E. Andrew Ochroch
Pulmonary hypertension is a common but underappreciated pathological condition in patients who undergo thoracic surgery, and being unaware of this condition or underestimating its severity can lead to significant perioperative complications. Management of this condition requires foresight and preparation as discussed in this chapter. Thus, this chapter will serve to: (1) review the pathogenesis of pulmonary hypertension, (2) describe the preoperative preparation and evaluation of patients with pulmonary hypertension who present for thoracic surgery, (3) explain the effects of anesthesia and surgery on the pulmonary vasculature, and (4) define the proper use of the pharmacological aids to control pulmonary hypertension.
NORMAL PULMONARY PHYSIOLOGY AND HYPOXIC PULMONARY VASOCONSTRICTION
At rest, the normal pulmonary vascular system is noted as a high-compliance, high-flow, low-pressure system. This stands in contrast to the systemic circulation, which has much higher resting level of arterial and venous tone. This difference stems partly from the anatomy because the pulmonary precapillary arterioles have a thinner media and less smooth muscle than their systemic counterparts. Furthermore, at rest, there are far more recruitable vessels in the pulmonary bed, which permits dramatic increases in flow with minimal impact on pressure.
The difference between the systemic and arterial systems is also due to the response of the pulmonary vascular endothelium to the challenges of hypoxia (hypoxic pulmonary vasoconstriction: HPV). This vasoconstriction is known as the Euler-Lijestrand reflex. Mitochondria play a key role as the primary sensor of hypoxia, with intracellular calcium increasing as a key response, but the basic mechanism is controversial.1 Figure 4–1 displays several of the key pathways for hypoxic vasoconstriction in which voltage gated potassium (K+) channels directly alter mitochondrial responses. L-type calcium (Ca2+) channels are facilitated by the depolarization of the K+ channels; they then directly increase intracellular Ca2+. Further, classical transient receptor potential channel 6 (TRPC6) also increases intracellular Ca2+ as do store operated channels (SOC) and sodium (Na+)/Ca2+ exchangers (NCX).1 This rise in intracellular Ca2+ also triggers release from sarcoplasmic reticulum via activation of the ryanodine receptors. The end result is constriction of the smooth muscle of the precapillary sphincters and pulmonary arterioles. This calcium-dependent vasoconstriction is the primary phase of HPV and lasts 15 to 30 minutes. The Ca2+ independent phase (the sustained phase) of pulmonary vascular constriction starts at 15 minutes and can last for hours. It is highly dependent on RhoA/Rho kinase (ROCK) mediated Ca2+ sensitization,2 and may be a key to the development of pulmonary hypertension.3 Interestingly, nitric oxide (NO)-induced relaxation and endothelin-1-induced vasoconstriction of pulmonary arteries have been shown to be due to regulation of ROCK-mediated Ca2+-sensitization, rather than altered Ca2+ metabolism.4,5 See Figure 4–1.
Figure 4–1. Ca2+ mobilization in HPV: mechanisms that have been implicated in the hypoxia-induced elevation of [Ca2+], and their potential signaling pathways. Note that some mechanisms are probably only applicable to one phase of HPV (see text). Not shown for clarity: possibility of functionally different types of SOC and Ca2+ store. Note that Na+ entry via NSCC would also contribute to depolarization. y: action of Mg2+ and ATP on KV channels depends on membrane potential (see text). DAG, diacylglycerol; cADPR, cyclic ADP ribose; depol, depolarization; KV, voltage-gated K+ channels; L-type, voltage-gated Ca2+ channels; NCX, Na+- Ca2+ exchanger; RyR, ryanodine receptors; SOC, store-operated channels. TRPC6, classical transient receptor potential channel 6. (From: Ward J, McMurtry I. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem. Curr Opin Pharmacol. 2009;9(3):287-296, with permission. Copyright © Elsevier.)
Anesthetics can influence pulmonary vascular function and inhibit HPV. Inhalational agents (halothane, enflurane, isoflurane, desflurane, and sevoflurane) will all inhibit HPV, but at concentrations of greater than 1 MAC.6 However, intravenous anesthetics such as propofol have a less profound impact on HPV than the inhalational agents.7 Opioids, benzodiazepines, and epidural analgesia/anesthesia have minimal impact. For further discussion on the effect of anesthetic drugs on HPV see Chapter 3.
