artery.
      making it an ideal agent for this patient population. Therefore, etomidate is generally considered a preferred agent for induction whereas the use of propofol is discouraged in most patients with significant PH and RV dysfunction.
      Volatile (inhaled) anesthetics have little direct effect on the pulmonary arteries at clinically relevant concentrations
      • Nakayama M
      • Kondo U
      • Murray PA
      Pulmonary vasodilator response to adenosine triphosphate-sensitive potassium channel activation is attenuated during desflurane but preserved during sevoflurane anesthesia compared with the conscious state.
      but can adversely affect RV contractility.
      • Priebe HJ
      Differential effects of isoflurane on regional right and left ventricular performances, and on coronary, systemic, and pulmonary hemodynamics in the dog.
      ,
      • Kerbaul F
      • Bellezza M
      • Mekkaoui C
      • et al.
      Sevoflurane alters right ventricular performance but not pulmonary vascular resistance in acutely instrumented anesthetized pigs.
      Nitrous oxide (N2O) in patients with PH continues to be discouraged due to older data demonstrating an increase in PVR, pulmonary artery pressure (PAP) and decreased CI with N2O administration in secondary PH.
      • Schulte-Sasse U
      • Hess W
      • Tarnow J
      Pulmonary vascular responses to nitrous oxide in patients with normal and high pulmonary vascular resistance.
      Modern neuromuscular blockers and opioids are mostly hemodynamically neutral agents in this group of patients,
      • McCoy EP
      • Maddineni VR
      • Elliott P
      • Mirakhur RK
      • Carson IW
      • Cooper RA
      Haemodynamic effects of rocuronium during fentanyl anaesthesia: comparison with vecuronium.
      ,
      • Searle NR
      • Thomson I
      • Dupont C
      • et al.
      A two-center study evaluating the hemodynamic and pharmacodynamic effects of cisatracurium and vecuronium in patients undergoing coronary artery bypass surgery.
      although mild systemic hypotension can occur. Opioids have been shown to vasodilate pulmonary arteries in animal studies.
      • Kaye AD
      • Hoover JM
      • Kaye AJ
      • et al.
      Morphine, opioids, and the feline pulmonary vascular bed.
      In the awake patient, they can cause respiratory depression, resulting in hypoxia and hypercarbia and potentially increasing PVR.

      Regional anesthesia

      The primary advantage of regional anesthesia in the PH population is the ability to avoid the negative effects of positive pressure ventilation on the right ventricle and the obligate use of systemic agents which affect hemodynamic parameters.
      The concern with spinal anesthesia is the speed of onset and inability to control the extent of sympathetic blockade, which can result in precipitous vasodilation and hypotension. If neuraxial anesthesia is to be employed, either a slowly titrated epidural or spinal catheter or CSE (Combined Spinal opioid with Epidural local anesthetic) is recommended.
      Some patients with PH are anticoagulated either for pulmonary (idiopathic PAH, CTEPH) or extra-pulmonary reasons (atrial fibrillation, systemic venous thrombosis, mechanical cardiac valves); these patients have greater risk of epidural hematoma with epidural anesthesia; therefore, oral anticoagulation should be held or reversed and the risks and benefits of bridging anticoagulation considered.
      • Jin HK
      • Chen YF
      • Yang RH
      • McKenna TM
      • Jackson RM
      • Oparil S
      Vasopressin lowers pulmonary artery pressure in hypoxic rats by releasing atrial natriuretic peptide.
      ,
      • Neal JM
      • Bernards CM
      • Hadzic A
      • et al.
      ASRA practice advisory on neurologic complications in regional anesthesia and pain medicine.
      Local anesthetic toxicity (LAST) is particularly devastating in this population, as symptoms include treatment-resistant myocardial depression, bradycardia, and hemodynamic collapse.
      • Bourne E
      • Wright C
      • Royse C
      A review of local anesthetic cardiotoxicity and treatment with lipid emulsion.

      Monitored anesthesia care (MAC)

      MAC is increasingly becoming the preferred strategy in PH patients. It utilizes a combination of local anesthesia with conscious sedation (benzodiazepines and opioids) in a monitored setting.

      Mechanical ventilation management

      Transition from spontaneous respiration to mechanical ventilation is a critical event in the PH patient. Active airway management is required to avoid a prolonged period of hypoventilation and resultant hypoxia and hypercarbia, particularly in patients who are spontaneously hyperventilating in order to maintain alveolar oxygenation and respiratory compensation for any metabolic acidosis.
      Mechanical ventilation mediates hemodynamic effects via changes in intrathoracic and transpulmonary pressures.
      • Vieillard-Baron A
      • Matthay M
      • Teboul JL
      • et al.
      Experts' opinion on management of hemodynamics in ARDS patients: focus on the effects of mechanical ventilation.
      Positive airway pressure ventilation increases pleural pressure and decreases right and left ventricular preload.
      • Marini JJ
      • Culver BH
      • Butler J
      Mechanical effect of lung distention with positive pressure on cardiac function.
      Additionally, there is a U-shaped relationship between lung volume and PVR, which is minimal at the functional residual capacity and increases at high or low lung volumes.
      • Strumpher J
      • Jacobsohn E
      Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management.
      PVR increases at high lung volumes due to compression of intraalveolar vessels. Large tidal volumes and high positive end-expiratory pressure (PEEP ≥ 10-15 mm Hg) may result in compression of the intraalveolar capillaries in well ventilated areas causing a marked increase in PVR and also an increase in dead space by diverting blood flow to less well-ventilated areas of the lung. PVR may also increase at low lung volumes or with the development of atelectasis, due to increased large vessel resistance through HPV and hypercarbia. Unfortunately, the optimum ventilation strategy requires ongoing recalibration in the OR and postoperatively, to find one that both avoids atelectasis and minimizes alveolar pressure.
      There have been no prospective studies on the influence of different intraoperative mechanical ventilation strategies in patients with PH. However, it is generally recommended that tidal volume and PEEP be adjusted to maintain the plateau pressure below 27 to 30 cm H2O and driving pressure below 14 cm H2O with typical tidal volumes of 6 ml/kg to 8 ml/kg of predicted body weight and PEEP at 5 to 10 cm H2O.
      • Strumpher J
      • Jacobsohn E
      Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management.
      ,
      • Aguirre MA
      • Lynch I
      • Hardman B
      Perioperative management of pulmonary hypertension and right ventricular failure during noncardiac surgery.
      The optimal PEEP is associated with the best PaO2/FiO2 ratio, lung compliance
      • Suter PM
      • Fairley B
      • Isenberg MD
      Optimum end-expiratory airway pressure in patients with acute pulmonary failure.
      – while avoiding high transpulmonary alveolar pressures. Traditional lung protective ventilation strategies can result in hypercarbia with respiratory acidosis and subsequent increase in PVR. Respiratory rate should be adjusted to achieve mild hypocarbia (target PCO2 30-35 mm Hg) with moderate hyperventilation under continuous blood gas analysis and without allowing the pH value to fall below 7.4.
      • Fischer LG
      • Van Aken H
      • Burkle H
      Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.
      • Pritts CD
      • Pearl RG
      Anesthesia for patients with pulmonary hypertension.
      • Blaise G
      • Langleben D
      • Hubert B
      Pulmonary arterial hypertension: pathophysiology and anesthetic approach.
      During emergence, the patient needs close monitoring for hypoventilation and alveolar de-recruitment, with a low threshold for deferring extubation. Table 5 provides perioperative ventilator management recommendations for PH patients.
      • Strumpher J
      • Jacobsohn E
      Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management.
      ,
      • Aguirre MA
      • Lynch I
      • Hardman B
      Perioperative management of pulmonary hypertension and right ventricular failure during noncardiac surgery.
      ,
      • Fischer LG
      • Van Aken H
      • Burkle H
      Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.
      • Pritts CD
      • Pearl RG
      Anesthesia for patients with pulmonary hypertension.
      • Blaise G
      • Langleben D
      • Hubert B
      Pulmonary arterial hypertension: pathophysiology and anesthetic approach.
      • Roberts DH
      • Lepore JJ
      • Maroo A
      • Semigran MJ
      • Ginns LC
      Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension.
      Table 5Ventilatory Management Principles
      Adequate oxygenation (Goal O2 sat > 92%)
      Moderate hyperventilation (goal PaCO2 30-35 mm Hg)
      Avoidance of acidosis (goal pH > 7.4)
      Plateau pressure <27 cm H2O via low tidal volume (6-8 ml/kg predicated body weight) and low PEEP (<5-10 cm H2O)

      Medical management

      Maintenance of SVR is crucial for preserving RV and systemic perfusion, especially in patients with PAH/CTEPH. All general anesthetics, including neuraxial techniques, lower SVR and therefore vasopressors are almost universally required to maintain hemodynamic stability in PH patients. Norepinephrine is a preferred agent to maintain SVR and support RV contractility. If hemodynamic monitoring suggests significantly decreased CO, inotropes are likely required. Clear clinical data does not exist to provide evidence-based recommendations on vasopressor or inotrope choice.
      • Price LC
      • Wort SJ
      • Finney SJ
      • Marino PS
      • Brett SJ
      Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review.
      Inodilators (i.e., milrinone or levosimendan) benefit cardiac output at the expense of decreased SVR, and it may be difficult to compensate for additional systemic vasodilation under GA. These agents are typically inappropriate for use in patients with PAH/CTEPH, especially intraoperatively when other agents that reduce SVR are being used. No clinical data exist to guide evidence-based recommendations on the use of specific inhaled agents in the intraoperative period. They are most useful for patients who are hemodynamically decompensated or in the face of acute intraoperative RV decompensation unresponsive to vasopressors or inotropes.
      An important tenet of intraoperative management for patients with PAH is to maintain their PAH medication regimen throughout the perioperative period. Patients should take their oral and inhaled medications immediately prior to surgery, and medications should be re-dosed throughout the perioperative period whenever possible. Subcutaneous and intravenous prostanoid infusions should be maintained at baseline levels, ensuring sufficient drug volume to last the duration of surgery, and backup cartridges for the patient's home infusion pump should be immediately available. Depending on the institution, subcutaneous treprostinil infusions may be switched to IV administration unless the procedure is relatively short. Importantly, trained personnel who can manage the patient's infusion pump should be available in case of pump malfunction. The PH team (nurse and MD) should be available to trouble shoot and assist in managing pump issues. For patients on epoprostenol, personnel trained on the infusing pump and a back-up pump should be present for the duration of the surgery, or else switching to an infusion pump that is more familiar to the operative and postoperative team should be considered, since interruptions in infusion may be poorly tolerated owing to its very short elimination half-life.

