Critical Care of Patients After Pulmonary Thromboendarterectomy

ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 117

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Review Article

Critical Care of Patients After Pulmonary Thromboendarterectomy 1

Wolf B. Kratzert, MD, PhD*, , Eva K. Boyd, MD*, Rajan Saggar, MDy, Richard Channick, MDy *

Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA y Department of Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA

Pulmonary thromboendarterectomy (PTE) remains the only curative surgery for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Postoperative intensive care unit care challenges providers with unique disease physiology, operative sequelae, and the potential for detrimental complications. Central concerns in patients with CTEPH immediately after PTE relate to neurologic, pulmonary, hemodynamic, and hematologic aspects. Institutional experience in critical care for the CTEPH population, a multidisciplinary team approach, patient risk assessment, and integration of current concepts in critical care determine outcomes after PTE surgery. In this review, the authors will focus on specific aspects unique to this population, with integration of current available evidence and future directions. The goal of this review is to provide the cardiac anesthesiologist and intensivist with a comprehensive understanding of postoperative physiology, potential complications, and contemporary intensive care unit management immediately after pulmonary endarterectomy. Ó 2019 Elsevier Inc. All rights reserved. Key Words: pulmonary endarterectomy; pulmonary thromboendarterectomy; chronic thromboembolic pulmonary hypertension; pulmonary hypertension; critical care; critically ill

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH) is a pulmonary vascular disease caused by chronic obstruction of pulmonary arteries and represents group 4 of the World Health Organization classification of pulmonary hypertension.1 It is defined as precapillary pulmonary hypertension with mean pulmonary artery pressure (PAPm)
25 mmHg and pulmonary arterial occlusion pressure  15 mmHg by right heart catheterization in the presence of organized flow-limiting thrombi or emboli in the pulmonary arteries after at least 3 months of therapeutic anticoagulation. The prevalence of CTEPH is estimated at 3 to 30 individuals per million per year, with an incidence after pulmonary embolus of up to 3%.2,3 When untreated, mortality is high with only 30% to 80% of patients surviving 3 years.4 Medical therapy remains unsatisfactory, and surgical pulmonary thromboendarterectomy (PTE) offers the only 1

Address reprint requests to Wolf B. Kratzert, MD, PhD, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, 757 Westwood Plz, Suite 3325, Los Angeles, CA 90095-7403. E-mail address: [email protected] (W.B. Kratzert). https://doi.org/10.1053/j.jvca.2019.03.005 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.

curative intervention. With evolving expertise, mortality rates are now less than 5% in highly specialized centers.5,6 The immediate postoperative course after PTE presents with several unique considerations for the intensivist. Preexisting pathophysiology and its sequelae, as well as intraoperative techniques, predispose these patients to specific postoperative complications and require expertise in their management. Although the field of critical care medicine continues to evolve, intensive care unit (ICU) management of patients undergoing PTE often follows historical strategies, is based on the general management of cardiac surgical patients, and relies on evidence taken from similar disease pathologies. In-depth understanding of pathophysiological mechanisms in the postoperative period remains sparse, and applying multidisciplinary knowledge and experience is vital to provide optimal ICU care. Pathophysiology and Clinical Manifestation Chronic thromboembolic pulmonary hypertension is a vascular disorder resulting in pathologic remodeling of the pulmonary

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arterial tree.7 Fibrotic transformation of chronic pulmonary arterial thrombus leads to obstruction of the pulmonary vasculature, and accompanying small vessel vasculopathy is caused by abnormal immunologic, inflammatory, and possibly infectious mechanisms. Although no specific genetic mutations have been identified, patients with CTEPH may have underlying autoimmune or hematologic disorders. Clinical signs are nonspecific or even absent, making early diagnosis difficult and resulting in a mean patient age at diagnosis of 63 years.8 Once present, symptoms resemble those of acute pulmonary embolus or pulmonary arterial hypertension, with signs of right heart failure indicating advanced disease. Specific diagnosis is made by ventilation/perfusion (V/Q) scintigraphy,9 and preoperative workup includes echocardiography, right heart catheterization, computed tomography imaging, and angiography.10 Although the use of the Jamieson surgical classification is currently standard in the evaluation for operability and outcome assessment,11 Jenkins and Madani et al. recently have proposed a new classification based on disease location (Table 1).6

and the decrease in pulmonary vascular resistance (PVR) and right ventricular workload with pulmonary vasodilators. Currently, most patients are started on lifelong warfarin with an international normalized ratio (INR) goal of 2 to 3. A number of pulmonary arterial hypertension-targeted therapies, including phosphodiesterase inhibitors, prostacyclins, and endothelin receptor antagonists, have been used in the management of patients with CTEPH.13 Although many of these therapies demonstrated improvement in pulmonary hemodynamics, to date only riociguat, a soluble guanylate cyclase stimulator, has shown statistically significant improvement in functional capacity and is approved for medical treatment of CTEPH.14 Interventional Strategies Balloon pulmonary angioplasty has been shown to improve hemodynamics and functional status in patients before PEA, in those ineligible for PEA, and in those for whom pulmonary hypertension persists after surgical intervention.15 Long-term outcomes are still unknown, but several randomized controlled trials in North America and Europe currently are comparing BPA and medical treatment. The most common complications of BPA are pulmonary vascular injury and reperfusion pulmonary edema.16 The use of ECMO as a bridge to surgical intervention has been described for the patient with significant hemodynamic decompensation but represents a significantly more invasive temporary intervention than BPA and comes with a high risk of complications.17

Contemporary CTEPH Management With the diagnosis of CTEPH, medical therapy is commonly initiated while further evaluation for pulmonary endarterectomy (PEA) candidacy is performed. Given the high mortality when untreated, surgical intervention still may be considered even in patients with increased perioperative risk, and surgical evaluation should not be delayed by initiation of medical therapies.12 Some patients require interventional bridging by balloon pulmonary angioplasty (BPA) or extracorporeal membrane oxygenation (ECMO) before surgical therapy. Failure to respond to medical and surgical intervention can lead to consideration for lung or combined heartlung transplantation as a last resort.

Surgical Management Pulmonary thromboendarterectomy currently remains the only curative intervention for patients with CTEPH, and 3-year survival approaches 90%.4 Concurrent cardiac procedures such as closure of persistent foramen ovale, coronary artery bypass grafting, or heart valve surgery can be performed safely without difference in surgical outcomes.18 Preexisting tricuspid regurgitation usually resolves with remodeling of the

Medical Management Conservative treatment of CTEPH follows 2 strategies: the prevention of further thrombosis by systemic anticoagulation Table 1 Surgical Classification of CTEPH Jamieson Classification

UCSD Classification

Type

Description

Level

Location of thromboembolic disease

I

Acute thrombus in main lobar pulmonary arteries

I

II

Organized thrombus and intimal thickening proximal to segmental pulmonary arteries Fibrosis and intimal thickening in distal segmental pulmonary arteries Vasculopathy of distal pulmonary arteriolar tree without visible intraluminal thrombotic disease

II III

Disease origin at level of main pulmonary arteries resulting in partial or complete occlusion of 1 lung Disease origin at level of lobar or intermediate pulmonary arteries Disease origin at level of segmental arteries

IV

Disease origin at level of subsegmental branches

III IV

NOTE. Surgical disease classification by visual criteria (Jamieson) or anatomical location (UCSD). The Jamieson classification has been validated to predict early surgical outcomes. Higher surgical types are associated with worse outcomes. The UCSD classification has been proposed by Jenkins et al.6 to address especially distal disease and long-term outcomes. Levels correlate with anatomical location and degree of surgical complexity, where a higher level represents more difficult resections. Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; UCSD, University of California San Diego.