The pathologic changes of pulmonary hypertension (PH) stem directly from a derangement of the basic mechanisms that lead to HPV. The increased vasoconstriction of the pulmonary arteries in PH has been attributed to a reduced expression or activity of voltage-gated K+ channels and dysfunction of the endothelium and platelets; this leads to imbalances in the production and release of both vasodilators such as NO and prostacyclin (PGI2) as well as vasoconstrictors such as endothelin-1 (ET-1) and serotonin (5-HT).8 Many of these regulators of vascular tone also have roles in the control of cell proliferation and apoptosis and thus may also contribute to the characteristic remodeling of the pulmonary vasculature in PH.3 Much of the pharmacologic management of PH is directed toward modulating these known mechanisms.
Pulmonary hypertension is diagnosed by measurements indicating that mean pulmonary arterial pressure (mPAP) exceeds 25 mm Hg at rest and 30 mm Hg during exercise. To make the diagnosis of primary PH left ventricular end diastolic pressure or pulmonary capillary wedge pressure has to be ≤15 mm Hg and the pulmonary vascular resistance (PVR) greater than 3 Wood units (mm Hg/L: 1 Wood unit = 80 dyn.cm.sec-5).9 Secondary PH is due to the increase in pulmonary vascular impedance from intrinsic parenchymal lung disease. Increased PVR, which requires the right ventricle (RV) to raise pulmonary artery pressure (PAP) to maintain cardiac output, can cause failure of the afterload-intolerant RV, ultimately leading to death. Median survival time for untreated idiopathic PH (formerly included in primary PH) in a historical series was 2.8 years.10
There are a myriad of causes of PH, and the World Health Organization’s list of causes is shown in Table 4–1.11 The most common cause of PH in patients presenting for lung cancer resection is cigarette smoking. Acute exposure to tobacco smoke increases vasoconstriction through multiple routes including increased expression of endothelin-1 (ET-1).12 Tobacco smoke also causes a widespread injury to the lung with epithelial and endothelial apoptosis and necrosis.13,14 Further, the normal healing mechanisms for the lung are inhibited by apoptosis of alveolar macrophages and release/expression of other inflammatory mediators.15 The “earliest” pathology in the lungs of smokers is the development of intimal thickening of pulmonary arteries, the severity of which is correlated to the pack-year history.16Thus, the lung and vascular changes seen in PH associated with chronic obstructive pulmonary disease (COPD) may represent alternate pathways and responses to the damage of tobacco smoke.17
Table 4–1. World Health Organization Classification of Pulmonary Hypertension
EFFECTS OF PULMONARY RESECTION ON RIGHT VENTRICULAR AND PULMONARY VASCULAR DYNAMICS
Lung resection reduces the available cross section of pulmonary vasculature. This is typically very well-tolerated at rest. However, when post-thoracotomy patients are examined in detail, cardiac output and stroke volume decrease, while pulmonary and systemic resistance increase.18 One study examined 40 “normal” subjects and 40 subjects with PH or restrictive pulmonary disease for thoracotomy utilizing transthoracic echocardiography and PA catheter data, preoperatively and postoperatively. They found that preoperatively the subjects with PH had higher right ventricular end diastolic volume (RVEDV), lower RV ejection fraction (RVEF), and higher pulmonary artery wedge pressures. After lobectomy or bi-lobectomy, all subjects demonstrated a rise in RVEDV, PVR and wedge pressure with a fall in RVEF. Subjects with preexisting PH or restrictive lung disease had a greater rise in RVEDV, PVR and wedge and a greater fall in RVEF than “normal” subjects.19 The authors comment that the rise in RVEDV and RV end diastolic pressure in subjects with PH caused a trend toward new postoperative wall motion abnormalities in the RV, suggesting that the myocardium was at significant risk.