      Hemodynamic monitoring and use of TEE

      The development of acute RVF is a clinical challenge that can become catastrophic intraoperatively without adequate monitoring for its early identification and management.

      Hemodynamic monitoring

      The use of continuous EKG and pulse oximetry are standard of care. End tidal CO2 monitoring is also required for patients under GA. Invasive monitoring (e.g., arterial line, CVC, PA line) is used depending on the anesthetic technique, baseline condition of the patient, the magnitude of the proposed procedure, and anticipated physiological perturbations (Table 6). This permits rapid assessment of the effects of pharmacologic interventions, fluid shifts, and other conditions on systemic blood pressure, RV function, pulmonary artery pressure, cardiac output and global oxygen delivery. Monitoring RV function hemodynamically can be challenging, and consideration should be given to the potential risks of invasive monitoring and balanced against the validity, reliability and usability of the information derived.
      Table 6Monitoring Considerations Based on Anesthesia Type and Perioperative Risk
      GA + low risk fluid shifts + short surgeryGA + high risk fluid shifts + mild-mod PHGA + high risk fluid shifts + mod-severe PHNeuraxial anesthesia + low risk fluid shiftsNeuraxial anesthesia + high risk fluid shifts or advanced PH/RVFMAC anesthesiaLocal/regional anesthesia
      Arterial LineXXXXX
      CVC?X?
      PACX
      TEE?X
      SpO2XXXXXXX
      BP cuffXXXXXXX
      EKGXXXXXXX

      Arterial line

      In patients with significant PH or right heart dysfunction undergoing GA or neuraxial anesthesia, an arterial line for continuous systemic arterial blood pressure monitoring is warranted. Arterial lines are not usually necessary for procedures using MAC or local anesthesia. Arterial access also permits serial blood sampling for assessment of arterial blood gases and for metabolic monitoring, particularly of acid-base status, and lactate. End-tidal CO2 (ETCO2) analysis is useful as a trend, and can also be used as an indirect indicator of pulmonary blood flow and CO (e.g., a drop in ETCO2 may indicate worsening CO). However, it is not an accurate for reflection of PaCO2 in patients with increased dead space ventilation. ABG sampling can therefore be beneficial for assuring adequate ventilation and central venous saturations for evaluating adequacy of global cardiac function / oxygen delivery.

      Central venous catheter

      Central venous catheter (CVC) access provides a secure route for administration of the vasopressors and inotropes that are frequently required. It also allows for venous blood sampling to assess oxygen saturation as an index of cardiac output adequacy and CVP monitoring. When an introducer catheter (Cordis®) is used for monitoring, a PAC can subsequently be added intraoperatively if needed. Although the CVP itself may not be a reliable measure of RV preload in PAH patients perioperatively, it can be useful as an indicator of the coupling between RV function and venous return. The sudden increase in CVP should trigger an urgent assessment of the cause, as it may signal impending RV decompensation. For most intermediate risk surgical cases, the combination of a CVC and arterial line can provide adequate intra- and postoperative monitoring capabilities.

      Pulmonary artery catheter

      Whereas a PAC are generally not indicated for low to intermediate risk procedures, it can be helpful in guiding intraoperative fluid administration, vasoactive therapies or assist in cases where significant blood loss or changes in RV afterload are anticipated and adequate systemic perfusion needs to be monitored. PA catheters are widely used in cardiac and solid organ transplant surgeries, however results of clinical trials studying its utility in the perioperative period during non-cardiac surgery have been conflicting. Still, Anesthesiology Society guidelines have recommended PAC use in selected patients undergoing procedures associated with significant hemodynamic changes or patients with preexisting risk factors for hemodynamic disturbances, such as advanced cardiopulmonary disease.
      American Society of Anesthesiologists Task Force on Pulmonary Artery C
      Practice guidelines for pulmonary artery catheterization: an updated report by the American society of anesthesiologists task force on pulmonary artery catheterization.
      Maintenance of euvolemia during the intraoperative period can be particularly challenging with significant intravascular volume fluxes, and the PAC affords the capacity to monitor CVP along with mixed venous saturation for real-time assessment of oxygen extraction and global cardiac performance and their trends. Variables may be directly monitored or intermittently calculated and derived. Specialized catheters that allow continuous cardiac output, mixed venous oximetry, and right sided-ejection fraction may not be available in all centers.
      • Tonelli AR
      • Minai OA
      Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: perioperative management in patients with pulmonary hypertension.
      When utilized intraoperatively in patients with PH, PAC may be employed as an alternative to, or in conjunction with transesophageal echocardiography (TEE). Interpretation relies on consideration of combined metrics and their trends rather than in isolation at specific time points beyond the baseline.

      Transesophageal echocardiography

      Intraoperative TEE affords constant and reproducible assessment of right and left ventricular performance as well as estimation of pulmonary artery pressures. However, the well-defined parameters described for transthoracic echocardiographic assessment lack validation in TEE for the intraoperative setting
      • Ashes C
      • Roscoe A
      Transesophageal echocardiography in thoracic anesthesia: pulmonary hypertension and right ventricular function.
      ; and challenges include the complex geometry and anterior location of the RV with respect to the probe and the need to incorporate additional RV specific views to provide a comprehensive assessment.
      Assessment of RV geometry provides insight into the nature and chronicity of the underlying pathology, as well as assisting with planning of intraoperative therapeutic intervention, particularly the identification of the volume vs pressure loaded ventricle where different therapeutic strategies may be warranted. Echocardiography offers the advantage of near simultaneous assessment of ventricular function, ventricular interactions, and indirect measures estimates of stroke volume. A comprehensive assessment following insertion of the TEE is paramount to provide a baseline against which regular and repeated evaluations may be compared.

      Key Points

      Tabled 1
      1. GA should be avoided in patients with PAH when adequate alternative anesthetic options are available, due to the hemodynamic risks related to induction, intubation, mechanical ventilation and anesthetic agents. Local/regional or Monitored Anaesthetic Care is preferred, as long as adequate analgesia can be provided.
      2. Etomidate has a more favorable profile for induction of anesthesia in patients with PH and should be considered first line, however the use of propofol in patients with PH and RV dysfunction is not recommended due to its known hazards.
      3. Vasopressors should be readily available at the time of induction for GA, and consideration should be given to starting infusion at the time of induction to prevent systemic hypotension.
      4. If neuraxial anesthesia is to be employed, either a slowly titrated epidural or spinal catheter or CSE is recommended.
      5. Arterial line monitoring is recommended for all patients receiving general and neuraxial anesthesia.
      6. A combination of arterial and central venous catheter monitoring is recommended for most intermediate risk surgeries.
      7. Perioperative monitoring with a PA catheter is recommended for selected patients undergoing procedures associated with anticipated significant hemodynamic changes or patients with advanced PH/RV dysfunction undergoing intermediate-to-high risk procedures.
      8. Supplemental oxygen should be used for all procedures at a level to ensure maintenance of adequate alveolar and systemic oxygenation and acid-base balance.
      9. If significant postoperative pain is anticipated, consideration should be given to preparation for postoperative regional analgesia with a paravertebral block or insertion of an epidural catheter for postoperative analgesia administration to mitigate the deleterious effects of oral/IV opioid use.
      10. Inhaled pulmonary vasodilators (nitric oxide, epoprostenol, iloprost) are of uncertain benefit for many PH patients. Caution should be applied to their use in patients with decompensated LV failure and PH.
      11. During mechanical ventilation, tidal volume and PEEP should be adjusted to maintain the plateau pressure below 27 to 30 cm H2O and driving pressure below 14 cm H2O with typical tidal volumes of 6 ml/kg to 8 ml/kg of predicted body weight and PEEP at 5 to 10 cm H2O.

      Gaps in Knowledge

      Tabled 1
      Additional clinical studies are needed to determine the best anesthetic, inopressor, and inhaled pulmonary vasodilator therapies for use in patients with PH/RV dysfunction during the perioperative period.

      Postoperative considerations in patients with PH

      Most perioperative complications and death in patients with PH occur during the postoperative setting within the first 48 to 72 hours. Postoperative clinical deterioration is often due to fluid shifts, respiratory failure and pulmonary vasoconstriction, systemic hypotension, arrhythmias, bleeding, infection/sepsis, and thromboembolism that can precipitate ADRVF and subsequently multisystem organ failure and death. Frequent serial evaluations should be performed in order to promptly identify and treat these triggers.
      Basic measures in the postoperative period to prevent RVF include optimal pain control and respiratory management, maintaining adequate systemic perfusion pressure to preserve coronary perfusion, early identification and treatment of postoperative complications (e.g., infection/sepsis, bleeding, arrhythmia, PE), avoiding excessive fluid administration that can overload the RV, and the selective use of pulmonary vasodilator therapies to minimize RV afterload when needed and appropriate for the type of PH (Figure 7).
      Figure 7
      Figure 7Peri-Operative Management Algorithm. Abbreviations: CVC, central venous catheter; PAC, pulmonary artery catheter; PE, pulmonary embolism; CVP, central venous pressure; IVF, intravenous fluid; AVP, arginine vasopressin; RRT, renal replacement therapy; RV, right ventricular; BP, blood pressure; CO, cardiac output; MAP, mean arterial blood pressure; CI, cardiac index; BB, beta blockers; PEEP, positive end-expiratory pressure; iNO, inhaled nitric oxide; PDE 5 Inhibitors, phosphodiesterase type 5 inhibitors.
      Figure 8
      Figure 8Summary of potential roles of vasodilator therapies for postoperative Ph based on Ph group * Note that off-label pulmonary vasodilator therapies mentioned have not been systematically studied for safety and efficacy beyond Group 1 PAH and should be used with caution, including monitoring for worsening hypoxemia, pulmonary edema, and systemic hypotension 1 If behaves like Group 2 PH 2 If behaves like Group 3 PH.