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right ventricle (RV) shortly after PEA, and tricuspid valve annuloplasty is not recommended routinely.5,19 The surgical technique and anesthesia management have been well established and are described widely in the literature.5,20,21 Several aspects of the intraoperative course are pertinent to the postoperative management in the ICU. The extent of surgical endarterectomy and resulting pulmonary artery pressure (PAP) determine postoperative hemodynamics and play a role in the occurrence of reperfusion lung injury (RLI). Deep hypothermic circulatory arrest (DHCA) is used standardly because it provides optimal surgical field visualization with no difference in neurologic outcome compared with antegrade perfusion without circulatory arrest.22 Cardiopulmonary bypass (CPB) and DHCA both result in impaired microcirculation from vasoconstriction and decreased blood viscosity affecting a broad range of organ systems. The length of CPB and DHCA is linked to neurologic outcomes, and key aspects of anesthetic management rely on optimal neurologic monitoring and protection. In addition, certain medications historically used in PTE surgery can affect anesthetic emergence, cognitive outcomes, and glucose homeostasis. Postoperative Physiology and ICU Care Evidence and guidelines for the immediate postoperative care of patients after pulmonary thromboendarterectomy remain unsatisfactory. Current ICU strategies rely greatly on experience gathered over time in high-volume centers while incorporating evidence-based knowledge from the care of similar cardiopulmonary disease states. Management is determined by disease- and surgery-specific components, and the key focus is aimed at neurologic, pulmonary, hemodynamic, and hematological aspects. Intensivists are challenged with complex pathophysiology and the potential for detrimental complications (Table 2). In-depth understanding of CTEPH physiology and intraoperative surgical and anesthesia aspects of PEA, in combination with post-cardiac surgery critical care and post-PTE considerations, is needed to provide optimal care. Risk Stratification Multiple pre- and perioperative risk factors have been identified that affect short- and long-term outcomes after PTE, and can be used by the intensivist to define early postoperative expectation and optimize ICU care (Tables 2 and 3). Foremost, a center’s expertise in the surgical and perioperative management of PTE is identified as major factor for mortality and morbidity.5,6,23 A further central component is the extent and location of chronic thromboembolic disease and associated hemodynamic compromise defined by PVR and RV systolic function.24 Distal CTEPH disease presents with increased surgical complexity and is associated with worse outcomes, whereas disease burden affecting predominantly lower lobes may predispose to increased postoperative hypoxia from V/Q mismatching. Preoperative hemodynamics correlate linearly with early outcomes, and patients with PVR values of

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>1000 dyn/s/cm have up to 3 £ higher in-hospital mortality compared to patients with a PVR of <1000 dyn/s/cm.25,26 Several noninvasive imaging techniques have shown predictive value in patients undergoing PTE. Higher pulmonary artery (PA) diameter by computer tomography imaging correlates with worse hemodynamics and increased mortality postoperatively.27,28 A promising echocardiographic parameter for postoperative outcome is the myocardial performance index (TEI index) because it has been shown to be independent of ventricular geometry and correlates well with RV hemodynamics in patients before and after PTE.29 In addition, evaluation of pulmonary flow profiles by Doppler echocardiography and the ratio of pulmonary flow systolic notch timing is associated with in-hospital mortality and midterm hemodynamic improvement postoperatively and presents as an attractive marker to predict early outcomes.30 Echocardiographicderived tricuspid annulus plane excursion has shown to improve over time after PTE, but early postoperative values do not correlate well with changes in PVR, making it less useful in the clinical ICU setting.31,32 Severe preexisting left ventricular (LV) dysfunction can lead to early hemodynamic complications in the postoperative period owing to the sudden increase in LV preload.5 The elderly population with >70 years of age can undergo PTE safely, but early mortality and utilization of ICU recourses have been shown to be higher.33,34 Known coexisting hematologic disease may complicate perioperative management and predisposes patients to bleeding or recurrent thromboembolic events after surgery.35 In addition, patients with chronic pulmonary diseases are at a significantly increased risk for postoperative pulmonary complications because ventilation remains impaired notably despite improved perfusion after thromboendarterectomy.5 Immediately after surgery, a few key hemodynamic parameters are associated with increased early morbidity and mortality. Specifically, insufficient reduction in PVR with residual PVR >500 dyn/s/cm and PAPm >38 mmHg in conjunction with low cardiac index correlate with poor postoperative outcomes and increased risk of death.25,36 Risk stratification of patients admitted to the ICU after PTE provides intensivists with pertinent information to identify the high-risk patient and anticipate postoperative complications. Recognition of specific risk factors may warrant closer hemodynamic monitoring and lead to adjustment in respiratory, hemodynamic, or hematologic management.

Role of Expert Centers and Multidisciplinary Team Care Most PTEs currently are performed in a few centers around the world with significant expertise in perioperative management of these patients, and the goal to define expert centers officially for PTE is ongoing. Jenkins et al. recently proposed criteria based on surgical expertise by annual number of PTEs performed (
50/y), outcomes (in-hospital mortality <5%), and availability of specialists for medical and interventional therapies for CTEPH.6 Referral to an expert center is recommended by specialty societies for patients initially diagnosed

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Table 2 Postoperative Complications After PEA Complication NEURO

PULMONARY

HEMODYNAMICS

HEMATOLOGIC

Risk Factor

ICU Management

Major neurologic insult

 Chronic hematologic abnormalities  Prolonged DHCA/CPB  PFO/ASD  Hyperthermia with rewarming

 Early neurologic assessment  Optimization of cerebral perfusion  Interventional/surgical management

Delayed emergence Postop delirium and cognitive dysfunction

 Advanced patient age  Use of long-acting CNS depressant drugs (benzodiazepines, barbiturates, anesthetics/ analgesics)  Prolonged DHCA

 Avoidance of long-acting sedatives  Early mobilization and ambulation  Orientation to day/night  Early removal of lines/drains/catheters

Hypoxia and prolonged intubation

 Coexisting chronic lung disease  CTEPH disease affecting primarily lower lobes  CTEPH disease affecting primarily distal segments  Suboptimal surgical disease removal  Postop persistent PHT

 LPV  Optimal PEEP  Diuresis  iNO  Pt position on non-operated lung

Reperfusion lung injury

 Preop PAP >1000 dyn/s/cm  Postop RPH  Post-CPB use of inotropes and vasodilators in combination with high Vt

 Avoid pulmonary overcirculation  Steroids  Neuromuscular blockade  Prone positioning  ECMO

Pulmonary hemorrhage

 Postop RPH  Postop hypertension  Postop coagulopathy

 Avoid hypertension  PPV  Topical vasoconstrictors  Correct coagulopathy  Selective OLV  Interventional vascular embolization  ECMO

Hemodynamic instability  Preop RV or LV dysfunction  Intraoperative severe vasoplegia  Prolonged DHCA/CPB  Postop RPH  Postop high PPV setting  Postop dysrhythmias

 Volume optimization  Inotropes/pressors  HR optimization  iNO  ECMO

Cardiac tamponade

 Postop prolonged bleeding  Coagulopathy/systemic anticoagulation

 Preload optimization  Inotropes  Surgical management

Residual pulmonary hypertension

 CTEPH disease affecting primarily distal segments  Suboptimal surgical disease removal