PREOPERATIVE MEDICAL MANAGEMENT OF PATIENTS WITH PULMONARY HYPERTENSION
Many patients with PH receive warfarin, diuretics, digoxin, and oxygen. These treatments are often referred to as background or conventional therapy. Diuretics and digoxin provide symptomatic relief but are not thought to affect the course of the disease. Warfarin might provide a survival advantage due to altered platelet and endothelial function in PH, but its contribution is difficult to estimate.20 Calcium channel blockers, such as nifedipine, offer considerable benefit to the patients that respond to them, although these account for only around 6% of patients with PH.21
Patients with PH have reduced production of prostacyclin (PGI2), a product of the arachidonic acid cascade that promotes vasodilation and inhibits vascular proliferation and platelet aggregation.22Activation of the prostacyclin receptor by PGI2 produces activation of the enzyme adenylate cyclase, increased intracellular cyclic adenosine monophosphate levels, and opening of Ca2+-activated K+channels.23 Increased K+ conductance produces hyperpolarization of the cell membrane, blockade of L-type Ca2+ channels, and decreased cytosolic Ca2+. The net result of this process in the vascular smooth muscle cell is relaxation with consequent vasodilation. Epoprostenol was the first PGI2 replacement to be studied; in addition to symptomatic improvement, it has been shown to offer a survival advantage.22,24,25 However, its administration (intravenous, via an indwelling catheter) is complex and it causes adverse effects such as decreased platelet function, hypotension, headache, nausea, and diarrhea.
Other prostanoid analogues have since been studied, including iloprost (inhalation),26 treprostinil (IV)27 and beraprost (oral).25 The duration of hemo-dynamic effect of nebulized iloprost averages approximately 90 minutes after inhalation; the drug requires 6 to 9 nebulizer treatments per 24 hours, with each treatment requiring up to 10 to 20 minutes. While iloprost improved 6-minute walk performance similar to epoprostenol, its use is cumbersome for outpatients. Treprostinil was developed as a longer acting intravenous epoprostenol, so that brief interruptions of the delivery would not have dramatic consequences. Beraprost is an oral drug that is under evaluation. Data from clinical trials support the short-term benefits of these drugs22 but their cost-effectiveness has been challenged by the United Kingdom’s National Institute for Health and Clinical Excellence.28
As previously discussed, in PH there is an imbalance between endogenous production of vasodilators and vasoconstrictors, with decreased levels of PGI2 and increased levels of endothelin-1.22Endothelin-1 is a vasoconstrictor which acts via two receptors, ETA and ETB to both regulate vascular tone and cell proliferation. Both receptor subtypes are found on vascular smooth muscle cells and their activation causes vasoconstriction, probably by augmenting Rho kinase Ca2+ sensitivity,4 while the ETB receptor activation on endothelial cells increases NO and prostacyclin release. There are three clinically available ET blockers: bosentan, a nonspecific blocker, and ambrisentan and sitaxsentan, which selectively block ETA. These drugs improve 6-minute walk distance, improve functionality and delay progression of PH.29 Hepatotoxicity limits their usefulness in some patients, and anemia is common. These drugs are eliminated through the cytochrome P450 system, and thus may alter anesthetic drug half-life.29
Pulmonary vascular tone can also be reduced through phosphodiesterase inhibitors. Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5). Present throughout the body, PDE5 is found in high concentrations in the lungs. Inhibition of PDE5 enhances the vasodilatory effects of nitric oxide in PH by preventing the degradation of cyclic guanosine monophosphate (cGMP).30,31 When added to conventional therapy, sildenafil increased exercise capacity in patients with PH due to both decreased PVR and improved ventilation-perfusion matching.31 Sildenafil was also associated with improvements in the World Health Organization functional class and hemodynamic parameters. Sildenafil has a short half-life, and it requires dosing three times a day for clinical effectiveness.
Preoperative preparation of patients with lung cancer is typically foreshortened due to the threat of metastasis. Several reviews and meta-analyses have focused on perioperative pulmonary complications and strategies to reduce morbidity and mortality. Collectively, these reviews indicate that most risk factors are not modifiable; the surgical incision site has been identified as the single most important risk factor, with thoracic incisions placing the patient at significant risk (odds ratio [OR] of 4.24) for perioperative morbidity and mortality.32-34 Age was the most important patient-related predictor with postoperative pulmonary complication rates being linearly related: age 50 to 59: 6.1%, age 60 to 69: 8.1% and 70 to 79: 11.9%.35 In a multivariate model that adjusted for cardiac and pulmonary comorbidities, the OR of postoperative pulmonary complication also varied by age 50 to 59 years OR 1.5 (CI 1.31–1.74), 60 to 69 OR 2.28 (CI 1.86–2.8), and 70 to 79 OR 3.9 (CI 2.7–5.7).33 Traditional spirometry did not stratify risk, and smoking cessation within 8 weeks of surgery did not impact risk.32-34
Although it is important to consider the risk of pulmonary complications in patients undergoing thoracic operations, epidemiologic studies have shown that perioperative cardiac complications remain the leading cause of death after anesthesia and surgery.36-38 Most of the data regarding perioperative myocardial risk comes from studies of noncardiac surgical patients, of whom thoracic surgical patients were only a small proportion. For example, The Coronary Artery Surgery Study (CASS) registry reported 1600 operations over a 3-year period. However, only 89 of the 1600 were thoracic operations.39Consequently, the published estimates of perioperative cardiac morbidity do not address the risks incurred specifically from the perturbations of the thoracic procedure itself on the typical patient presentingfor thoracic surgery. Instead, they address the average risk of a patient with coronary risk factors undergoing either high-risk or low-risk procedures. While few studies have addressed the incidence of perioperative cardiovascular complications in thoracic surgical patients selectively, it is likely that cardiovascular events are a major cause of perioperative mortality in this subgroup. Further discussion on cardiac and pulmonary complications following thoracic surgery procedures may be found in Chapter 24.