      Postoperative monitoring

      The immediate postoperative monitoring modalities, such as an arterial line, CVP or PAC, are determined by preoperative planning and placed intraoperatively. Patients at intermediate to high perioperative risk warrant being monitored initially in the ICU for at least 24 to 48 hours or more with providers experienced in managing PH, however for low-risk surgeries in patients with stable disease several hours of monitoring in the post-anesthesia care unit may be sufficient. Patients on infused parenteral therapy should be monitored in a location staffed by providers and nurses experienced in the management of these complex medications, regardless of surgical risk.
      Invasive hemodynamic monitoring in patients suffering from PH and/or RVF postoperatively ensures early detection of hemodynamic instability; important since any delay in the management of RVF can worsen its outcome,
      • Vieillard-Baron A
      • Naeije R
      • Haddad F
      • et al.
      Diagnostic workup, etiologies and management of acute right ventricle failure: a state-of-the-art paper.
      and the rapid assessment of treatment effects. PAC monitoring has been criticized for its risk of complications and the absence of demonstrable improvement on outcomes.
      • Marik PE
      Obituary: pulmonary artery catheter 1970 to 2013.
      The lack of a demonstrable benefit of PAC in the ICU setting is explained by experts who emphasize that outside of the cath lab and OR, unless reliable data is being obtained from the PAC (i.e., proper transducer leveling and zeroing regularly ensured) and other clinical parameters are being followed, medication titration can lead to worse outcomes if the data is erroneous. Indeed, PAC usage in experienced hands to monitor complex patients is still advocated by experts in the field, especially in the context of PH and decompensated RVF.
      • De Backer D
      • Vincent JL
      The pulmonary artery catheter: is it still alive?.
      A potential alternative to continuous PA line monitoring is to obtain reliable RHC data when needed, make therapeutic adjustments, follow clinical parameters, and repeat RHC again if necessary, but this is not feasible or necessary in most situations. The duration of postoperative invasive monitoring should be adapted to each patient, considering the risks associated with an unnecessary prolongation of invasive monitoring (mainly infection and reduction of the early mobilization) balanced against the risk of hemodynamic instability with premature withdrawal during a sensitive period.
      Critical care echocardiography is also a useful tool for postoperative monitoring of biventricular function, ventricular interactions, estimated RV systolic pressure and CVP, velocity time integral in the outflow tracts as a surrogate for stroke volume, and to exclude intracardiac shunting or pericardial effusion when suspected.
      PAC and critical care echocardiography are considered adjunctive monitoring modalities, and their respective advantages are compared in Table 7.
      Table 7Pulmonary Artery Catheter and Critical Care Echocardiography Postoperative Monitoring Comparisons
      Pulmonary artery catheterCritical care echocardiography
      Global hemodynamic monitoring
      Continuous CO monitoring without calibration.Insights into RVF mechanisms, including ventricular interdependence and tricuspid regurgitation severity.
      Continuous feedback on CO adequacy with the SVO2 monitoring (including lactate and V-A PCO2 gradient measurements to assess microcirculation).Early detection of RV dilation and dysfunction (before a pathognomonic RAP elevation); screening for postoperative tamponade exclusion.
      Fluid management
      Live monitoring of a volume expansion safety by tracking any abrupt rise in RAP.Detection of a potential CO transient increase induced by fluid responsiveness maneuvers (ex: PLR or EEOT).
      Left heart disease
      Detection and monitoring of pre- and post-capillary components to PH, with PCWP and PVR (or DPG) indices.Insights into LVF mechanisms, including contractility reduction, valvular disease or dynamic obstruction.
      Specific insights
      Continuous estimation of the driving pressure for RV myocardium perfusion.Live guidance for the invasive mechanical ventilation settings (cardiopulmonary interactions).
      Practical considerations
      Basic hemodynamic monitoring (CO, SVO2, RAP) is continuously available and also interpretable without particular expertise (even for ICU nurses).Versatile and completely non-invasive tool (but requiring a dedicated training and some level of expertise).
      CO, cardiac output; DPG, diastolic pulmonary pressure gradient; EEOT, end-expiratory occlusion test; ICU, intensive care unit; LVF, left ventricular failure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PLR, passive leg raising; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV, right ventricle; RVF, right ventricular failure; SVO2, mixed venous oxygen saturation; V-A PCO2, veno-arterial gradient in CO2 partial pressure.

      General postoperative medical management

      Pain control

      In the postoperative setting, adequate analgesia is important to prevent sympathetic activation and increased oxygen demand and PVR. Treatment of postoperative pain typically involves opioids. However higher doses can lead to decreased respiratory drive in response to hypercarbia and episodes of hypoxemia related to hypoventilation. In order to avoid exacerbating PH, non-opioid pain control methods such as regional blocks or epidural anesthesia, injection of local anesthetics, acetaminophen or ketorolac can reduce the need for opioid analgesics.

      Respiratory management

      Respiratory failure is a common complication of surgery in patients with PH and one of the most frequent contributing causes of morbidity and mortality.
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      Approximately 3 quarters of respiratory complications occur within the first 24 hours postoperatively.
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      ,
      • Kruthiventi SC
      • Kane GC
      • Sprung J
      • Weingarten TN
      • Warner ME
      Postoperative pulmonary complications in contemporary cohort of patients with pulmonary hypertension.
      In addition, patients with PH are at increased risk for prolonged mechanical ventilation. As discussed previously, HPV and respiratory acidosis must be avoided. Supplemental oxygen, an effective pulmonary vasodilator, should be used to maintain oxygen saturation greater than 92% to reduce PVR and increase cardiac output.
      • Roberts DH
      • Lepore JJ
      • Maroo A
      • Semigran MJ
      • Ginns LC
      Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension.
      All attempts to avoid intubation in the ICU for respiratory failure among patients with WHO Group 1 PAH should be made, including the liberal use of high-flow nasal cannula oxygen, non-invasive positive pressure ventilation, inhaled pulmonary vasodilators to improve V/Q matching, early mobilization to reduce atelectasis, and in select dire cases, potentially veno-arterial ECMO (if the patient is a transplant candidate or if treatment to recovery is anticipated).

      Volume management

      Postoperative fluid shifts can lead to significant changes in intravascular volume. In assessing cardiac function, it is important to consider RV preload. The hypertrophied right ventricle in PH may have impaired diastolic function and therefore be more susceptible to a reduction in preload and tachycardia than a normal RV. On the other hand, in a volume and pressure overloaded RV, additional preload may further impair RV stroke volume via Starling forces increased RV wall tension, and left ventricle (LV) filling and CO can decrease due to ventricular interdependence. Indeed, optimization of volume status after surgery is a key issue to monitor and address postoperatively.
      The optimal CVP range to maintain adequate but not excessive preload las not been determined, at least partially because the CVP does not necessarily correlate with preload. However, for most spontaneously breathing patients, a CVP goal between 5 and 12 mm Hg is reasonable. In a hypotensive PH patient with evidence of reduced tissue perfusion, the effectiveness of small fluid bolus (es) of intravenous fluid can be considered as long as there is a positive response. Conversely, if the CVP is > 15 mm Hg or there is no increase in MAP with leg raising maneuver or a small fluid bolus, support of the systemic BP and RV with inopressor (s), consideration of inhaled pulmonary vasodilator therapies where appropriate (based on clinical PH phenotype), and consideration of diuretics may be more effective. Gentle diuresis should be considered in patients with a CVP higher than 15 mm Hg (especially with evidence of systemic venous congestion), in order to minimize the effect of LV preload via ventricular interdependence.

      Anticoagulation

      Anticoagulants should be held or reversed (if possible) prior to surgery. All patients should receive guideline based DVT prophylaxis in the perioperative period. Patients with WHO Group 1 PAH on oral anticoagulants do not require heparin bridging in the perioperative period. Anticoagulants for CTEPH (WHO Group 4 PH) and other chronic conditions (e.g., atrial fibrillation, mechanical heart valves, left ventricular assist device [LVAD]) should be resumed with/without heparin bridging when safe from a surgical standpoint.

      Management of acute decompensated RV failure

      Inotropes and vasopressors

      Many postoperative factors can lead to ADRVF and require stabilization and support with the use of vasopressors and/or inotropes.
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      Invasive hemodynamic monitoring, when its use is combined with proper technique and interpretation, can be quite helpful to guide choice of inotrope vs pressor and their combination in postoperative patients with PH and RV dysfunction.
      Norepinephrine has an advantage over phenylephrine as it both increases cardiac output and increases afterload to help with RV perfusion.
      • Kwak YL
      • Lee CS
      • Park YH
      • Hong YW
      The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension*.
      In vitro evidence suggests that vasopressin may have some selectivity in increasing SVR without increasing PVR.
      • Jin HK
      • Yang RH
      • Chen YF
      • Thornton RM
      • Jackson RM
      • Oparil S
      Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia.
      ,
      • Currigan DA
      • Hughes RJ
      • Wright CE
      • Angus JA
      • Soeding PF
      Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: an in vitro study.
      For patients with PH and RVF, we recommend first line treatment of hypotension with norepinephrine or vasopressin.
      • Strumpher J
      • Jacobsohn E
      Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management.
      ,
      • Price LC
      • Dimopoulos K
      • Marino P
      • et al.
      The CRASH report: emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension.
      Dobutamine is generally recommended as the inotrope of choice in the setting of PAH and right heart failure although there are no randomized clinical trials to provide guidance in the perioperative setting.
      • McGlothlin D
      • Ivascu N
      • Heerdt PM
      Anesthesia and pulmonary hypertension.
      Epinephrine is typically reserved for patients with severe RV dysfunction and refractory hypotension.
      • Strumpher J
      • Jacobsohn E
      Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management.
      Inotrope-induced arrhythmias are poorly tolerated in these patients, and chemical cardioversion with amiodarone or electrical cardioversion may be required. Inodilators (i.e., milrinone or levosimendan) benefit cardiac output at the expense of decreased SVR, and they often require the addition of a pressor to maintain systemic pressure, especially in the postoperative state in patients receiving sedation and pain medication. They should be used with caution in patients with WHO Group 1 PAH. Tables 8 and 9 describe characteristics of the various inotropes and pressors used to treat patients with PH and RVF.
      Table 8Inotropic Drugs Used for Postoperative RV Failure in PH
      DrugPharmacological propertiesBeneficial hemodynamic effectsSide effectsRecommended dosesClinical experience
      Dobutamineβ1-adrenergic agonist- increase in CO