 Selective pulmonary vasodilators (inhaled/oral)

 Chronic hematologic abnormalities  Reoperation  Prolonged DHCA/CPB  Postop coagulopathy and systemic anticoagulation  Postop hypothermia and acidosis Thromboembolic events  Chronic hematologic abnormalities

Postop bleeding

 Correction of coagulopathy  Resuscitation  § surgical re-exploration  Systemic anticoagulation

NOTE. Common postoperative complications after PEA by organ systems. Risk factors for specific complications are listed. Abbreviations: ASD, atrial septum defect; CNS, central nervous system; CPB, cardiopulmonary bypass; CTEPH, chronic thromboembolic pulmonary hypertension; DHCA, deep hypothermic circulatory arrest; ECMO, extracorporeal membrane oxygenation; HR, heart rate; iNO, inhaled nitric oxide; LPV, lung protective ventilation; LV, left ventricle; OLV, one-lung ventilation; PAP, pulmonary artery pressures; PEA, pulmonary endarterectomy; PEEP, positive endexpiratory pressure; PFO, persistent foramen ovale; PHT, pulmonary hypertension; PPV, positive-pressure ventilation; postop, postoperative; preop, preoperatively; Pt, patient; RPH, residual pulmonary hypertension; RV, right ventricle; Vt, tidal volume.

with CTEPH, and those deemed non-operable, to obtain a second opinion.37 Multidisciplinary teams that care for these patients are composed of surgeons, pulmonologists, cardiologists, radiologists, interventionalists, cardiac anesthesiologists, intensivists,

perfusionists, nurses, and respiratory therapists. In the immediate postoperative period, daily management is provided best by the joint care of an intensivist, cardiac surgeon, and pulmonologist in an ICU familiar with cardiac surgical patients. The type of ICU is less important than provider expertise with this

ARTICLE IN PRESS W.B. Kratzert et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 117 Table 3 Perioperative Risk Factors Associated With Early Surgical Morbidity and Mortality Risk Factor Preoperative  CTEPH team and surgical experience  Distal surgical disease (type 3 and 4)  NYHA functional class  PVR >1000 dyn/s/cm  RV systolic dysfunction  Severe LV systolic dysfunction  Age >70 y  Chronic pulmonary disease Intraoperative  CPB >90 min  DHCA >60 min Postoperative  Inotropic support needed  Persistent PVR >500 dyn/s/cm  PAPm >38 mmHg  CI <2.1 L/min/m2 NOTE. Preoperative, intraoperative, and postoperative factors that can be used by intensivist for decision-making and to predict early postoperative risk for complications and outcomes. Abbreviations: CI, cardiac index; CPB, cardiopulmonary bypass; CTEPH, chronic thromboembolic pulmonary hypertension; DHCA, deep hypothermic circulatory arrest; LV, left ventricle; PAPm, mean PAP; NYHA, New York Heart Association; PAP, pulmonary artery pressures; PVR, pulmonary vascular resistance; RV, right ventricle.

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specific patient population, invasive and noninvasive monitoring techniques, and contemporary hemodynamic and ventilatory management. In addition, the ability to perform rescue procedures such as lung isolation and ECMO, in addition to the immediate availability for emergent pulmonary and vascular interventional procedures, are essential for optimal ICU care. General Aspects and Monitoring of Post-PTE Care The typical postoperative course after PTE follows a certain trajectory, and patients must meet significant milestones before discharge from the ICU as early as postoperative day (POD) 2 or 3 (Fig 1). Within the first 12 hours, assessment of neurologic status, weaning of ventilatory support, endotracheal extubation, and weaning of residual vasopressor is accomplished. Initiation of diuresis and short-term anticoagulation follows promptly. On POD 1, patient mobilization and safety assessment for nutritional support is performed. Any concern for insufficient ability to swallow or protect the airway should prompt an official speech and swallow evaluation, given the potentially detrimental consequences from aspiration in this population. At the same time, long-term anticoagulation usually is introduced in conjunction with gastric ulcer prophylaxis. Depending on the hemodynamic status and surgical drain output, the discontinuation of pulmonary artery catheters

Fig 1. Postoperative milestones. The expected ICU course of patients after PTE. Uncomplicated postoperative patient progression includes meeting certain milestones on postoperative day 0, 1, and 2 to qualify for potential discharge from the ICU on POD 2 or 3. A-line, arterial line; GI, gastrointestinal; ICU, intensive care unit; PAC, pulmonary artery catheter; PO, per os; POD, postoperative day; VTE, venous thromboembolism.

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(PACs), arterial lines, chest tubes, and Foley catheter follows within the first 24 to 48 hours. The postoperative course is highly dependent on individual complexity, and the abovedescribed progression frequently is altered in the high-risk patient. Monitoring Early postoperative hemodynamic monitoring is accomplished standardly by arterial line with or without a PAC. The use of a PAC commonly is decided in the operating room and depends on provider preference, proximity of disease to the main PA, and the patient’s comorbidities. Patients with a high disease burden and severe PAP, RV dysfunction, and significant perioperative hemodynamic instability benefit most from the presence of a PAC in the postoperative period. If placed, the catheter only should be used to monitor central venous pressure and PAP, cardiac output (CO), and mixed venous oxygen saturation (SvO2) because advancement of the catheter into distal PA branches and balloon inflation to measure pulmonary artery occlusion pressures carries the potential of causing pulmonary vascular injury. Aside from direct information on CO and systemic oxygen balance obtained by the PAC, there are several alternatives that can be used to evaluate more specifically for RV failure. Analysis of RV pressure waveforms, calculation of pulmonary artery pulsatility index (PAPi), ultrasound assessment of portal vein flow, and echocardiography in the absence of PAC monitoring all can provide pertinent information on RV function.38-41 In particular, echocardiography has high value in the assessment of acute hemodynamic deterioration in the ICU because it is readily available and often provides information pertinent to differentiate etiology of shock and instability. Aside from anatomical findings, subjective judgment of ventricular systolic function, and incorporation of tricuspid regurgitation and hepatic vein flow, specific parameters commonly used to assess the RV are 2-dimensional fractional area change, tricuspid annulus plane excursion, and spectral-Doppler derived parameters of myocardial performance index (TEI index) and myocardial systolic excursion (S’).29,42-44 Indirect and less specific markers in the assessment of CO and end-organ perfusion are patient’s mental status; cerebral oximetry; electrocardiogram; urine output; and certain laboratory values such as lactate levels, worsening metabolic acidosis, and rise in creatinine or transaminases. Neurologic Management Postoperative Physiology Pulmonary thromboendarterectomy presents with multiple risks for neurologic complications owing to disease, procedural, and pharmacologic-related aspects. Cerebral vascular events have been reported in 0.3% to 5.6% of patients after PTE.20,22,30 Hematological disorders associated with prothrombotic states or increased blood viscosity are seen in patients with CTEPH and may predispose them to cerebral ischemic events, especially in the perioperative setting.35,45 Most patients

