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Hap review 2011

  1. 1. American Journal of Therapeutics 0, 000–000 (2011) Pulmonary Hypertension: A Review of Pathophysiology and Anesthetic Management Ali Salehi, MD Pulmonary hypertension is a condition that can result in serious complications in patients undergoing any type of anesthesia during the perioperative period. By definition, pulmonary artery hypertension is caused by a persistent rise in mean pulmonary artery pressure $25 mm Hg with Pulmonary capillary wedge pressure # 15 mm Hg or exercise mean pulmonary artery pressure $35 mm Hg and pulmonary vascular resistance $ 3 wood unit’s. The severity of the complications depends on the severity of the underlying condition, other comorbidities, and type of procedure, anesthetic technique, and anesthetic drugs. In this article, we briefly review the pulmonary vascular physiology, pathophysiology of the disease, clinical assessment and diagnosis, treatment options, and the anesthetic management of these patients. Keywords: pulmonary hypertension, pulmonary vasoconstriction/dilatation, nitric oxide, prostacycline, phosphodiesterase-3, phosphodiesterase-5, anesthetic agents, anesthetic management PHYSIOLOGY A pulmonary vascular bed is a high flow, low pressure system. Normal PA pressure is about one-fifth of the systemic pressure.1 It has a lower resistance compared with systemic vasculature (40–120 vs. 800–1200 dynÁs/cm5)1 due to thinner media and less smooth muscle. Factors that can affect the pulmonary vascular resistance (PVR) include oxygenation, hypercarbia and acidosis, cardiac output, lung volumes and airway pressure, gravity, pulmonary vascular endothelium and vascular mediators.2–4 Pulmonary vasculature constricts in response to hypoxia (Euler–Liljestrand reflex) and dilates in response to hyperoxia. PVR rises as the PO2 decreases below 60 mm Hg.5 Ronald Regan UCLA Medical Center, Department of Anesthesiology, Division of Cardiothoracic Anesthesia, David Geffen School of Medicine at UCLA, Los Angeles, CA. Address for correspondence: Ronald Regan UCLA Medical Center, Department of Anesthesiology, Division of Cardiothoracic Anesthesia, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Suite 3325, Los Angeles, CA 90095-7403. E-mail: asalehi@ mednet.ucla.edu 1075–2765 Ó 2011 Lippincott Williams & Wilkins Hypercarbia does not directly affect PVR. It increases PVR through an increase in H+ ion and resulting acidosis. Hypoxia and acidosis have a synergistic effect on PVR.5 Increase in cardiac output enrolls the closed blood vessels and dilates the open vessels in the lung resulting in a net increase in pulmonary circulation area and hence a decrease in PVR. An increase in left artrial (LA) pressures also has the same effect. Clinically, the use of inotropes or enhanced blood volume will passively decrease PVR.4 VR is maximum with small lung volumes (vasoconstriction of alveolar blood vessels) and large lung volumes (compression of extraalveolar vessels), and it is minimum at functional residual capacity. This results in a ‘‘U’’ shape relationship (Fig. 1) between PVR and lung volumes.4 High positive end expiratory pressure (PEEP) also compresses the vasculature in the wellventilated areas of the lung and diverts the flow to less ventilated areas resulting in [PVR and YPaO2. Hence, in clinical practice, one should avoid hypo/hyperventilation and high PEEP in patients with pulmonary hypertension. Gravity increases the blood flow to the dependent parts of the lung. This is important in patients with unilateral lung disease. To obtain the best gas www.americantherapeutics.com
  2. 2. 2 FIGURE 1. Relationship between lung volume and PVR. RV, residual volume, FRC, functional residual capacity, TLC, total lung capacity.4 exchange, these patients should be ventilated with their diseased side up.6 There are 2 main mechanisms in the pulmonary vascular endothelium that affect the pulmonary vascular tone and PVR: The first mechanism initiated in the endothelium is the activation of nitric oxide (NO) syntase. NO syntase converts L-Argenine to L-Citrulin and release of NO. NO diffuses to the smooth muscle and increases the activity of the enzyme Guanylate synthase, which converts guanosine triphosphate to cGMP resulting in vasodilatation. Phosphodiesterase-5 (PDE-5) catalyzes the breakdown of cGMP limiting the duration