      - decrease in PVR

      - improved V-A coupling
      - decrease in SVR

      - tachycardia/arrhythmia (dose dependent)
      2-10 µg/kg/minLarge clinical experience in acute PH decompensation
      Levosimendan
      Not approved for use in North America, UK, or Australia.
      calcium-sensitizing agent- increase in CO

      - decrease in PVR

      - improved V-A coupling
      - decrease in SVR

      - tachycardia/arrhythmia (++)
      0.05-0.2 µg/kg/min without bolus- mainly studied in postcapillary PH after cardiac surgery or transplantation

      - limited data, use with caution in PAH
      Milrinoneselective PDE-3 inhibitor- increase in CO

      - decrease in PVR

      - improved V-A coupling
      - decrease in SVR

      - tachycardia/arrhythmia (+++)
      0.25-0.75 µg/kg/min infusion
      Dopamineα- and β- agonist effects at higher doses- increase in CO

      - increase in SVR
      - tachycardia/arrhythmia2-10 µg/kg/minIncrease in renal blood flow

      Few clinical data in PH
      CO, cardiac output; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; V-A, ventriculo-arterial.
      low asterisk Not approved for use in North America, UK, or Australia.
      Table 9Vasopressor Drugs Used for Postoperative RV Failure in PH
      DrugPharmacological propertiesBeneficial hemodynamic effectsSide effectsRecommended dosesClinical experience
      Norepinephrineβ1 and α- adrenergic agonist- increase in SVR- tachycardia/ arrhythmia increase in PVR at high dose0.05-0.1 µg/kg/minFirst line vasopressor agent with RV dysfunction
      - increase in CO
      VasopressinAVP agonist- increase in SVR- tachycardia/ arrhythmia0.01-0.04 U/minPreferred vasopressor over phenylephrine
      - decrease in PVR/SVR ratio
      Phenylephrineα-adrenergic agonist- increase in SVR and MAP- increase in PVR, may reduce CO0.5-6 µg/kg/minOften reserved for sepsis/SIRS
      CO, cardiac output; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; V-A, ventriculo-arterial; AVP, Arginine Vasopressin.

      Pulmonary vasodilators

      Postoperatively there may be a need to initiate a pulmonary vasodilator for worsening PH and RV dysfunction. In this setting, short-acting vasodilators are usually the easiest to titrate. Selective pulmonary vasodilator therapies and their potential role in postoperative care of PH patients are summarized in Table 10.
      Table 10Vasodilator Therapies with a Potential Role in Postoperative PH
      GroupMedicationRouteDose
      Nitric oxideNitric oxideIH5-20 ppm
      ProstacyclinEpoprostenolIH10 mcg/ml
      IV1-10 ng/kg/min
      Prostacyclin AnalogIloprost, TreprostinilIH/IV9-25 µg by ultrasonic neb
      SQ/IV/IH1-20 ng/kg/min
      PDE-5 inhibitorSildenafilPO20-80 mg every 8 hours
      Although higher doses are sometimes used clinically, sildenafil is approved for the 20 mg dose only.
      IV2.5/10 mg every 8 hours
      PDE-3 inhibitorMilrinoneIV50 µg/kgBW bolus, followed by 0.5-0.75 µg/kgBW/min
      IHContinuous

      1 mg/ml nebulizer
      VasodilatorNitroglycerinIV2-10 µg/kgBW/min
      IH20 mcg/kg
      NitroprussideIV0.2-0.3 µg/kgBW/min
      a Although higher doses are sometimes used clinically, sildenafil is approved for the 20 mg dose only.
      Inhaled pulmonary vasodilators (iNO, epoprostenol, iloprost, milrinone, levosemendan), intravenous prostanoids (epoprostenol and treprostinil), and oral PDE 5 inhibitors (e.g., sildenafil) can be used in patients with severe PAH and acute decompensated right heart failure. Inhaled vasodilators are particularly attractive in the postoperative setting because they are shorter acting and have the advantage of preferential vasodilation of the pulmonary circulation leading to improved V/Q matching with minimal or no effect on systemic blood pressure. However many patients with Group I and 4 PAH may not respond to these agents acutely. Furthermore the role of these agents in Group 3 PH disease is uncertain but may be considered when there is little recourse. The use of these agents in Group II PH is also uncertain and should be balanced against effective strategies to optimize LV function and recognize the potential inherent risks of pulmonary vasodilators in this group of patients where their use may cause pulmonary edema in the setting of elevated left ventricular end-diastolic pressure.
      Most commonly used agents include nitric oxide (iNO) and inhaled prostacyclin analogs (iloprost and epoprostenol). Inhaled NO (iNO) works rapidly through activation of cGMP and thus relaxes pulmonary vasculature, resulting in a rapid decrease in PVR and mean pulmonary artery pressure (mPAP) without systemic vasodilation.
      • Ichinose F
      • Roberts Jr., JD
      • Zapol WM
      Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential.
      Those changes, along with maintenance of coronary perfusion pressure, can improve RV performance. It is deactivated immediately after binding to hemoglobin in red blood cells and therefore has no systemic effects. It can be delivered via endotracheal tube, mask, and high-flow nasal cannula in the doses of 10 to 40 ppm. Higher doses increase risk of methemoglobinemia. Inhaled prostanoids are generally less expensive than iNO but can be more cumbersome to administer. Inhaled nitric oxide and epoprostenol are administered continuously whereas iloprost is dosed intermittently. Rebound PH following abrupt discontinuation of both agents has been described and can be mitigated by re-initiation of the medication with a slower down-titration.
      • Augoustides JG
      • Ochroch EA
      Pro: inhaled prostaglandin as a pulmonary vasodilator instead of nitric oxide.
      Sildenafil has also been used to help facilitate weaning of iNO without rebound PH.
      • Atz AM
      • Wessel DL
      Sildenafil ameliorates effects of inhaled nitric oxide withdrawal.
      ,
      • Namachivayam P
      • Theilen U
      • Butt WW
      • Cooper SM
      • Penny DJ
      • Shekerdemian LS
      Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children.
      Given that sildenafil does have some systemic effects, caution should be exercised when using in patients on vasopressors.
      The initiation or addition of PAH-specific therapies peri- and postoperatively intended for long-term use should be guided by a PH specialist. Vasodilator therapies started perioperatively should also slowly be transitioned to the baseline regimen or continued based on clinical practice guidelines for PH prior to discharge.

      Combined systemic and pulmonary vasodilators

      Combined systemic and pulmonary vasodilators including intravenous nitroprusside, nitroglycerin and nesiritide are reserved for patients with PH in acutely decompensated HF. All 3 medications can be quite effective at reducing PAP and PVR as well as increasing CO when the LV filling pressure is high.
      • Price LC
      • Wort SJ
      • Finney SJ
      • Marino PS
      • Brett SJ
      Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review.
      These agents typically work by decreasing SVR and increasing venous capacitance, thus reducing hydrostatic and reactive vasoconstrictive component of PH. They typically cause a significant decrease in SVR and LV filling pressure, and thus should not be used in patients with systemic hypotension or pre-capillary PH. Methemoglobinemia and/or cyanide are potential toxicities associated with the (prolonged) use of IV nitroglycerin or nitroprusside, respectively.
      Inhaled nitroglycerin can be administered through continuous nebulization due to its short half-life, however, it appears to be less effective than 100% oxygen, inhaled milrinone, and iloprost.
      • Singh R
      • Choudhury M
      • Saxena A
      • Kapoor PM
      • Juneja R
      • Kiran U
      Inhaled nitroglycerin versus inhaled milrinone in children with congenital heart disease suffering from pulmonary artery hypertension.
      ,
      • Yurtseven N
      • Karaca P
      • Uysal G
      • et al.
      A comparison of the acute hemodynamic effects of inhaled nitroglycerin and iloprost in patients with pulmonary hypertension undergoing mitral valve surgery.

      Combination therapy

      Combination therapy approaches with agents of different classes intuitively makes sense. There have been a number of small studies and case reports combining various agents that demonstrated additive benefits. Potentially effective combinations include an inhaled medication such as iNO, iloprost or epoprostenol, and an oral sildenafil or parenteral/oral prostanoid.
      • Matamis D
      • Pampori S
      • Papathanasiou A
      • et al.
      Inhaled NO and sildenafil combination in cardiac surgery patients with out-of-proportion pulmonary hypertension: acute effects on postoperative gas exchange and hemodynamics.
      ,
      • Vater Y
      • Martay K
      • Dembo G
      • Bowdle TA
      • Weinbroum AA
      Intraoperative epoprostenol and nitric oxide for severe pulmonary hypertension during orthotopic liver transplantation: a case report and review of the literature.
      Another approach is to combine 2 inhaled pulmonary vasodilators that work on different pathways to enhance pulmonary specificity without systemic side effects.
      • Flondor M
      • Merkel M
      • Hofstetter C
      • Irlbeck M
      • Frey L
      • Zwissler B
      The effect of inhaled nitric oxide and inhaled iloprost on hypoxaemia in a patient with pulmonary hypertension after pulmonary thrombarterectomy.
      • Haraldsson s A
      • Kieler-Jensen N
      • Ricksten SE
      The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.
      • Rocca GD
      • Coccia C
      • Pompei L
      • et al.
      Hemodynamic and oxygenation changes of combined therapy with inhaled nitric oxide and inhaled aerosolized prostacyclin.