are on systemic anticoagulation in the pre-, intra-, and postoperative period, and there is mounting evidence that they are at higher risk of developing subdural hematomas.46,47 Right ventricular dysfunction with an increased incidence of persistent foramen ovale and right-to-left shunting is associated with greater stroke risk.48,49 Intraoperatively, DHCA adds to the already heightened risk of neurologic injury with CPB because of impaired microcirculation from vasoconstriction and decreased blood viscosity, as well as periods with complete lack of circulation.50,51 In addition, fluctuation in body temperatures after rewarming resulting in hyperthermia postoperatively has been associated with higher incidence of stroke, poor neurologic outcomes, and increased 30-day mortality.52,53 Aside from major neurologic events as described above, the association between PTE surgery and less discernable neurologic injury, such as postoperative cognitive dysfunction and delirium, is much less clear. Although cognitive dysfunction has been described in 20% to 50% of patients after cardiac surgery,54 a recent randomized-controlled trial looking at the incidence of postoperative cognitive dysfunction after endarterectomy could not support these findings.22 It is unclear whether these current findings differ owing to study design or patient selection, or if this specific population actually may benefit neurologically from improvement in pulmonary and circulatory status. Certain pharmacologic agents used during PTE can predispose patients to postoperative complications of seizures, delayed emergence, cognitive dysfunction, and delirium. The use of tranexamic acid and aminocaproic acid both are associated with increased risk of seizures, which may lead to worse clinical outcomes.55 Even though the evidence for pharmacologic neuroprotection remains weak and their clinical benefits arguable, high-dose steroids and barbiturates still are used frequently during PTE surgery. These medications may delay emergence and predispose to the development of delirium, contributing to prolonged ICU stay and worse outcomes.56-59 Similarly, persistent use of benzodiazepines during anesthesia and in the postoperative period is associated with postoperative delirium.60,61 Given the multifactorial risks for neurologic compromise in patients with CTEPH undergoing PTE, meticulous neurologic assessment and optimization of management strategies is important in the postoperative period. Postoperative Management After intraoperative rewarming, the patient’s core body temperature after admission to the ICU should be maintained as normothermic with strict avoidance of hyperthermia.62,63 Early assessment of neurologic status is essential independent of readiness for extubation. When prolonged ventilation is necessary, use of modern sedation-agitation-delirium guidelines including sedation regimens with propofol or dexmedetomidine, use of sedation scales, and daily spontaneous awakening trials are recommended. Once extubated, focus on early mobilization, pain control, and delirium prevention is prioritized.60,64 Immediate pharmacologic and non-pharmacologic management of pain, delirium, and agitation is crucial to

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avoid increasing PVR and the risk of associated acute hemodynamic and respiratory compromise. Communication with the patient’s relatives should include the possibility of prolonged emergence and neurologic recovery because it may lessen existing concerns on their part. Observation of the patient’s neurocognitive status by family members can provide intensivists with important insights and aid in the advancement to full neurologic recovery.

Pulmonary Management Postoperative Physiology Postoperative pulmonary pathophysiology and complications are determined by underlying pulmonary comorbidities, expected changes in pulmonary physiology after anesthesia, sternotomy, CPB, and procedure-specific changes after PTE in the CTEPH population. Patients with preexisting comorbidities resulting in airflow limitations or decreased functional residual capacity may present with added difficulties in ventilation and oxygenation in the immediate postoperative period, independent of surgical- and CTEPH-associated compromises.65 Common respiratory consequences of cardiac surgery are a decrease in total, vital, and functional residual capacities related to pain, atelectasis, decreased chest-wall compliance, and diaphragmatic dysfunction. Pulmonary compliance is decreased by increased extravascular lung water and atelectasis, and V/Q mismatching occurs owing to atelectasis, positioning, and alteration in hypoxic pulmonary vasoconstriction.66 Key changes in pulmonary physiology specific to PTE lie in the redistribution of blood flow, increased permeability of the pulmonary vasculature, and lack of hypoxic pulmonary vasoconstriction in endarterectomized segments. This can result in PTE-specific postoperative complications of prolonged hypoxemia, RLI, and pulmonary hemorrhage. Temporary alteration of blood flow toward the newly opened pulmonary segments and away from previously well-perfused areas has been termed pulmonary artery steal syndrome and results in higher V/Q mismatching of the non-diseased lung.67-69 Initial increased permeability of endarterectomized vasculature leads to variable severity of localized pulmonary edema. In addition, preoperative development of bronchopulmonary collateral arteries can lead to dual blood supply of the reperfused lung segments after PTE, causing subsequent overcirculation.70 Although dead-space ventilation generally is alleviated in the reopened regions, an increased prevalence of atelectasis in the immediate postoperative course can lead to worsening pulmonary shunting. This may be amplified by the loss of vasoregulatory mechanisms in the endarterectomized vasculature, especially in CTEPH disease affecting predominantly the lower lobes. Clinical consequences and the extent of pulmonary compromise by these factors in the immediate postoperative period depends on the preexisting extent and location of CTEPH disease and surgical success of the surgery and is difficult to predict. Within 6 to 12 months overall dead-space ventilation and oxygenation improves significantly and most patients experience clinical benefit from surgical intervention.71

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Postoperative Management Unique pulmonary pathophysiology and the lack of sufficient evidence-based data challenge the intensivist when caring for the patient after PTE surgery. Postoperative management relies on understanding underlying physiology and adaptation of universal respiratory strategies to patients at risk for specific PTE-related pulmonary and hemodynamic complications. These include lung-protective ventilation, optimal positive end-expiratory pressure (PEEP), early extubation, post-extubation pulmonary physiotherapy, early mobilization, and conservative fluid management. More severe complications may require advanced supportive measures such as inhaled pulmonary vasodilators, positional mechanical ventilation, ECMO, or interventional management of pulmonary hemorrhage.

Mechanical Ventilation Ventilatory strategies after surgery aim to provide adequate oxygenation and maintain a normal acid-base status while minimizing the risk of lung injury and hemodynamic compromise. Despite the lack of data in patients with CTEPH, excessive oxygen levels during lung reperfusion have been associated with increased risk of acute lung injury,72 and fraction of inspired oxygen (FIO2) levels should be weaned to minimal concentrations as tolerated to avoid potential harm from hyperoxia. Because these patients are more prone to shunting in the setting of atelectasis, attention must be directed toward adequate recruitment of lung tissue, particularly the lower lobes. The use of adequate PEEP can improve oxygenation significantly in these settings, but comes with the risk of RV compromise when PVR subsequently is increased.73 Higher tidal volumes (Vt) historically have been used in the CTEPH population to optimize oxygenation, but with mounting evidence that lower Vts may be lung protective in the perioperative period, this strategy is becoming controversial.74-76 Mares et al. compared Vt of <8 mL/kg versus Vt of 10 to 15 mL/kg after PTE and showed a significant reduction in mortality, RLI, and right heart failure with lower volumes when combined with avoidance of inotropes.77 Bates et al. recently looked at 128 patients in a single-center, randomized study comparing low tidal volume (6 mL/kg) versus usual care (10 mL/kg) in the first post-PTE days.78 Their results did not show a statistically significant difference in the incidence of RLI, mean airway pressures, ratio of partial pressure of oxygen (PaO2) to FIO2, length of mechanical ventilation, or ICU length of stay between groups. Because the pathophysiological mechanisms are complex, the definition of RLI remains broad, and current data are insufficient, these opposing findings are not unexpected. Support for lower Vt may be drawn from the postlung transplantation population and those with acute lung injury.74,79,80 Even though the mechanism of lung and reperfusion injury differs, current evidence shows better outcomes with lung-protective ventilatory strategies in these patients. Given the seeming lack of benefit with higher Vt and the known potential benefits with lower Vt in the non-CTEPH