Pulmonary rehabilitation combines optimizing bronchodilator management, improving anti-inflammatory therapy, treating preexisting pneumonia/atelectasis, increasing exercise capacity, and optimizing oxygen therapy. Typical regimens last 4 to 9 weeks. Although lung mechanics are usually not altered, exercise capacity, severity of dyspnea and quality of life are improved.40 One small trial of pulmonary rehabilitation in patients with Stage 1 lung cancer indicated that while exercise capacity increased, no discernable effect on perioperative morbidity was found.41 Specifically for PH, only prolonged oxygen therapy has been shown to stop the progression of the disease, but not to reverse the condition.42
Determination of Presence of Pulmonary Hypertension
Pulmonary hypertension is an uncommon and underdiagnosed disease. Although the effect of PH on perioperative outcome of thoracic procedures has not been extensively studied, preoperative diagnosis should promote optimal intra- and postoperative care. Determining whom to evaluate for PH is difficult, because the typical presenting symptoms of PH, such as breathlessness, decreased exercise tolerance, and fatigue, are nonspecific and easily attributable to COPD. In patients with COPD significant enough to be evaluated for lung volume reduction surgery, pulmonary function tests did not distinguish between those with and without PH. A study by Bach et al, determined that PaO2 while breathing room air was significantly lower in PH patients (51.5 +/– 1.4 vs 69 +/– 1.3 mm Hg, p = 0.000008), but this finding had a poor positive and negative predictive value.43 Similarly, end tidal CO2 did not distinguish those with and without PH. However, this study only examined the criteria for PH at rest. When patients with significant or severe COPD were examined for PH during exercise, one-third met criteria with mean PA pressures greater than 30 mm Hg.44 Consequently, patients with COPD may have limited cardiopulmonary reserve to deal with exercise or perioperative challenges due to rises in pulmonary artery pressures.
In patients with PH, or those suspected of it, further testing may help to delineate risk. Trans-thoracic echocardiography (TTE) can provide significant data on cardiac function. Of 207 subjects with significant COPD studied prior to surgery with TTE, 98% had adequate studies of right and left ventricular wall motion. Right heart abnormalities were found in 40% of subjects and included right atrial enlargement (32%), right ventricular hypertrophy (12%), and RV systolic dysfunction (7%).43 Unfortunately, pulmonary arterial pressure could not be consistently measured as it relies on detection and measurement of tricuspid regurgitant jet, not attainable in all patients.
Right heart catheterization has also been used in an attempt to better assess risk. Patients who had exercise induced decreases in RVEF were at significantly greater risk for developing postoperative cardiopulmonary complications than patients who had exercise induced increases in RVEF.45 The authors claim that decreases in RVEF in response to exercise indicated a limited cardiopulmonary reserve. Further reduction of the pulmonary vascular bed after lung resection may stress this limited reserve leading to an increased risk of cardiopulmonary decompensation and complications.45 Similarly, unilateral pulmonary artery occlusion has been used to determine if the right heart can compensate for a decrease in the vascular bed by assessing the subsequent rise in total pulmonary vascular resistance.46 Unfortunately, both of these methods are highly invasive and risky, and neither have been prospectively evaluated in randomized, blind studies; neither methods are commonly used.
