If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Université Paris–Saclay; INSERM UMR_S 999; Assistance Publique Hôpitaux de Paris Hôpital Bicêtre, Hôpital Marie Lannelongue, Le Plessis Robinson, France
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.
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
(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
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
Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
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.
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.
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.
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,
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.
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?
Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
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 4Preoperative multidisciplinary communications and planning: the core team.
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.
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
Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
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.
Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
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.
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.
Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: updated recommendations from the cologne consensus conference 2018.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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
Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic alpha- and beta-adrenoreceptor activation.
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
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.
Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation.
Anesth Analg.2007; 105 (table of contents): 1578-1584
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
Pulmonary vasodilator response to adenosine triphosphate-sensitive potassium channel activation is attenuated during desflurane but preserved during sevoflurane anesthesia compared with the conscious state.
Differential effects of isoflurane on regional right and left ventricular performances, and on coronary, systemic, and pulmonary hemodynamics in the dog.
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.
A two-center study evaluating the hemodynamic and pharmacodynamic effects of cisatracurium and vecuronium in patients undergoing coronary artery bypass surgery.
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.
Local anesthetic toxicity (LAST) is particularly devastating in this population, as symptoms include treatment-resistant myocardial depression, bradycardia, and hemodynamic collapse.
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.
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.
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.
– 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.
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.
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.
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 surgery
GA + high risk fluid shifts + mild-mod PH
GA + high risk fluid shifts + mod-severe PH
Neuraxial anesthesia + low risk fluid shifts
Neuraxial anesthesia + high risk fluid shifts or advanced PH/RVF
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.
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
; 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.
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.
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 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.
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,
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.
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.
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 catheter
Critical 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.
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.
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.
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.
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.
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.
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
Drug
Pharmacological properties
Beneficial hemodynamic effects
Side effects
Recommended doses
Clinical experience
Dobutamine
β1-adrenergic agonist
- increase in CO - decrease in PVR - improved V-A coupling
- decrease in SVR - tachycardia/arrhythmia (dose dependent)
2-10 µg/kg/min
Large clinical experience in acute PH decompensation
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
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.
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.
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.
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.
A comparison of the acute hemodynamic effects of inhaled nitroglycerin and iloprost in patients with pulmonary hypertension undergoing mitral valve surgery.
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.
Inhaled NO and sildenafil combination in cardiac surgery patients with out-of-proportion pulmonary hypertension: acute effects on postoperative gas exchange and hemodynamics.
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.
The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.
Anesth Analg.2001; 93 (table of contents): 1439-1445
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Anesthetic management and outcomes for patients with pulmonary hypertension and intracardiac shunts and Eisenmenger syndrome: a review of institutional experience.
Anesthetic management and outcomes for patients with pulmonary hypertension and intracardiac shunts and Eisenmenger syndrome: a review of institutional experience.
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)
Mortality
7%
18%
9.7%
7%
2.4% all 5% PPH
1%
3.5%
0%
3.8%
4.4% all 8.3% PAH
3%
Morbidity
42%
14%
24%
29%
–
28%
6.1%
34.7%
–
8.3% MACE
27%
Major surgery
79%
86%
58%
57%
THA/TKA
100%
100%
THA
30%
100%
GA
100%
79%
58%
50%
–
100%
82%
1%
68%
–
PH due to LHD included
No
No
Yes
No
Yes
Yes
No
Yes
No
Yes
No
Study type/ limitations
RS No control Echo
RS No control Severe PAH
RS Control Echo
RS No control RHC
RS NIS Dx codes Matched
RS Control RHC
PS No control RHC
RS Control Ortho Echo
RS No control ES
RS NIS Dx codes Matched
RS 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.
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.
Apneic oxygen insufflation decreases the incidence of hypoxemia during one-lung ventilation in open and thoracoscopic pulmonary lobectomy: a randomized controlled trial.
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,
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.
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
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.
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.
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,
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).
The risk of fat embolism may be reduced with newer surgical approaches, such as early fracture stabilization in trauma, or alternative cementation techniques.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
01992-1&id=gr1.jpg){kind=link}
01992-1&id=gr2.jpg){kind=link}
01992-1&id=gr3.jpg){kind=link}
01992-1&id=gr4.jpg){kind=link}
01992-1&id=gr5.jpg){kind=link}
01992-1&id=gr6.jpg){kind=link}
01992-1&id=gr7.jpg){kind=link}
01992-1&id=gr8.jpg){kind=link}
Not approved for use in North America, UK, or Australia.