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population, initial postoperative ventilatory management should use lung-protective strategies. Time of Extubation Early extubation within the first 6 to 8 hours after cardiac surgery has gained popularity because it is shown to be safe, improve efficiency, and be cost-effective.81 Approximately 50% of patients undergoing PTE currently are extubated within the first 24 hours postoperatively, and 80% to 90% within 48 hours. Shorter time to extubation correlates positively with institutional experience, and RLI is the most common reason for prolonged intubation.82 Prolonged positivepressure ventilation (PPV) in patients after PTE can impede neurologic assessment, lead to hemodynamic and pulmonary compromise, and is associated with a higher risk of ventilatorassociated pneumonia.83,84 Although fast-track protocols increasingly are used to optimize timing of extubation in the general population,85,86 no published reports describe their use

for enhanced recovery after PTE surgery. Early extubation attempts should be made, if appropriate, to minimize potential harm of positive-pressure ventilation in this tenuous population. Exceptions in patients with delayed neurologic recovery or those at high risk for developing RLI should be considered carefully because they may benefit from deferral of extubation for 24 to 48 hours. A protocolized approach with adjustment to specific PTE-associated pathophysiology may be useful to optimize timely extubation in this population (Fig 2).

Persistent Hypoxemia and Reperfusion Lung Injury Common etiologies of hypoxemia after cardiac surgery are atelectasis, pulmonary edema, mainstem intubation, diaphragmatic paralysis, and pneumothorax. Patients undergoing PTE have additional risks of prolonged hypoxemia, development of reperfusion lung injury, and, in extreme cases, occurrence of pulmonary hemorrhage.

Fig 2. Post-PTE extubation protocol. Extubation protocol directed toward patients after pulmonary thromboendarterectomy. Within the first 3 hours after surgery, a neurologic exam is performed and the patient’s risk factors for reperfusion lung injury assessed. Patients at low risk advance to general weaning protocols with the goal of extubation within the first 12 hours. The high risk population remains intubated and is closely monitored for the development of RLI within the first 12 to 48 hours postoperatively before proceeding to extubation. MS, mental status; PTE, pulmonary thromboendarterectomy; postop, postoperative; RLI, reperfusion lung injury; SBT, spontaneous breathing trial.

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Postoperative hypoxia from PA steel syndrome or increased pulmonary shunting requires defined supportive therapies for an extended period. During mechanical ventilation, V/Q mismatch from atelectasis is addressed best by the use of PEEP. Significant perfusion mismatch between revascularized and non-operated lung areas may be mitigated by the use of inhaled nitric oxide (iNO) or by altering the patient’s position to the lateral decubitus position for better perfusion of the nondiseased lung. In the immediate post-extubation phase, noninvasive respiratory therapy with high-flow nasal cannula or continuous positive airway pressure, scheduled intermittent hyperinflation therapy, incentive spirometry (IS), and patient mobilization are imperative to decrease V/Q mismatch from atelectasis. Prolonged utilization of iNO via high-flow or regular nasal cannula can promote the patient’s recovery by allowing earlier mobilization and activity, but individual responsiveness to iNO and improvement in oxygenation should be evaluated during its use. Slow weaning of iNO and FIO2 often is warranted in patients with severe post-PTE hypoxia, and supplemental oxygen may be needed for months after hospital discharge.71,87 Throughout the early postoperative period, continuous diuresis for daily negative fluid balances while avoiding overt injury to the kidneys is crucial to minimize further compromise from coexisting pulmonary edema. Most patients experience some degree of reperfusion edema in the postoperative period, which usually responds to conservative measures of increase in FIO2, PEEP, and diuresis. More severe cases of reperfusion lung injury occur in up to 30% to 40% of patients within 48 hours after surgery, and represent the main reason for prolonged intubation after the first 24 hours.82 Although a clear definition has not been established, hypoxemia (PaO2-to-FIO2 <300) in the presence of sterile infiltrates affecting the reperfused lung segment on chest radiography has been used for diagnosis (Fig 3).78,88 The underlying pathophysiology combines an inflammatory process with increased vascular permeability, blunted hypoxic pulmonary vasoconstriction, and possibly a mechanical component caused by reperfusion. Together, it results in local inflammation with cytokine release and an increase in extravascular lung water.69,88-90 Several preventive strategies directed at minimizing underlying pathologic mechanisms have been evaluated for their impact on the

Fig 3. Reperfusion lung injury. Chest radiograph showing a right unilateral reperfusion lung injury. Flourishing of a right RLI on POD 1 and 2 is seen with unilateral pulmonary edema development. POD, postoperative day; RLI, reperfusion lung injury.

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development of RLI. Steroids. In 2012, Kerr et al. published a randomized controlled trial of 98 patients undergoing PTE who received either perioperative methylprednisolone or placebo.88 The incidence of lung injury was similar in both treatment groups (45% placebo v 41% control, p = 0.72), and there was no statistical difference in secondary clinical outcomes of ventilator, ICU, or hospital-free days. Interestingly, the study found that patients who developed RLI were more symptomatic, demonstrated a higher PAPm preoperatively, and had a higher postoperative PVR, supporting the idea that the incidence of RLI greatly depends on the extent of CTEPH disease and surgical success. Pulmonary Perfusion. Another potential mechanism relates to the localized dysfunctional pulmonary vasoconstriction and risk for relative overcirculation in reperfused lung segments after thromboendarterectomy. Knowledge from animal studies and the pediatric congenital literature suggest an increased risk for acute lung injury and pulmonary edema with pulmonary overcirculation.91-93 Although this concept remains unclear in the adult clinical setting, several studies may support this theory. Mares et al. showed a significantly higher incidence of RLI when positive inotropes and vasodilators were used in combination with higher Vt immediately after PTE.77 Gan et al. recently looked at the same concept by mechanically decreasing blood flow to the reperfused lung segments and showed a decrease in RLI and improvement in hemodynamics with embolization of bronchopulmonary collateral arteries preoperatively.70 Given the complexity of underlying pathophysiological mechanisms after PTE and the dynamic changes in the postoperative period, a better understanding is needed to integrate this concept fully into clinical management, but caution should be taken to avoid unnecessary pulmonary overcirculation. Pulmonary Vasodilators. Preventive use of inhaled pulmonary vasodilators has not shown any decrease in the incidence of RLI, but they do improve oxygenation in the acute setting of hypoxemia.94-96 Although many clinicians use iNO to bridge prolonged hypoxemia during mechanical ventilation and after extubation, current evidence does not show any improvements in mortality.97,98 The central benefit of iNO lies in the hemodynamic support of patients with persistent pulmonary hypertension and RV dysfunction after PTE. Given the lack of evidence, current ICU strategies for the acute management of RLI remain similar to those for patients with acute respiratory distress syndrome (ARDS) or those developing RLI after lung transplantation. Supportive lungprotective ventilation with emphasis on maintaining normocapnia and conservative fluid management are recommended, but the use of steroids remains in question.99-101 Utilization of higher levels of PEEP and pulmonary recruitment maneuvers can improve oxygenation significantly when hypoxemia is due to overt pulmonary shunting and may be useful in the setting of RLI.102 Variable manifestation of localized pulmonary edema in RLI remains a complicating factor because it may mitigate the benefits of PEEP seen in ARDS while resulting in overt distension of normal lung tissue. In addition, the PTE population can be prone particularly to significant hemodynamic compromise from PPV-induced increases in