There are no studies in which pulmonary pressures have been linked to outcome after thoracic surgery. The oft-quoted cutoff of 35 mm Hg for maximal pulmonary pressure for pulmonary resection candidates is an arbitrary number that originated from guidelines for lung volume reduction surgery patients.45 It remains unclear if there is a better test to determine likelihood of postsurgical survival than having the patient walk two flights of stairs, as it is primarily a broad test of cardiopulmonary reserve.
Coagulation and Epidural Analgesia
All preoperative medications for the management of PH should be continued except warfarin. Perioperative management of coagulation will depend on the patient’s history of thromboembolic disease with the understanding that all patients with PH are at increased risk of embolism due to increased platelet adhesion.47 This embolic risk needs to be balanced against the significant benefit of epidural analgesia. Similarly, if patients are receiving intravenous prostacyclin, epidural catheterization needs to be considered in the light of the significant platelet inhibition. Acute withdrawal of intravenous prostacyclin puts the patient at significant risk of rebound pulmonary hypertension. A discussion with the patient’s pulmonologist needs to occur to determine if the patient can be safely transitioned to inhaled prostacyclin immediately prior to the operation. The 5-minute half-life of IV prostacyclin would allow for epidural placement 15 to 20 minutes after transition to inhaled medication. While the use of epidural analgesia is both desirable and important, the amount of sympathetic blockade of the epidural must be increased slowly to allow time for adequate right heart preload to occur, to prevent hypotension and to avoid decreased myocardial perfusion.
Central Venous Catheterization
Central venous pressure (CVP) monitoring can provide valuable information used to direct perioperative therapy and permit indirect monitoring of right heart function. Typically the CVP should be placed on the operative side due to the small risk of pneumothorax. Once the patient is positioned, the CVP waveform itself should be closely analyzed and printed out, because the waveform can indicate right ventricular and valvular abnormalities.48 A central catheter is also preferred for delivery of concentrated cardiac and vascular medications.
Pulmonary Artery Catheterization
The usefulness of pulmonary artery catheterization (PAC) in CABG and vascular surgery is hotly debated as a PAC has never been demonstrated to improve outcome.49-52 Further, PAC use in thoracic surgery has never been studied prospectively in humans in sufficient numbers to determine the effect on outcome. Despite the paucity of data, PAC catheters are successfully used in clinical care,53,54 but authors note a need for caution;55 it has been recommended that a PAC needs to be placed preoperatively with fluoroscopic guidance to ensure placement into the nonoperative lung. The alternative is the process of: (1) placing the catheter during two-lung ventilation, (2) withdrawing the catheter into the main PA or RV prior to OLV, and (3) readvancing the catheter once the operative lung is collapsed due to the continued uncertainty of the placement of the catheter in the surgical field. Although the surgeon can place a temporary clamp on the main PA on the surgical side prior to readvancement of a PAC, this procedure increases cardiac stress; PH patients are especially at risk and the temporary clamp may be enough to trigger right heart failure. Regardless of the choice of positioning techniques, the CVP and PA waveforms need to be closely analyzed and printed out, as their baseline shape holds information that is probably more important than the absolute number.48 Waveform changes can indicate ventricular failure, regurgitant valvular lesions, and changes in volume status.
Transesophageal echocardiography (TEE) is a profoundly powerful tool for perioperative hemodynamic measurement. TEE in thoracic surgical patients has been reviewed, with most of the data derived from lung transplant patients.56 The TEE probe is best placed while the patient is supine, but can be placed with the patient in the lateral position; prior planning and coordination are optimal. While the presence of a double lumen tube may make passage more difficult and increase the risk of oral and/or esophageal injury, TEE probes have been successfully placed for many types of thoracic surgery using caution and skill. However, an option to be considered is the use of a single lumen tube and a bronchial blocker when intraoperative TEE monitoring is planned. TEE has the advantage of determining volume status, ventricular performance, and valvular function.
Comparison of Echocardiography and PA catheter
No prospective human data has been collected to compare the accuracy of PA catheters and echocardiography during the dynamic changes of RV and PA function with lateral positioning, OLV, and/or hypoxemia. When pigs were ventilated with hypoxemic mixtures, the PA catheter accurately tracked pulmonary pressures and RV area (loading), but could not track pulmonary vascular resistance.57Consequently, TEE maybe preferable for intraoperative management during thoracic surgery.