      Vasodilator choice based on clinical PH phenotype

      Groups 1 and 4 PH

      2014 ACC/AHA Guidelines recommend continuation of chronic pulmonary vascular targeted therapy (i.e., phosphodiesterase type 5 inhibitors [PDE5I], soluble guanylate cyclase stimulators, endothelin receptor antagonists [ERA], and prostanoids) in patients with PAH (unless contraindicated or not tolerated) in patients with PH who are undergoing surgery.
      • Fleisher LA
      • Fleischmann KE
      • Auerbach AD
      • et al.
      2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American college of cardiology/American heart association task force on practice guidelines.
      Unlike other oral medications, in patients unable to take medications by mouth, sildenafil can be given either intravenously or via NG/OG tube. Bosentan is the only ERA that can be crushed and given through a NG/OG tube but there is no IV formulation. Patients on oral prostanoids such as treprostinil or selexipag unable to take medications by mouth may need to be converted to intravenous/inhaled pulmonary vasodilator. Inhaled treprostinil should be switched to another inhaled agent in a patient who cannot self-administer the medication.

      Group 2 PH

      As PAH specific ERA and prostanoid therapies may worsen left heart failure and pulmonary venous hypertension, the initial treatment should be directed at optimizing heart failure management. This may include the use of IV systemic vasodilators (IV nitroglycerin, nitroprusside, nesiritide). Inhaled pulmonary vasodilators may be preferred, as they may have preferential vasodilation in well-ventilated lung zones and are less likely to have effects on systemic blood pressure. At present, there is insufficient data (limited to small case series) to support the use of inhaled prostanoids, inhaled nitroglycerin, inhaled/IV milrinone/levosimendan, as well as sildenafil, in the routine perioperative care of patients with group 2 PH. If “off label” pulmonary vasodilator therapy is utilized in Group 2 PH (e.g., PH is severe and/or RVF is predominant), they should be used with caution, and patients’ volume status should be optimized. They should be monitored for development of pulmonary edema or systemic hypotension.

      Group 3 PH

      Systemically administered pulmonary vasodilators can worse hypoxemia via V/Q mismatching and are not recommended. Based on the small series, inhaled therapies appear to be safe. The recent INCREASE trial of inhaled treprostinil for PH related to ILD demonstrated that it is effective at increasing 6 minute walk distance, decreasing NT-pro BNP levels and improving time to clinical worsening compared to placebo.
      • Waxman A
      • Restrepo-Jaramillo R
      • Thenappan T
      • et al.
      Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease.
      Under current regulations, inhaled treprostinil via an iNEB device can only be started in the outpatient setting. A combination of inhaled prostanoids with IV milrinone, IV levosimendan or PO/IV sildenafil can be considered in the presence of significantly reduced CI, particularly with severe PH and RV dysfunction, with careful attention to systemic blood pressure and oxygen saturation.

      Group 5 PH

      PH in patients with Group 5 PH should be dictated by their underlying pathophysiology and volume status. For example, patients with sarcoidosis without left ventricular dysfunction and predominantly parenchymal lung disease would be approached as Group 3 PH patients. On the contrary, patients with end-stage renal disease and fluid overload should be treated as Group 2 PH patients. As noted previously, cautious consideration of off-label pulmonary vasodilator therapies should be reserved for patients with more severe PH and RV dysfunction, and when they are used, patients should be closely monitored for the development of pulmonary edema, hypoxemia, and/or hypotension.

      Management of complications

      The incidence of different postoperative complications among patients with PH is poorly known. Postoperative complications such as atrial tachyarrhythmias, infection/sepsis, bleeding, and thromboembolic events can precipitate hemodynamic instability and increase the risk of RVF and death and should be promptly identified and treated.

      Arrhythmias

      Atrial tachyarrhythmias (e.g., atrial fibrillation and flutter) are associated with RVF and death in patients with PH.
      • Olsson KM
      • Nickel NP
      • Tongers J
      • Hoeper MM
      Atrial flutter and fibrillation in patients with pulmonary hypertension.
      For this reason, restoration of sinus rhythm is recommended for patients with PH and postoperative atrial arrhythmias. Amiodarone is the safest pharmacotherapy to restore sinus rhythm (with or without electrical cardioversion) in most cases. In patients with PAH and RV dysfunction, beta-blockers should generally be avoided, as they are poorly tolerated in these patients due to their negative inotropic effect on the RV.
      • Peacock A
      • Ross K
      Pulmonary hypertension: a contraindication to the use of {beta}-adrenoceptor blocking agents.
      Likewise, the calcium channel blocker verapamil should be avoided because of its negative inotropic and vasodilatory effects than can precipitate systemic hypotension. Digoxin should be considered for rate control.
      • Olsson KM
      • Nickel NP
      • Tongers J
      • Hoeper MM
      Atrial flutter and fibrillation in patients with pulmonary hypertension.

      Infection and sepsis

      Infection and sepsis are poorly tolerated in patients with poor RV reserve. Systemic hypotension from sepsis may precipitate hemodynamic collapse by decreasing coronary perfusion and promoting RV ischemia, RV-PA uncoupling, and ventricular interdependence leading to inadequate LV preload and CO. Vigilant monitoring for symptoms and signs of postoperative infection and early treatment are recommended. The risk vs benefit of invasive lines and Foley catheters should be reassessed on a daily basis and removed as soon as they are not needed.

      Bleeding and anemia

      Bleeding and severe anemia may be poorly tolerated and lead to hemodynamic instability in patients with PH due to a reduction in preload and increased myocardial oxygen demand. Moreover, multiple transfusions can lead to RV volume overload and acute RVF. Dosing of an IV diuretic between transfusion units may help control intravascular volume and maintain goal CVP.

      Mechanical circulatory support

      Despite careful preoperative planning, intra- or postoperative decompensation can still occur, typically in patients with more advanced cardiopulmonary disease. In the postoperative period, when decompensated RV failure persists despite maximal medical interventions (e.g., circulatory failure not improving despite 2 or more inopressors and/or respiratory failure at/near maximal support) mechanical support may be needed. Indications for mechanical support in patients with PAH remain a subject of debate. Mechanical support as a bridge to lung or heart/lung transplantation is the indication most supported by the literature. Other indications require a careful discussion of the risks and benefits of mechanical support between the patient, their family and the medical team. Such relative indications include patients who have a reversible cause of decompensation with reasonable chance of recovery, as may be the case in postoperative acute on chronic RV failure. Because failure to wean from mechanical support is a significant risk, mechanical support is contraindicated in patients without a reasonable chance of recovery or without the option of transplantation.
      Extra-corporeal membrane oxygenation (ECMO) is currently the preferred method of mechanical support for decompensated patients with PAH who have not responded to medical therapy. Because of the failure of the right ventricle, an arteriovenous configuration is preferred to a venovenous (V-V) configuration in the majority of patients. The arteriovenous (V-A) configuration allows an immediate “unloading” of the right ventricle. In most situations, because of the emergent requirement for cannulation, a femoral-femoral approach is utilized. However, centers have reported cases involving utilization of an upper extremity configuration in PAH patients that allows mobility during the convalescent or transplant waiting period.
      • Abrams DC
      • Brodie D
      • Rosenzweig EB
      • Burkart KM
      • Agerstrand CL
      • Bacchetta MD
      Upper-body extracorporeal membrane oxygenation as a strategy in decompensated pulmonary arterial hypertension.
      Finally, in patients with a large patent foramen ovale or an atrial septal defect, utilization of a bi-caval dual lumen catheter in the internal jugular vein with directed oxygenated return across the interatrial defect has been described. This configuration has been reported as a way of achieving systemic mechanical support while preserving the advantages of venous cannulation.
      • Rosenzweig EB
      • Brodie D
      • Abrams DC
      • Agerstrand CL
      • Bacchetta M
      Extracorporeal membrane oxygenation as a novel bridging strategy for acute right heart failure in group 1 pulmonary arterial hypertension.
      Preserving mobility is of particular concern when mechanical support is being used as a bridge to transplantation. The settings of and monitoring of PAH patients while on mechanical support is similar to patients who utilized ECMO for other indications. If the V-A femoral-femoral approach is used, careful monitoring of upper body vs lower body oxygenation should be performed. Assurance of adequate brain and cardiac oxygenation should be monitored with right radial artery partial pressure of oxygen and venous troponin measurements, respectively. ECMO flows of 2.5 to 4 liter/min are appropriate for PAH patients who have been accustomed to lower cardiac outputs. This flow rate is enough to allow unloading of the right ventricle, preservation of pulmonary blood flow and adequate systemic oxygen delivery while avoiding overload of the left heart that may have secondary dysfunction in patients with severe RV failure.
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      ,
      • Avriel A
      • Klement AH
      • Johnson SR
      • de Perrot M
      • Granton J
      Impact of left ventricular diastolic dysfunction on lung transplantation outcome in patients with pulmonary arterial hypertension.
      A retained PAC can confirm achievement of these goals.
      Pulmonary artery-left atrium oxygenators, or lung-assist devices, are also available for mechanical support of PAH patients. These pumpless devices utilize the patient's right ventricle but decrease the afterload on the right ventricle by bypassing the pulmonary circulation. An advantage of this approach is that it is an upper configuration that, again, allows ambulation of the patient. One disadvantage is that the cannulation itself is a more involved surgical procedure with a median sternotomy or thoracotomy and is therefore less practical in a patient with cardiogenic shock.
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      ,
      • Strueber M
      • Hoeper MM
      • Fischer S
      • et al.
      Bridge to thoracic organ transplantation in patients with pulmonary arterial hypertension using a pumpless lung assist device.
      RV assist devices have been attempted in patients with RV failure due to PAH, with disappointing results published in case reports. Complications such as increased pulmonary pressures with the increased flow, hemorrhage and pulmonary edema have been reported. Although some of the complications may be mitigated by using lower flows with the device, ECMO or extra-corporeal lung support remain the preferred mechanical devices in patient with PAH.
      • Punnoose L
      • Burkhoff D
      • Rich S
      • Horn EM
      Right ventricular assist device in end-stage pulmonary arterial hypertension: insights from a computational model of the cardiovascular system.
      ,
      • Rosenzweig EB
      • Chicotka S
      • Bacchetta M
      Right ventricular assist device use in ventricular failure due to pulmonary arterial hypertension: lessons learned.
      In summary, mechanical support may be utilized in the PAH patient who develops decompensated, refractory RV failure in the postoperative setting but careful consideration of overall prognosis, likelihood of recovery and candidacy for transplantation should be undertaken antecedently.