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intrathoracic pressures given their often coexisting RV dysfunction and dry intravascular fluid status. Although the benefits of recruitment maneuvers, high PEEP in ARDS patients, and determination of best PEEP remains debated, specific data for patients after PTE are lacking.103,104 Therefore, finding the optimal PEEP and implementing recruitment maneuvers in postoperative hypoxic patients need to be determined on an individual basis and performed in close observation of hemodynamic parameters to balance risks and benefits.105 Advanced supportive therapies described in the management of ARDS, such as paralysis, prone positioning, inhaled pulmonary vasodilators, or ECMO, can improve hypoxia and may be beneficial for patients with severe RLI, but insufficient outcome data is currently available.106 Severe states of RLI resulting in pulmonary hemorrhage are rare and occur in 0.5% to 2.0% of cases.107 Exact risk factors have not been identified, but postoperative systemic and residual pulmonary hypertension can contribute, and high blood pressures after PTE should be treated aggressively. Conservative management with positive airway pressure, topical vasoconstrictors, and reversal of any existing coagulopathy is recommended when adequate hemodynamics and gas exchange are maintained. More aggressive interventions may require lung isolation by double-lumen endotracheal tube or bronchial blocker, interventional embolization of the bleeding source, or in extreme cases the use of ECMO.108,109 Hemodynamic Management Postoperative Physiology In the immediate postoperative period, transient hemodynamic effects resulting from CPB are vasodilation, myocardial stunning, and hypovolemia. Ongoing surgical or medical bleeding, rhythm disturbances, effects of PPV, and drugs used for sedation and analgesia often play an additive role. Key determinants of postoperative circulatory physiology specific to the CTEPH population are RV function and PVR. Within 24 hours after thromboendarterectomy, most patients experience a significant reduction in PVR and subsequent right heart workload, which leads to improved RV systolic function and circulatory hemodynamics.110 Although the immediate decrease in PVR is a consequence of reopening diseased pulmonary vasculature, concomitant development of PA steel syndrome, as described earlier, may result in relative overcirculation of the operated areas. Changes in RV chamber size and ventricular septal position further lead to improved LV systolic and diastolic function. Over time, structural remodeling of the right atrium and ventricle occurs, leading to longstanding improvements in exercise tolerance and reduction in tricuspid regurgitation, if present preoperatively.111-113 Persistent elevation of PAP immediately postoperatively may be due to the use of vasopressors, PPV, hypoxia, increased extravascular lung water, or acidbase derangements, and often resolves within the first 48 hours.69 From 10% to 30% of patients experience lasting residual pulmonary hypertension with variable improvement after surgery that may require further intervention.5

Early Postoperative Management Preoperative RV function, degree of PVR reduction, risk of RLI, and intraoperative course determine the postoperative hemodynamic management after PTE. Goals are directed toward maintenance of end-organ perfusion while avoiding increases in PVR and worsening RV dysfunction. Conservative strategies to optimize PVR, such as providing adequate oxygenation and ventilation, minimizing sympathetic stimulation and negative effects from PPV, correcting acidosis, and maintaining normothermia, should be performed on a regular basis.83,114 The uncomplicated patient requires minimal postoperative hemodynamic support, and routine use of inotropes and vasodilators is avoided, whereas restrictive fluid management can be initiated immediately.77 Fluids. Although the overall fluid strategy in post-PTE patients is directed toward volume removal, differences in short-term fluid goals as well as initiation and forcefulness of diuresis have to be decided on an individual patient basis. In the immediate postoperative phase, a well-functioning and hypertrophied RV temporarily may require gentle fluid resuscitation for preload optimization, especially when in combination with increased postoperative bleeding. Once fluid loss has ceased and the patient appears adequately resuscitated, transition to a restrictive fluid management and diuresis should be initiated as soon as tolerated to minimize the risk for RLI. As dynamic fluid shifts persist throughout the first 72 hours of ICU stay, the close monitoring of intravascular volume status is imperative, and diuretics may require adjustment to maintain a restrictive fluid balance. In patients with RV dysfunction, much more caution has to be taken with volume administration because overt resuscitation and RV dilation can lead to acute RV failure. Vasopressors. In the postoperative vasodilatory state, use of vasopressors is oriented toward supplying adequate perfusion to the hypertrophied RV while minimizing effects on PVR. Despite an overall decrease in RV wall tension and myocardial oxygen consumption after successful pulmonary endarterectomy, the thickened and hypertrophied RV remains at increased risk for ischemia from hypotension. Mean arterial pressure goals need to be set consciously and may target higher values than in the general postcardiac surgery population to provide a safety margin for RV support. The choice of specific vasopressors often is guided by provider and institutional preference, but advantages and disadvantages of individual agents should be considered. Key aspects rest in their effect on PVR and CO and their arrhythmogenicity. Vasopressin may be especially advantageous given its lack of pulmonary vasoconstriction compared with other drugs such as norepinephrine.115 Once the vascular tone is improving in isolated vasodilatory shock states, vasopressors can be weaned as tolerated while avoiding hypotension. Extreme states of vasoplegia after cardiac surgery have been treated successfully with methylene blue,116 but given its mechanism of action and potential risk of significant pulmonary vasoconstriction, use of methylene blue in the CTEPH population is not recommended. Likewise, venoarterial (VA) ECMO as rescue therapy in refractory distributive shock has to be considered with caution. Accompanied

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systemic inflammation often results in worsening vasodilation, pump flows may not be sufficient enough to support high CO states, and poor outcomes have been associated with ECMO in vasodilatory shock.117 Even though severe vasodilatory states are uncommon in patients after PEA, novel agents such as angiotensin II may be the best option as rescue therapy in this setting.118 RV Failure. Patients with poor preoperative RV systolic function or persistent postoperative pulmonary hypertension can develop acute RV dysfunction and failure after CPB. Poor intraoperative myocardial protection and postoperative dysrhythmias, high ventilatory settings, hypotension, and volume overload may precipitate its occurrence. The goal in the setting of acute RV compromise is to provide adequate endorgan perfusion, avoid right-sided congestion, and minimize RV workload. Prevention of arrhythmias and maintenance of higher heart rates to assures adequate forward flow of the

struggling RV is beneficial and can be achieved by the use of antiarrhythmics, such as amiodarone, and epicardial atrial pacing.39,119 Aggressive diuresis, inotropic support, and selective pulmonary vasodilators are used to optimize RV myocardial performance. Inotropic Support. Excessive iatrogenic increase in right-ventricular CO, particularly by the combined use of inotropes and vasodilators, should be avoided because it may worsen overcirculation of the revascularized pulmonary bed and increases the risk of RLI.64 When inotropes are required to maintain adequate end-organ perfusion, usage should be balanced carefully. Once the RV function improves, weaning of inotropic support can be initiated and executed as tolerated dependent on individual etiology and expected recovery of RV failure. Depending on the vascular tone, either inopressors or inodilators are appropriate in supporting RV contractility. Although the choice of inotrope and pressor support is partly

Table 4 Pulmonary Vasodilators Vasodilators INHALED

INTRAVENOUS

ICU Considerations + Improved oxygenation + Selective decrease in PVR + Minimal effect on SVR + Easily titratable + Administration via regular NC ¡ Methemoglobinemia