Induction and Maintenance
Typical goals of induction for thoracic surgery patients and patients with PH are nearly identical. Maintenance of hyperoxia and hypocarbia require a plan to maintain a patent airway and adequate ventilation at all times. Sympathetic stimulation of laryngoscopy and intubation needs to be thoroughly blunted without producing deleterious hypotension. Significant analgesia can be achieved from short-acting intravenous narcotics in 2 to 5 minutes;58 this peak effect should be timed to occur during laryngoscopy. Lidocaine can also be used to reduce the response to laryngoscopy. Propofol, muscle relaxants, and mask ventilation are then used as usual. In the event of hypotension, as discussed below, phenylephrine is not the best agent for hypotension in PH patients; norepinephrine and vasopressin have theoretical advantages.
Maintenance of anesthesia during thoracic surgery requires attention to the activities of the surgeon. Given the typically long duration between induction and incision, epidural bupivacaine loaded after induction should blunt the majority of the reaction to the incision. Manipulation of the visceral pleura and bronchi stimulates vagal and phrenic afferents, which will not be blocked by epidural anesthesia (see Chapter 24) and may require supplemental inhalational agents.
The placement of the patient into the lateral decubitus position from the supine position can lead to abrupt hemodynamic changes including a decrease in preload due to venous pooling from bed flexion, particularly if the patient has a sympathectomy from the epidural anesthetic. Further, movement of the endotracheal tube with position changes can cause sympathetic stimulation. All of these positioning maneuvers may especially alter the stability of PH patients.
The initiation of OLV can also be fraught with risk in patients with PH and COPD. Hypoxemia and hypercarbia can lead to HPV with subsequent shunting of blood to the oxygenated, dependent lung. This will increase PVR, worsen PH and place the RV at risk of failure. However, without HPV, the shunt fraction could remain greater than 25% to 30%, which would also lead to hypoxemia. A typical maneuver to decrease shunt is the use of continuous positive airway pressure (CPAP) to the operative, nonventilated lung. If CPAP is unsuccessful, temporary occlusion of the operative pulmonary artery can be considered. Results of a preoperative pulmonary artery occlusion test will tell the anesthesiologist if intraoperative temporary clamping of the operative PA is an option, but this test is rarely performed. Two-lung ventilation should be maintained as long as possible and reinitiated as soon as possible.
There are four primary reasons for a thoracic surgical patient to become hypotensive:
1. Decreased SVR from the epidural analgesia/sympathectomy or inhaled anesthetics
2. Inadequate RV preload leading to inadequate left heart filling
3. RV failure from myocardial ischemia, increased PVR, embolism, LV failure, or new mitral regurgitation from myocardial ischemia
4. LV failure from myocardial ischemia
The detection of hypotension should be prompt and the treatment guided by clinical acumen and hemodynamic monitors. These issues are covered in depth in most major anesthesia and cardiovascular texts. They are briefly outlined in Table 4–2.
Table 4–2. Diagnosis of Hypotension with PAC
Determination of Intraoperative Pulmonary Hypertension
Without CVP, PA, or TEE monitoring, determining PH as the cause of intraoperative hemodynamic compromise will be difficult, but it can be done as a matter of exclusion. The typical causes for hemodynamic compromise must be addressed. Hypoxemia and hypercarbia need to be corrected. Left ventricular failure is the most common cause of RV failure59; it should be addressed with fluid boluses and consideration for the use of inotropic support to optimize hemodynamics and ensure myocardial perfusion. Simultaneously, discussion with the surgeon needs to occur to determine if two-lung ventilation can be resumed, which will augment oxygenation, reduce pulmonary vascular tone and thus unload the right ventricle. Epinephrine is the agent of choice in a patient with hemodynamic compromise of undetermined etiology.59
Intraoperative echocardiography can be sought to quickly guide therapy. If the patient has significant esophageal disease, the experienced surgeon may perform an epicardial echocardiographic examination; very atypical images will be obtained, which will need to be evaluated by a person expert in echocardiography. While this application of echocardiography is a non-continuous monitor, it can provide valuable information.