      Role of palliative care in patients with PH undergoing surgery

      With increased risk of intraoperative and postoperative morbidity for patients with PH, a high degree of complex care coordination and uncertainty regarding outcomes, proactively addressing concerns can be difficult. In these situations, consultation with specialty palliative care (PC) for patients with PH undergoing surgery may be a useful adjunctive approach to aggressive, life-prolonging therapy. In addition to having basic discussions regarding prognosis, goals of treatment, suffering and resuscitation preference, PC consultation is particularly important prior to major surgical interventions in patients with PH where they can be expected to have a period of incapacity during recovery. While many patients place highest priority on cure, prolonged survival, improved function and quality of life, and independence; others may prioritize comfort, achieving specific life goals, and obtaining support for caregivers as equally or more important. PC can work to assist PH specialists and patients in determining the optimal patient-centered care plan based on the patient's goals and preferences.
      Additionally, if patients with PH develop life-threatening postoperative complications and fail to respond to maximal therapy, PC can help with end of life discussions including transitioning goals of care to comfort measures or hospice care.

      Key Points

      Tabled 1
      1. Frequent postoperative evaluations should be performed in the patient with PH and/or RVF in order to promptly identify and treat any triggers of acute decompensation.
      2. Patients at intermediate-to-high perioperative risk warrant being monitored initially in the ICU for 24 to 72 hours in most cases with providers experienced in managing PH. For low risk surgeries in patients with stable disease, several hours of monitoring in the post-anesthesia care unit may be sufficient.
      3. Patients on infused parenteral therapy should be monitored in a location staffed by providers and nurses experienced in the management of these complex medications, regardless of surgical risk.
      4. Duration of postoperative invasive hemodynamic monitoring must be individualized balancing the risk and benefits of an indwelling catheter.
      5. Fluid management must be monitored and adjusted with the goal to maintain near baseline preoperative values. A CVP of 5 to 12 mm Hg is an acceptable target for most patients.
      6. Norepinephrine or vasopressin are recommended as first line agents for the treatment of systemic hypotension in patients with PH and RVF.
      7. Dobutamine is the first line inotrope for treating patients with PH and acutely decompensated RVF.
      8. Patients who belong to group 1 and 4 PH should continue their chronic pulmonary vascular targeted therapy during the postoperative period.
      9. In WHO Groups 2, 3, and 5 PH, systemically administered selective pulmonary vasodilator therapies may worsen left heart failure and/or worse hypoxemia and should be avoided.
      10. V-A ECMO is the preferred mode for a patient with PAH who requires mechanical circulatory support as bridge to recovery or transplantation. Consideration of overall prognosis, likelihood of recovery and candidacy for transplantation should be undertaken antecedently.
      11. Experts in palliative care should be involved to promote proactive, high quality goals of care conversations for high-risk PH patients in anticipation of surgery, and for discussions regarding transitioning goals of care to comfort measures or hospice care when appropriate.

      Gaps in Knowledge

      Tabled 1
      1. Studies comparing the effectiveness of various inopressors and vasodilators in the perioperative setting of PH patients undergoing surgery are needed.
      2. Future studies should clarify the relative effectiveness of different inhaled pulmonary vasodilators in the perioperative setting.
      3. More research is needed into the indications/contraindications and the optimal configuration of mechanical circulatory support in PAH patients to allow recovery while avoiding complications.

      Non-cardiac surgery procedures in patients with PH

      Perioperative mortality rates in published studies of patients with PH undergoing elective non-cardiac surgery range between 0% and 18%.
      • Meyer S
      • McLaughlin VV
      • Seyfarth H-J
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      ,
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      ,
      • Ammash NM
      • Connolly HM
      • Abel MD
      • Warnes CA
      Noncardiac surgery in Eisenmenger syndrome.
      • Deljou A
      • Sabov M
      • Kane GC
      • et al.
      Outcomes after noncardiac surgery for patients with pulmonary hypertension: a historical cohort study.
      • Smilowitz NR
      • Armanious A
      • Bangalore S
      • Ramakrishna H
      • Berger JS
      Cardiovascular outcomes of patients with pulmonary hypertension undergoing noncardiac surgery.
      • Memtsoudis SG
      • Ma Y
      • Chiu YL
      • Walz JM
      • Voswinckel R
      • Mazumdar M
      Perioperative mortality in patients with pulmonary hypertension undergoing major joint replacement.
      • Bennett JM
      • Ehrenfeld JM
      • Markham L
      • Eagle SS
      Anesthetic management and outcomes for patients with pulmonary hypertension and intracardiac shunts and Eisenmenger syndrome: a review of institutional experience.
      • Kim D
      • Jules-Elysee K
      • Turteltaub L
      • et al.
      Clinical outcomes in patients with pulmonary hypertension undergoing total hip arthroplasty.
      • Minai OA
      • Venkateshiah SB
      • Arroliga AC
      Surgical intervention in patients with moderate to severe pulmonary arterial hypertension.
      Study characteristics and outcomes of studies of PH undergoing NCS are compared in Table 11.
      • Meyer S
      • McLaughlin VV
      • Seyfarth H-J
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      ,
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      ,
      • Deljou A
      • Sabov M
      • Kane GC
      • et al.
      Outcomes after noncardiac surgery for patients with pulmonary hypertension: a historical cohort study.
      • Smilowitz NR
      • Armanious A
      • Bangalore S
      • Ramakrishna H
      • Berger JS
      Cardiovascular outcomes of patients with pulmonary hypertension undergoing noncardiac surgery.
      • Memtsoudis SG
      • Ma Y
      • Chiu YL
      • Walz JM
      • Voswinckel R
      • Mazumdar M
      Perioperative mortality in patients with pulmonary hypertension undergoing major joint replacement.
      • Bennett JM
      • Ehrenfeld JM
      • Markham L
      • Eagle SS
      Anesthetic management and outcomes for patients with pulmonary hypertension and intracardiac shunts and Eisenmenger syndrome: a review of institutional experience.
      • Kim D
      • Jules-Elysee K
      • Turteltaub L
      • et al.
      Clinical outcomes in patients with pulmonary hypertension undergoing total hip arthroplasty.
      • Minai OA
      • Venkateshiah SB
      • Arroliga AC
      Surgical intervention in patients with moderate to severe pulmonary arterial hypertension.
      An international, prospective study collected data from 114 patients with PAH undergoing non-cardiac and non-obstetric surgery.
      • Meyer S
      • McLaughlin VV
      • Seyfarth H-J
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      Major complications and perioperative mortality were observed in 6% and 3.5%, respectively, with the highest mortality (15%) occurring in patients requiring an emergency procedure. The following risk factors predicted major complications: (1) emergency surgery, (2) RAP > 7 mm Hg, (3) 6MWD ≤ 399 meters, and (4) perioperative vasopressor use.
      Table 11Studies of PH in Non-Cardiac Surgery
      Ramakrishna (2005) (n = 145)Minai (2006) (n = 21)Lai (2007) (n = 62)Price (2010) (n = 28)Memtshoudis (2010) (n = 3543)Kaw (2011) (n = 96)Meyer (2013) (n = 114)Kim (2014) (n = 115)Bennett (2014) (n = 33)Smilowitz (2019) (n = 143,846)Deljou (2020) (n = 196)
      Mortality7%18%9.7%7%2.4% all 5% PPH1%3.5%0%3.8%4.4% all 8.3% PAH3%
      Morbidity42%14%24%29%28%6.1%34.7%8.3% MACE27%
      Major surgery79%86%58%57%THA/TKA100%100%THA30%100%
      GA100%79%58%50%100%82%1%68%
      PH due to LHD includedNoNoYesNoYesYesNoYesNoYesNo
      Study type/ limitationsRS No control EchoRS No control Severe PAHRS Control EchoRS No control RHCRS NIS Dx codes MatchedRS Control RHCPS No control RHCRS Control Ortho EchoRS No control ESRS NIS Dx codes MatchedRS No control
      Dx, diagnosis; ES, Eisenmenger syndrome; MACE, major adverse cardiac events; NIS, US based national inpatient study; PPH, primary pulmonary hypertension; PS, prospective study; RS, retrospective study; THA, total hip arthroplasty; TKA, total knee arthroplasty.
      In addition to the general perioperative recommendations outlined earlier, certain surgical procedures present additional challenges for PH patients. This section provides an overview of the perioperative implications for patients with PH undergoing specific non-cardiac surgery procedures.