1-40 ppm

 Inhaled milrinone

0.5 mg/kg/min

+ Inotropic effect + Less systemic vasodilation ¡ Limited practicality in extubated Pt

Prostacyclin pathway  Epoprostenol (Flolan, Veletri)

25-50 ng/kg/min

+ Most reduction in PVR ¡ Limited effect on oxygenation ¡ May result in systemic hypotension ¡ Limited practicality in extubated Pt

0.1-0.7 mg/kg/min 5-50 mg/min

+ Easy titratable + Peripheral use

2-20 ng/kg/min 1-100 ng/kg/min

¡ Difficult to use ¡ Central access required ¡ Significant systemic side effects

Nitric oxide pathway  Sildenafil (Viagra, Revatio)  Tadalafil (Adcirca, Cialis)  Riociguat (Adempas)

5-40 mg/dose 10-40 mg/dose 0.5-2.5 mg/dose

 Riociguat only officially approved drug for inoperable/persistent/recurrent CTEPH after PTE

Prostacyclin pathway  Selexipag (Uptravi)

60-250 mg/dose 0.2 mg - 1,6 mg/dose

Endothelin pathway  Bosentan (Tracleer)  Ambrisentan (Letairis)  Macitentan (Opsumit)

5-10 mg/dose 10 mg/dose

Prostacyclin pathway  Epoprostenol (Flolan, Veletri)  Teprostinil (Remodulin) ORAL

Dosing

Nitric oxide pathway  Inhaled nitric oxide

Nitric oxide pathway  Milrinone  Nitroglycerin

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NOTE. Commonly used inhaled, intravenous, and oral pulmonary vasodilators; dosing; and their clinical advantages and disadvantages. Inhaled pulmonary vasodilators act most specifically on pulmonary vasculature with minimal effect on systemic vascular tone, causing the least amount of systemic hypotension. Intravenous agents require continuous infusion via central access. Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; ICU, intensive care unit; NC, nasal cannula; PPM, parts per million; Pt, patient; PTE, pulmonary thromboendarterectomy; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance.

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determined by institution, inodilators such as milrinone or dobutamine in combination with vasopressin may be advantageous compared with epinephrine in minimizing pulmonary vasoconstriction.114 PVR Reduction. The lowering of RV afterload with subsequent increases in right-sided CO can be achieved by intravenous or inhaled pulmonary vasodilatory agents (Table 4). Intravenous milrinone, nitroglycerine, and prostacyclin all cause additional dilation of the systemic vasculature and often result in unwanted hypotension. Selective inhaled pulmonary vasodilators (ie, inhaled nitric oxide, epoprostenol, iloprost, or milrinone) have been shown to decrease pulmonary vascular resistance, improve hemodynamics, and increase PaO2 in the immediate postoperative period after PTE, but no outcome data exist supporting their routine use in the prevention of RV failure or in residual pulmonary hypertension (RPH).120-122 Although patients with normal RV function and successful surgical reduction of PVR do not benefit from the use of pulmonary vasodilators, their use in patients at high risk for postoperative RV failure may be warranted. Especially in patients with acute RV failure, selectively lowering PVR with iNO, inhaled prostacyclin, or milrinone can be invaluable to maintain systemic perfusion. Although inhaled pulmonary vasodilators commonly are initiated intraoperatively and used during mechanical ventilation, they can be continued after extubation in selected patients. The choice of drug, dosing, and duration depends on individual patients and provider preference. The practicality of use, their effect on systemic blood pressures, recovery of RV function, and ability to transition to oral pulmonary vasodilators are determining factors (Table 4). Inhaled nitric oxide, with its beneficial effects on both oxygenation and PVR, lack of side effects, and broad range of clinical applicability, remains the most commonly used drug in the postoperative ICU period. Alternatively, inhaled prostacyclins may offer the advantage of greater pulmonary vasodilation, whereas inhaled milrinone adds additional inotropy, and these agents can be used in specific patients.123 RPH Residual pulmonary hypertension after PTE results either from incomplete removal of thrombus or, in most cases, from small-vessel vasculopathy owing to pathologic remodeling distal to previously obstructed segments. The former often depends on surgical expertise, whereas the latter has been associated with poorly controlled long-term anticoagulation.6 Up to one-half of patients may have elevated PAP in the immediate postoperative period, but only by POD 4 do hemodynamics correlate with long-term values.124 Although most patients have significant hemodynamic and functional improvement over time, RPH with a PVR over 450 dyn/s/cm and PAPm over 38 mmHg is associated with increased mortality.36,125,126 The decision on long-term medical management should be based on clinical symptoms and hemodynamics obtained from right heart catheterization 3 to 6 months after PEA.36,125 Asymptomatic patients with normal or mildly elevated mean PAP can be followed carefully. For those with

RPH, Cannon et al. suggested a clinically relevant threshold of PAPm
30 mmHg for pharmacologic treatment.36 The initiation of medical or interventional treatment in the immediate postoperative period only is warranted when persistent elevated PAP is associated with significant RV compromise and ongoing hemodynamic instability. Management aims to reduce PVR by the use of selective pulmonary vasodilators and, if warranted, rescue therapies of BPA, VA ECMO, or even lung transplantation. Lasting transition to off-label use of oral pulmonary vasodilators such as prostacyclins, endothelin receptor antagonists, and phosphodiesterase inhibitors has shown mixed results. The decision should be guided by the patient’s hemodynamic profile in conjunction with the pulmonary hypertension specialists.127 Recently, riociguat has been approved as a pulmonary vasodilator in patients with persistent or recurrent CTEPH after surgical treatment. Improvements in hemodynamics and exercise capacity are promising for long-term use, but given its prolonged elimination half-life of »12 hours and accompanied hypotension in 9% of patients, its role in the immediate postoperative period may be as equally limited as other nonselective pulmonary vasodilators.128,129 Extracorporeal Life Support, Reoperations, and Lung Transplantation Extracorporeal Life Support Intra-aortic balloon counterpulsation, ECMO, and shortterm RV-assist devices all represent rescue therapies in acute postoperative respiratory and circulatory decompensation. Although intra-aortic balloon counterpulsation and short-term RV-assist device support have been used for RV failure after cardiac surgery and PTE,130,131 most clinicians have moved toward venovenous (VV) and VA ECMO as a bridge to recovery or bridge to transplantation.132-134 Pulmonary hemorrhage, pneumonia, and RV failure are the most common pathologies resulting in ECMO support. The decision of initiation and timing is complex and is made in consideration of patient-specific, provider, and institutional factors. Early discussion among surgeons, intensivists, and pulmonologists can facilitate evaluation of ECMO candidacy significantly and optimize timing of initiation in the patient at risk for needing mechanical support. Key components to assess risk and benefits are viability of alternative medical or mechanical options for enhanced respiratory and hemodynamic support, reversibility of underlying pathologic mechanism, likelihood of ECMO use as a bridge to recovery or transplantation, transplantation candidacy, surgical feasibility of ECMO initiation, and presence of significant patient comorbidities that may prohibit ECMO use. In-hospital ECMO survival is better in younger patients, those patients who have faster hemodynamic recovery, and when respiratory failure is the sole cause for ECMO initiation after PTE.134 Although overall ECMO outcomes are improving with growing expertise, mortality in the post-PTE population remains high and half of patients do not survive. Venovenous ECMO is a supportive option for patients in pure respiratory failure without hemodynamic compromise and has the advantage of