INITIAL MANAGEMENT OF INTRAOPERATIVE PULMONARY HYPERTENSION
Once PH is determined, the initial management is to optimize ventilation to achieve hyperoxia, hypocarbia, and alkalosis.60 This metabolic milieu minimizes HPV, optimizes ventilation/perfusion matching, and decreases PVR. However, careful attention to ventilatory patterns is crucial as over distension of the alveoli through high-ventilatory pressures, excessive PEEP or auto-PEEP can further increase PVR. With the diagnosis of PH, inhalational agents should be reduced to less than 1 MAC so as not to interfere with pulmonary vascular tone. After goal-oriented ventilation, RV inotropic support may be required with the recognition that the failing RV is volume dependent. End-diastolic RV volume should be optimized by intravascular volume expansion and maintenance of sinus rhythm. The heart rate should be high–normal, typically 90 to 100 beats per minute, since the failing RV is also rate sensitive.59,61,62 (Table 4–3).
Table 4-3. Initial Management of Pulmonary Hypertension
Milrinone, as an inodilator, not only augments RV systolic function but also decreases PVR, and therefore unloads the RV. Milrinone is a phosphodiesterase inhibitor and prevents breakdown of cyclic guanosine monophosphate (cGMP).63 Higher intracellular cGMP levels explain milrinone’s inodilatory effects. cGMP increases intracellular calcium levels which increase myocardial inotropy. Milrinone will often also cause systemic hypotension. Epinephrine, vasopressin or norepinephrine should be considered for the treatment of this hypotension, instead of phenylephrine.
Epinephrine directly increases intracellular myocardial cAMP through activation of β1 adrenergic receptors; its inotropic effect is thus synergistic with milrinone, since they both increase myocardial second messengers by different mechanisms. Similar to epinephrine, dobutamine primarily activates β1 adrenergic receptors. It has been used as a sole agent64-66 or in conjunction with other inotropes and pulmonary vasodilators59,64,67 to treat PH, left and right ventricular heart failure.
A selective pulmonary vasodilator should only be considered after all the aforementioned approaches have been implemented, particularly if RV failure or its inotropic state is in question.
SELECTIVE PULMONARY VASODILATORS
Inhaled NO (iNO) results in relaxation of pulmonary vascular smooth muscle. The intracellular mechanism involves activation of guanylate cyclase to produce cGMP. NO is then rapidly inactivated by binding to hemoglobin in the pulmonary vascular compartment, and therefore never reaches the systemic circulation.68,69 This explains its lack of systemic effects; its pulmonary selectivity is due to its route of administration and its rapid inactivation. The clinical dosage of iNO is typically 5 to 40 parts per million.69 The routine clinical application of iNO has been limited by a multitude of factors:
• High per day expense of administration (on the order of thousands of dollars per day of treatment).
• Reaction with oxygen in the lung to form nitrogen dioxide, a known trigger of pulmonary edema and bronchospasm. NO and nitrogen dioxide levels must be continuously monitored during iNO administration.
• Reaction with hemoglobin to form methemoglobin, which also must be monitored during iNO administration. Methemoglobin levels above 5% may cause hypoxia and thus may require management with methylene blue.69
• Possible pulmonary edema in isolated left ventricular dysfunction. Since NO decreases PVR, it may increase pulmonary blood flow, and hence acutely increase left ventricular end-diastolic volume. This may trigger left ventricular failure.70
• Rebound PH with hypoxemia and RV failure during rapid iNO weaning.69 The iNO wean should be gradual, titrated to hemodynamics/gas exchange and should include alternative pulmonary vasodilators.
Intravenous prostacyclin (PGI2, Epoprostenol, Flolan) has a half-life of 5 to 6 minutes due to spontaneous hydrolysis; there are no known toxic effects or metabolites. It is a pulmonary vasodilator and a potent platelet inhibitor; it may act as an anticoagulant in vivo.26 The primary mechanism of its vasodilation is via the production of cAMP, an endovascular smooth muscle relaxant.68,71 Inhalational delivery of PGI2 (iPGI2) has been studied and is equivalent to iNO in its effect on the pulmonary vasculature while sparing the systemic vasculature.26 The cost of iPGI2 50 ng/kg/min is significantly less than iNO, both with respect to actual drug and to the delivery system. iPGI2 has no significant systemic effects. It is effective in decreasing PVR, improving RV performance, and it can also improve systemic oxygenation by improving V/Q matching and thus reducing shunt.