      Thoracic surgery

      No rigorous clinical trials specifically address perioperative care across the spectrum of PH in non-cardiac thoracic surgery. Published case reports and invited commentary suggest the greatest experience has been with patients undergoing lung biopsy or transplantation, with anatomic resections (segmentectomy, lobectomy) less common.
      • Heller AR
      • Litz RJ
      • Koch T
      A fine balance–one-lung ventilation in a patient with Eisenmenger syndrome.
      ,
      • Ichinokawa M
      • Hida Y
      • Kaga K
      • Kawada M
      • Niizeki H
      • Kondo S
      A case of primary pulmonary hypertension with pulmonary tumor.
      • Kreider ME
      • Hansen-Flaschen J
      • Ahmad NN
      • et al.
      Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease.
      • Ross AF
      • Ueda K
      Pulmonary hypertension in thoracic surgical patients.
      • Nonaka DF
      • Grichnik KP
      • Whitener GB
      Pulmonary hypertension and thoracic surgery: diagnostics and advances in therapy and intraoperative management.
      It should be noted that lung biopsy for diagnostic evaluation in patients with PH is not recommended due to the associated risk.
      A unique feature of many procedures in the chest is non-ventilation of lung in the operative field.
      • Huang A
      • Marseu K
      Pulmonary resection in the patient with pulmonary hypertension.
      In single lung ventilation (SLV), the goal is to optimize exposure by rendering lung in the operative field still and atelectatic. Minimally invasive thoracic surgical techniques involving video assistance and robotics are especially dependent upon SLV. SLV induces physiological perturbations related to increased airway pressure, impaired ventilation/perfusion matching, and re-expansion/reperfusion that can alter mechanical coupling between the RV and pulmonary circulation.
      • McGlothlin D
      • Ivascu N
      • Heerdt PM
      Anesthesia and pulmonary hypertension.
      ,
      • Jung DM
      • Ahn HJ
      • Jung SH
      • et al.
      Apneic oxygen insufflation decreases the incidence of hypoxemia during one-lung ventilation in open and thoracoscopic pulmonary lobectomy: a randomized controlled trial.
      ,
      • Lohser J
      • Slinger P
      Lung injury after one-lung ventilation: a review of the pathophysiologic mechanisms affecting the ventilated and the collapsed lung.
      Overdistention or de-recruitment of the ventilated lung will augment the increased RV afterload imposed by extensive HPV in the non-ventilated lung.
      • Jung DM
      • Ahn HJ
      • Jung SH
      • et al.
      Apneic oxygen insufflation decreases the incidence of hypoxemia during one-lung ventilation in open and thoracoscopic pulmonary lobectomy: a randomized controlled trial.
      Multiple lines of evidence demonstrate that when hypoxic or ischemic lung is re-expanded with oxygen, a marked oxidative stress response is elicited that can affect distant organs and persist postoperatively,
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      and the potential sequelae include exacerbation of PH and arrhythmias.
      • Heerdt PM
      • Stowe DF
      Single-lung ventilation and oxidative stress: a different perspective on a common practice.
      Atrial tachyarrhythmias are relatively common following thoracic surgery and may be poorly tolerated. Pulmonary arterial pressure and PVR may not return to baseline, particularly if the procedure involved vascular ligation and anatomic lung resection.
      • Misthos P
      • Katsaragakis S
      • Theodorou D
      • Milingos N
      • Skottis I
      The degree of oxidative stress is associated with major adverse effects after lung resection: a prospective study.
      Finally, patients with PH requiring SLV include the spectrum of etiology including ILD with restrictive lung mechanics, and in this context the relative risks of acute changes in RV afterload during SLV and postoperative lung injury and residual function should be considered. For these reasons, the risk of thoracic surgery with SLV is very high in patients with significant PH, particularly those with parenchymal lung disease or PAH, and therefore should generally be avoided.

      Laparoscopic abdominal surgery

      Laparoscopy can have deleterious effects on RV hemodynamics and potentially increased risk of complications in PH patients. Insufflation of the abdomen with CO2 can cause diaphragmatic displacement and an increase in inspiratory airway pressures, altering RV preload and afterload. Increased positive end expiratory pressure, often required to counteract increased intrathoracic pressures while mechanically ventilating patients with pneumoperitoneum, can increase PVR. In addition, mesenteric and aortic circulations may be compressed, causing increased LV afterload, increased pulmonary capillary wedge pressure and systemic hypotension
      • Alfonsi P
      • Vieillard-Baron A
      • Coggia M
      • et al.
      Cardiac function during intraperitoneal CO2 insufflation for aortic surgery: a transesophageal echocardiographic study.
      The carbon dioxide insufflated in the abdomen, can lead to systemic hypercarbia, which, in turn, can increase PVR and RV afterload. Data also suggests that the increase in PA pressures during laparoscopy may not reverse immediately or completely when the pneumoperitoneum is relieved.
      • Joris JL
      • Noirot DP
      • Legrand MJ
      • Jacquet NJ
      • Lamy ML
      Hemodynamic changes during laparoscopic cholecystectomy.
      • Harris SN
      • Ballantyne GH
      • Luther MA
      • Perrino Jr, AC
      Alterations of cardiovascular performance during laparoscopic colectomy: a combined hemodynamic and echocardiographic analysis.
      • Lestar M
      • Gunnarsson L
      • Lagerstrand L
      • Wiklund P
      • Odeberg-Wernerman S
      Hemodynamic perturbations during robot-assisted laparoscopic radical prostatectomy in 45 degrees Trendelenburg position.
      Delayed hypercapnia, often seen postoperatively from the carbon dioxide absorbed from subcutaneous emphysema occurring during laparoscopic procedures may also adversely influence cardiac function.
      Another consideration with laparoscopic surgery is the effect of positioning. Laparoscopic surgery is often performed in head-up or head-down position to allow intraabdominal organs to fall away from the surgical field. These positions can affect RV loading conditions and cardiovascular function. Head-up position (reverse Trendelenburg) leads to venous pooling, can reduce venous return to the heart and can result in hypotension, especially in hypovolemic patients.
      • Meyer S
      • McLaughlin VV
      • Seyfarth HJ
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      ,
      • Hirvonen EA
      • Poikolainen EO
      • Paakkonen ME
      • Nuutinen LS
      The adverse hemodynamic effects of anesthesia, head-up tilt, and carbon dioxide pneumoperitoneum during laparoscopic cholecystectomy.
      Head-down position (Trendelenburg) increases venous return and cardiac filling pressures.
      • Perilli V
      • Sollazzi L
      • Bozza P
      • et al.
      The effects of the reverse trendelenburg position on respiratory mechanics and blood gases in morbidly obese patients during bariatric surgery.
      CVP, mPAP, and pulmonary capillary wedge pressure (PCWP) increase 2-to-3-fold, and mean systolic blood pressure by ∼1/3, without changes in CO, heart rate, or SV. Although these filling pressures usually normalize upon repositioning the changes in venous return may be poorly tolerated by patients with PH. Thus, the benefits of laparoscopic surgery (i.e., less bleeding and pain) may be outweighed by its risks, and open laparotomy should be considered in patients with PAH and RV dysfunction. Some centers advocate for open laparotomy and avoidance of laparoscopy in all patients with PAH, and in other centers, laparoscopic surgery may be planned with early conversion to open laparotomy in the occurrence of any adverse intraoperative hemodynamic changes during laparoscopy.

      Orthopedic surgery

      Orthopedic surgery offers the option to consider procedures under regional anesthesia. However, it also offers specific challenges, such as high risk for intraoperative cement or fat embolizing to the already compromised pulmonary circulation,
      • Christie J
      • Robinson CM
      • Pell AC
      • McBirnie J
      • Burnett R
      Transcardiac echocardiography during invasive intramedullary procedures.
      • Eriksson EA
      • Pellegrini DC
      • Vanderkolk WE
      • Minshall CT
      • Fakhry SM
      • Cohle SD
      Incidence of pulmonary fat embolism at autopsy: an undiagnosed epidemic.
      • Rothberg DL
      • Makarewich CA
      Fat embolism and fat embolism syndrome.
      in addition to postoperative risk of pulmonary thromboembolism, which increases the risk for patients with PH. In a large case matched, retrospective study, patients with PH undergoing THA experienced an approximately 4-fold increased risk adjusted mortality (2.4% vs 0.6%), and those undergoing TKA had a 4.5-fold increased adjusted risk of mortality (0.9% vs 0.2%) compared with patients without PH in the matched sample (p < 0.001 for each comparison).
      • Memtsoudis SG
      • Ma Y
      • Chiu YL
      • Walz JM
      • Voswinckel R
      • Mazumdar M
      Perioperative mortality in patients with pulmonary hypertension undergoing major joint replacement.
      The risk of fat embolism may be reduced with newer surgical approaches, such as early fracture stabilization in trauma, or alternative cementation techniques.
      • Rothberg DL
      • Makarewich CA
      Fat embolism and fat embolism syndrome.
      however we recommend that patients with moderate to severe PH and significant RV dysfunction not undergo elective total joint replacement, with few exceptions. Patients with PH who do undergo joint replacement surgery should receive the usual prophylactic drugs (low-molecular weight heparin, direct anticoagulants).
      • Lieberman JR
      • Cheng V
      • Cote MP
      Pulmonary embolism rates following total hip arthroplasty with prophylactic anticoagulation: some pulmonary emboli cannot be avoided.