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requiring less systemic anticoagulation and a reduced risk for major vascular complications.132 Nevertheless, most patients require VA ECMO for additional circulatory support, and Boulate et al. showed that in post-PTE patients, outcomes are similar to those on venovenous ECMO, even if initiated for isolated respiratory failure. This may be explained by the added decrease in pulmonary circulation, minimizing the risk for pulmonary hemorrhage and RLI. Because many critically ill patients exhibit some degree of coexisting RV dysfunction when escalated to ECMO support, even minimal hemodynamic compromise should be taken into close consideration for prioritizing VA ECMO. In patients with an inferior vena cava filter in place, type and access location for ECMO needs to be evaluated closely to avoid potential dislocation of the device, and prior retrieval may be warranted. Reoperations Only a few life-threatening events require surgical interventions during the early ICU phase, and most postoperative complications are addressed by medical or interventional therapies. Acute pericardial tamponade or airway bleeding in the rare setting of arteriotomy disruption are true surgical emergencies and require immediate return to the operating room for re-exploration. Although there is no immediate role in the acute setting after recent primary surgery, reoperative pulmonary thromboendarterectomy for patients with recurrent thromboembolic disease has been performed successfully, and perioperative outcomes are similar to initial PTE.135,136 The main indications are symptomatic residual or recurrent pulmonary hypertension with an average interval between surgeries of 5 years. Lung Transplantation Lung or heartlung transplantation after failed PTE and complicated postoperative course is a rare but potentially curative intervention. These patients are often on extracorporeal life support as a bridge to transplantation, and their mortality remains high.134 Therefore, in patients with significant postoperative complications on extracorporeal life support, especially those with poor long-term prognosis owing to distal disease burden and RPH, multidisciplinary transplant evaluation should be initiated as early as possible, following the current guidelines of the International Society for Heart and Lung Transplantation.137 Although this may be a final option after failed PEA, primary transplantation as an alternative to PEA is contraindicated owing to higher mortality rates with lung transplantation in pulmonary hypertension, along with the risks of lifelong immunosuppression and possible allograft rejection.20 Hematologic Management Postoperative Physiology Several preexisting or acquired hematologic disorders such as sickle cell disease, antiphospholipid syndrome, heparininduced thrombocytopenia and other platelet abnormalities, as well as secondary polycythemia, are associated with

13

pulmonary hypertension and PTE.21,138-141 Hepatic impairment from longstanding RV dysfunction can alter coagulation and metabolism of systemic anticoagulants in these patients. Resulting multifactorial hematologic abnormalities lead to a higher risk for postoperative complications after PEA in the CTEPH population and may require alteration of postoperative care.35,142 Low and dysfunctional platelets after CPB predispose to postoperative bleeding. Antiphospholipid syndrome and heparin-induced thrombocytopenia are associated with additional thromboembolic risks. Perioperative thromboembolic events, sickle cell crisis, or relative anemia in patients used to higher hemoglobin levels all can impair oxygen delivery to major end organs. Postoperative Management Initial postoperative hematologic management prioritizes routine goals of hemostasis and resuscitation for adequate endorgan perfusion and oxygen delivery. Resuscitation follows current recommendations for the general cardiac surgery population while incorporating the increased thromboembolic risk.143 With no specific evidence for the CTPEH population published, choice and trigger for blood product transfusion, the use of coagulation factor concentrates, and addition of desmopressin should follow available laboratory and point-ofcare testing in conjunction with careful risk-benefit analysis. Given the increased incidence of thromboembolic events, reocclusion prophylaxis with lifelong systemic anticoagulation is recommended and should be initiated as soon as possible. Timing of initiation in the immediate postoperative period is determined by the propensity for bleeding, existing coagulopathy, and additional comorbidities of individual patients. Warfarin is started within the first 24 hours postoperatively, whereas bridging anticoagulation with unfractionated systemic heparin is achieved concomitantly. Hemodynamic parameters, chest tube output and its Hgb levels, laboratory values or viscoelastic hemostatic assays reflecting coagulation and Hgb levels, and imaging with radiographic or ultrasonographic modalities all serve as immediate markers to determine the significance of postoperative bleeding and when systemic heparin can be introduced. Specific parameters of chest tube output remain provider and institutional specific, but most surgeons and intensivists feel comfortable initiating low systemic heparin when the observed output is less than 100 mL/h for 4 to 6 hours postoperatively. Target goals for appropriate heparinization are aimed at low-therapeutic levels based on individual patient variables and continued until the INR is in therapeutic range. No specific data exist on timing and choice of venous thromboembolism (VTE) prophylaxis after PTE when systemic heparinization is omitted. The use of mechanical VTE prophylaxis with pneumatic compression devices is initiated immediately after surgery, and chemical prophylaxis starts within 24 hours in accordance with recommendations from the general postcardiac surgery population.144 It remains unclear which chemical regimen is superior for optimal VTE prophylaxis, and the choice may be determined by institutional preference and individual patient specifics. The use of inferior

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vena cava filters in the perioperative period has been controversial. Although some institutions recommend routine placement in the postoperative period after PTE to limit recurrent pulmonary emboli, supportive data are weak, and the risk-benefit profile should be determined on an individual basis.145,146 Once systemic anticoagulation with warfarin to an INR goal of 2 to 3 is reached, VTE prophylaxis can be discontinued.147 Although the bleeding risk in CTEPH patients on warfarin is acceptably low,148,149 certain antiarrhythmics, antimicrobials, centrally acting agents, and other commonly used ICU medications may increase the risk of supratherapeutic anticoagulation and subsequent bleeding. In addition, pulmonary vasodilators also have been associated with an increased risk of bleeding in patients on warfarin,148 and Simonneau recently showed a higher occurrence of hemoptysis in patients on warfarin and riociguat.150 Novel nonvitamin K antagonists, such as rivaroxaban, dabigatran, and apixaban, have been reported as safe and viable anticoagulation alternatives in patients with CTEPH and may challenge the traditional use of warfarin.151,152 With the exception of rivaroxaban, which was recently approved by the US Food and Drug Administration (FDA) for the long-term management of recurrent VTE’s, NOACs are currently only approved for the initial treatment and prevention of VTEs.153 Although their pharmacologic profiles provide benefits in clinical use, predictability, and bleeding risks, a notable unknown is their potential interaction with pulmonary vasodilator therapy in the CTEPH population.154-156 Because their therapeutic action is immediate, initiation of direct oral anticoagulants should be deferred until the postoperative bleeding risk is at a minimum and the patient has left the ICU, and systemic anticoagulation is achieved with unfractionated heparin in the meantime. Further understanding of thromboembolic mechanisms in CTEPH disease and mounting evidence in the use of novel non-vitamin K antagonists in this particular patient population soon may lead to their integration into common clinical practice. Conclusion The postoperative management of patients after PTE confronts intensivists with significant challenges specific to CTEPH disease and PTE surgery. Knowledge of underlying physiology, intraoperative management, and postoperative complications is imperative to optimize outcomes. Intensive care unit management by a multidisciplinary team can provide contemporary care in an evolving field of highly specialized patients. Key attention is paid to avoidance and management of neurologic insults, residual pulmonary hypertension, RLI, RV failure, and postoperative recurrent thromboembolic events. Advancement of expert centers and collaboration among them may offer more evidence-based research in the future and is warranted to optimize postoperative ICU care for this population. Conflicts of Interest The authors have no conflicts of interest to disclose.

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