The clinical administration of iPGI2 is also more straightforward, less expensive, and more readily available than iNO. Its lack of toxicity means that no monitoring of the drug or its metabolites is required, in distinction to iNO. The nebulized prostacyclin is added to the inspiratory limb of the breathing circuit72 (Table 4–4). There should be continuous nebulization with an external gas source. The dose range for clinical effect is 5 to 50 ng/kg/min, but most practitioners start with 50 ng/kg/min.73 Further, unlike iNO, the dose of iPGI2 is weight-based. When using an in-circuit nebulizer that is fed off of a separate oxygen source, volume cycled ventilation (with pressure limit) is preferred to pressure controlled ventilation; alteration in delivered volumes with pressure control may occur, due to the possibility of the pressure from the nebulizer being falsely sensed.
Table 4–4 Iloprost/Epoprostenol Continuous Aerosol Delivery Protocol
If intravenous PGI2 is to be used, the infusion is initiated at a rate of 2 ng/kg of body weight per minute and increased by increments of 2 ng/kg/min every 10 to 15 minutes.22 Significant systemic hypotension and platelet inhibition can occur, putting the patient at risk for systemic and epidural bleeding.
Nesiritide is recombinant human B-type natriuretic peptide (BNP), an endogenous peptide produced by the ventricular myocardium.74,75 BNP achieves endovascular smooth muscle cell relaxation by boosting intracellular cGMP, the second messenger for vasodilation of veins and arteries. The half-life of BNP is 18 minutes.74,75 It is administered as a 2 mcg/kg intravenous bolus, followed by an infusion of 0.01 mcg/kg/min. BNP significantly decreases PVR, improves pH and cardiac index, promotes diuresis and natriuresis, and rarely causes more than mild systemic hypotension. Pharmacologic tolerance to BNP has not been reported in any of the clinical studies.74,75 These properties prompted its pilot evaluation in cardiac surgical patients. In PH after coronary artery surgery, BNP significantly reduced PH and PVR, improved cardiac index, facilitated withdrawal of inotropic support, and enhanced diuresis.76
As described above, milrinone, dobutamine, and epidural anesthetics have the potential to cause hypotension, which should be avoided due to the increased oxygen demands of a stressed RV. Vasopressin may be advantageous for the treatment hypotension in patients with PH as it is a selective systemic vasoconstrictor. It results in the maintenance of SVR, without a concomitant increase in PVR, unlike systemic vasopressors such as phenylephrine. Vasopressin is also a pulmonary vasodilator; this effect is mediated by vasopressin 1 receptor activation, subsequent pulmonary endothelial NO release77 and cGMP effects, with NO as an intermediary. Vasopressin’s mild pulmonary vasodilatory effect has been established in animal models of hypoxemia.78 Although vasopressin has been extensively investigated as a systemic vasoconstrictor, it has not been widely evaluated as a pulmonary vasodilator in humans. In vasodilatory shock, boluses of 1 to 4 units and infusion rates of 0.04 to 0.1 unit/min are acceptable, but for intraoperative use infusions should be less than or equal to 0.04 units/min.
Norepinephrine is also preferred over phenylephrine due to its β1 effects, which should assist with the maintenance of myocardial performance. Typical bolus doses are 1 to 5 micrograms with infusions of 1 to 10 mcg/min.
The postoperative period is fraught with danger for the patient with PH who has undergone lobectomy. Supplemental oxygen should be used and oxygen saturation should be kept above 93%. Aggressive pulmonary toilet needs to be enforced because hypoxemia, atelectasis, and pneumonia can increase PVR and risk RV failure. Inhaled beta agonists should be routinely used. Noninvasive ventilation should be considered as an early intervention to elevate oxygenation and promote CO2 elimination. All measures described for intraoperative management of PH should be used postoperatively. For example, inhaled prostacyclin has been effectively used via facemask. Preoperative therapy for PH should be reinstituted as soon as appropriate.
Epidural and multimodal analgesia need to be maintained to optimize analgesia, leading to improved pulmonary function, thus promoting the prevention of atelectasis, hypoxemia, and hypercarbia. The sympathetic response to surgery can further increase the thromboembolic risk of patients with PH, so subcutaneous heparin and thromboprophylactic compression stockings or mechanical devices should be used.
1. Ward J, McMurtry I. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem. Curr Opin Pharmacol. 2009;9(3):287-296.
2. Aaronson PI, Robertson TP, Knock GA, et al. Hypoxic pulmonary vasoconstriction: mechanisms and controversies. J Physiol. 2006;570(Pt 1):53-8.
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