      Obstetric surgery

      Pregnancy is a particularly vulnerable time for patients with PH. Generally, the pulmonary vasculature is maximally dilated and recruited in patients with PH, thus the increase in CO that normally occurs in pregnancy cannot be accommodated by these normal physiologic mechanisms and right heart failure, may be precipitated or exacerbated, if already present.
      Pregnancy outcomes in patients with PAH have been poor for both the mother and the fetus.
      • Duarte AG
      • Thomas S
      • Safdar Z
      • et al.
      Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience.
      • Curry RA
      • Fletcher C
      • Gelson E
      • et al.
      Pulmonary hypertension and pregnancy–a review of 12 pregnancies in nine women.
      • Ma L
      • Liu W
      • Huang Y
      Perioperative management for parturients with pulmonary hypertension: experience with 30 consecutive cases.
      • Rosengarten D
      • Blieden LC
      • Kramer MR
      Pregnancy outcomes in pulmonary arterial hypertension in the modern management era.
      • Kiely DG
      • Condliffe R
      • Webster V
      • et al.
      Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach.
      • Bendayan D
      • Hod M
      • Oron G
      • et al.
      Pregnancy outcome in patients with pulmonary arterial hypertension receiving prostacyclin therapy.
      and recent literature has suggested a potentially elevated mortality among patients with other PH etiologies.
      • Sun X
      • Feng J
      • Shi J
      Pregnancy and pulmonary hypertension: an exploratory analysis of risk factors and outcomes.
      • Sliwa K
      • van Hagen IM
      • Budts W
      • et al.
      Pulmonary hypertension and pregnancy outcomes: data from the registry of pregnancy and cardiac disease (ROPAC) of the European society of cardiology.
      • Thomas E
      • Yang J
      • Xu J
      • Lima FV
      • Stergiopoulos K
      Pulmonary hypertension and pregnancy outcomes: insights from the national inpatient sample.
      In the era of PAH-directed therapy a multinational report of 20 pregnancies reported 4 deaths.
      • Jais X
      • Olsson KM
      • Barbera JA
      • et al.
      Pregnancy outcomes in pulmonary arterial hypertension in the modern management era.
      However, a more recent prospective cohort of 16 patients and 25 pregnancies where an individualized, risk-based approach with shared decision making and a multiprofessional team experienced in managing PAH and pregnancy was used, reported no maternal deaths during pregnancy and no maternal or fetal deaths in all of the 13 patients and 18 offspring.
      • Kamp JC
      • von Kaisenberg C
      • Greve S
      • et al.
      Pregnancy in pulmonary arterial hypertension: midterm outcomes of mothers and offspring.
      However, 8 pregnancies ended in abortion, 2 patients required ECMO as bridge to lung transplantation, and 6 patients showed signs of clinical worsening within 9 to 22 months after successful delivery.
      There is a general consensus that pregnancy should be avoided in patients with PAH, and likely PH more broadly.
      • Hemnes AR
      • Kiely DG
      • Cockrill BA
      • et al.
      Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute.
      However, for cultural or personal reasons, patients may desire to conceive or continue a pregnancy regardless of risk to themselves or the fetus. Recognizing that there is scant literature to guide recommendations about obstetric surgery in PAH patients and even less for patients with other etiologies of PH, the following summarizes consensus recommendations from experts in the field.
      • Hemnes AR
      • Kiely DG
      • Cockrill BA
      • et al.
      Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute.
      In addition to these recommendations, there is a strong recommendation for care to occur at a center expert in care of pregnant PH patients and for involvement of a multi-disciplinary team to plan delivery including high risk obstetrics, anesthesia with experience in PH and neonatology. A risk based approach to counseling and managing patients has been proposed. Ideally this should involve maximizing medical treatments inclusive of the involvement of an interprofessional team before a woman elects to become pregnant.
      Caesarean section is typically recommended as the preferred mode of delivery in the context of PH and pregnancy.
      • Hemnes AR
      • Kiely DG
      • Cockrill BA
      • et al.
      Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute.
      In general, it is felt that vaginal delivery carries more relative risks including Valsalva maneuver, which decreases venous return and may compromise CO, vasovagal syncope, sympathetic nervous stimulation, acid-base changes that may worsen PH and autotransfusion of blood after delivery of fetus that can precipitate acute RVF. Elective Caesarean section potentially allows for avoiding most of these risks, and also facilitates ready availability of the multidisciplinary team to assist in the delivery. Regional anesthesia is generally recommended to avoid risks associated with GA, which is supported by data from Bedard et al showing higher mortality with GA in delivery of the pregnant PH patient.
      • Bedard E
      • Dimopoulos K
      • Gatzoulis MA
      Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension?.
      Recent publications support epidural, spinal and combine spinal-epidural anesthesia in pregnant PH patients, suggesting that the experience of the anesthesiologist should play a key role in selection of method.
      • Duggan AB
      • Katz SG
      Combined spinal and epidural anaesthesia for caesarean section in a parturient with severe primary pulmonary hypertension.
      In a recent prospective cohort, all 13 patients successfully delivered 17 offspring via Caesarean section without any perioperative deaths, however 1 patient required ECMO support within a few hours after delivery.
      • Kamp JC
      • von Kaisenberg C
      • Greve S
      • et al.
      Pregnancy in pulmonary arterial hypertension: midterm outcomes of mothers and offspring.
      There are several considerations with regard to anesthesia during the delivery. Continuous monitoring of ECG, pulse oximetry, CVP and intraarterial blood pressure is recommended universally.
      • Hemnes AR
      • Kiely DG
      • Cockrill BA
      • et al.
      Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute.
      The use of PAC during delivery is not considered mandatory and CVP monitoring with echocardiography is an alternative hemodynamic monitoring route that some centers prefer. Patients should be euvolemic to optimize RV function and IV fluids administered judiciously to avoid worsening RV function. Inotropes and vasopressors may be required to support RV function and should thus be available at the bedside. Finally, in patients with significant RV dysfunction, the multidisciplinary team may consider use of ECMO or ensuring it's availability as a reserve measure.
      Therapy for PAH, in particular, should be optimized predelivery to the extent possible. As prostacyclins (epoprostenol, treprostinil, iloprost), calcium channel blockers (for those patients that have demonstrable acute vasodilatory response), and PDE5Is are the only medications generally considered safe in pregnancy, the choices are limited.
      • Hemnes AR
      • Kiely DG
      • Cockrill BA
      • et al.
      Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute.
      In patients with significant RV dysfunction, prostacyclin therapy is indicated. Some institutions have used inhaled prostacyclins more frequently, while others generally prefer parenteral prostacyclins. At the time of delivery, inhaled and/or parenteral prostacyclins should be available, if not already in use.
      The post-partum period is a high risk period for PAH patients, with the majority of mortality in some reports occurring in the month following delivery.
      • Rosengarten D
      • Blieden LC
      • Kramer MR
      Pregnancy outcomes in pulmonary arterial hypertension in the modern management era.
      Monitoring in the ICU for at least 48 hours post-partum to manage fluid shifts with efforts to ensure that the patient is kept in a net negative daily fluid balance to mitigate the adverse influence of the mobilization of the extravascular fluid into the intravascular space on RV function.
      • Hemnes AR
      • Kiely DG
      • Cockrill BA
      • et al.
      Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute.
      This is especially relevant for high-risk patients. Routine obstetric care, including prophylactic anticoagulation, is also recommended.

      Gynecologic non-obstetric surgery (GNOS)

      There is a paucity of data regarding operative and perioperative management of patients with PH undergoing GNOS with most literature limited to case reports
      • Myles PS
      Anaesthetic management for laparoscopic sterilisation and termination of pregnancy in a patient with severe primary pulmonary hypertension.
      • Rodriguez RM
      • Pearl RG
      Pulmonary hypertension and major surgery.
      • Foresman RN
      • Connors CW
      Severe pulmonary hypertension and right ventricular failure complicate a total abdominal hysterectomy.
      and small case series.
      • Lai HC
      • Lai HC
      • Wang KY
      • Lee WL
      • Ting CT
      • Liu TJ
      Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.
      • Price LC
      • Montani D
      • Jais X
      • et al.
      Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension.
      • Kaw R
      • Pasupuleti V
      • Deshpande A
      • Hamieh T
      • Walker E
      • Minai OA
      Pulmonary hypertension: an important predictor of outcomes in patients undergoing non-cardiac surgery.
      • Ramakrishna G
      • Sprung J
      • Ravi BS
      • Chandrasekaran K
      • McGoon MD
      Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.
      • Meyer S
      • McLaughlin VV
      • Seyfarth HJ
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      ,
      • Minai OA
      • Venkateshiah SB
      • Arroliga AC
      Surgical intervention in patients with moderate to severe pulmonary arterial hypertension.
      A contemporary international survey of outcomes in patients with PAH undergoing non-cardiac surgery showed an overall 3.5% mortality and 6.1% morbidity rate; this study included 16% (n = 18) gynecologic procedures which had lower mortality (0%) but comparable morbidity (5.5%) rates.
      • Meyer S
      • McLaughlin VV
      • Seyfarth HJ
      • et al.
      Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
      Many gynecologic procedures are considered low (cone biopsy) to intermediate (hysterectomy) risk. Procedures with potential for large-volume blood loss (hysterectomy of large fibroid uterus) and extensive fluid shifts (laparotomy for ovarian cancer with malignant ascites) are high-risk procedures for patients with PH.
      Lithotomy is the most commonly used position in GNOS and has the effect of redistributing blood volume from the legs centrally and increasing venous return. Vaginal hysterectomy often requires exaggerated “head-down” lithotomy which has been showed to increase PAP and PCWP and decrease CO in PH.
      • Bessa Junior RC
      • Silva Filho AL
      • Maia PV
      • Quites LO
      • Triginelli SA
      [Hemodynamic repercussions of exaggerated lithotomy position for vaginal hysterectomy in cardiac patient: case report.].
      Laparoscopy is frequently used in GNOS due to faster recovery and lower incidence of postoperative ileus
      • Holte K
      • Kehlet H
      Postoperative ileus: a preventable event.
      but is not without problems in patients with PH as described in the section on abdominal surgery.
      Existing data support the use of regional anesthesia over GA as with other types of general surgery.
      • Martin JT
      • Tautz TJ
      • Antognini JF
      Safety of regional anesthesia in Eisenmenger's syndrome.
      ,
      • Hsu CH
      • Gomberg-Maitland M
      • Glassner C
      • Chen JH
      The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients.
      Epidural anesthesia is generally preferred to spinal anesthesia because of more gradual onset and relatively less risk of systemic hypotension as discussed in the intraoperative management section. Recent studies have highlighted the benefits of combined low-dose spinal-epidural anesthesia (better sensory block with fewer blood pressure-lowering effects) in peripartum management of PAH
      • Hsu CH
      • Gomberg-Maitland M
      • Glassner C
      • Chen JH
      The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients.
      ,
      • Bonnin M
      • Mercier FJ
      • Sitbon O
      • et al.
      Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases.
      and can be used in GNOS. Central hemodynamic monitoring is indicated for patients with severe PH or those undergoing high-risk procedures.
      Epidural analgesia offers superior analgesia and decreased risk of hypercarbia due to opioid-related respiratory depression for pain control. Transversus abdominus plane blocks offers short term pain relief and reduces IV opioid use post hysterectomy
      • Champaneria R
      • Shah L
      • Geoghegan J
      • Gupta JK
      • Daniels JP
      Analgesic effectiveness of transversus abdominis plane blocks after hysterectomy: a meta-analysis.
      ; the successful use of a transversus abdominus plane block has been described in PH.

      Sterilization

      Due to poor maternal and fetal outcomes with pregnancy and the teratogenic effects of endothelin-receptor antagonists, all female patients of child-bearing age should be counseled on effective contraception (sterilization or 2 methods of birth control). Hysteroscopic sterilization has been shown to be well-tolerated in a case series of 4 patients with relatively advanced PAH
      • Nonaka DF
      • Grichnik KP
      • Whitener GB
      Pulmonary hypertension and thoracic surgery: diagnostics and advances in therapy and intraoperative management.