of vasodilatation (Fig. 2). The second mechanism initiated in the endothelium involves the activation of the enzyme Cyclooxygenase. This results in production of prostacycline (PGI2) from arachidonic acid. PGI2 diffuses to the smooth muscle and increases the activity of the enzyme Adenylate syntase, which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). PDE-3 catalyzes the breakdown of cAMP (Fig. 2). These mechanisms are stimulated by O2, shear force, ATP, and vascular endothelial growth factor.3,7 PGF2a, endothelin (ET-1), angiotensin, serotonin result in pulmonary vasoconstriction. Pulmonary vascular response to autonomic nervous system depends on the baseline vascular tone. b-Receptors mediate the response when PVR is low (vasodilatation), and a receptors mediate the response when PVR is high (vasoconstriction). PATHOPHYSIOLOGY The natural history of the disease consists of 3 stages: 1. Endothelial dysfunction and vasoconstriction. In this stage, there is a decrease in the endothelial-derived NO and PGI2 and an increase in thromboxane American Journal of Therapeutics (2011) 0(0) Salehi A2 and ET-1, which result in pulmonary vasoconstriction, smooth muscle (SM) proliferation, and platelet aggregation. Platelet aggregation leads to in situ thrombosis and further releases of endothelial derived factors.1,3,8–10 2. Vascular remodeling and in situ thrombosis. Chronic hypoxia, inflammation (due to acute respiratory distress syndrome, chronic obstructive pulmonary disease, and sepsis) leads to endothelial damage and failure of these cells to eliminate the factors that initiate SM proliferation: Angiotensin 2, ET-1, Thromboxane A2, Superoxide radicals. SM proliferation occurs in both muscular and nonmuscular vessels. There is also an increase in the activity of Protein kinase C, which mediates fibroblast proliferation and collagen deposition in the adventitia layer.1,8,9 3. The last stage is the formation of plexiform lesions that irreversibly obliterate the pulmonary arterioles. This is seen in late pulmonary artery hypertension FIGURE 2. Mechanism of endothelium-dependent vasodilation in the pulmonary artery. Endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX) are stimulated by physiologic agonists ATP and vascular endothelial growth factor (VEGF) and directly by oxygen and shear stress. NO and PGI2 diffuse to vascular smooth muscle, where they activate soluble guanylate cyclase (sGG) and adenylate cyclase, respectively, to increase the levels of cGMP and cAMP. These cyclic nucleotides initiate smooth muscle relaxation. Specific PDEs promote breakdown of the cyclic nucleotides. The arginine analog, asymmetric dimethyl arginine (ADMA), superoxide (OÀ ), and ET-1 2 decrease NO release and cause vasoconstriction. NSAID, nonsteroidal anti-inflammatory drug; PGIS, prostacyclin synthase.7 www.americantherapeutics.com
  3. 3. Pulmonary Hypertension: A Review (idiopathic pulmonary hypertension, scleroderma, Eisenmenger’s syn).1 There are factors that can accelerate the progression of the disease in either acute or chronic setting. These factors include hypoxia, acidosis, increased cardiac output (pregnancy, obesity, anemia, hyperthyroidism). Progression of the disease increases the right ventricular (RV) afterload and RV dilation and eventually RV failure. The slower the rate of progression, the higher the chances for RV to adapt and better prognosis. CLINICAL ASSESSMENT AND DIAGNOSIS Pulmonary hypertension in the past was classified into primary and secondary pulmonary arterial hypertension (PAHTN). In 1998, the World Health Organization introduced a new classification based upon categories sharing similar pathophysiology, clinical presentation, and treatment options. WHO classified PAHTN into 5 categories: (1) Pulmonary artery hypertension, (2) Pulmonary hypertension with left heart disease, (3) Pulmonary hypertension with respiratory disease, (4) Pulmonary hypertension caused by chronic embolic/ thrombotic disease, and (5) Miscellaneous. Symptoms vary based on the severity of the disease. Patients could be asymptomatic in the mild form of the disease to demonstrating fatigue, weakness, dyspnea, leg swelling, abdominal fullness, palpitations, angina, syncope, and cyanosis in more advanced stages.4 Frequent signs of pulmonary hypertension during physical examination include normal to low blood pressure (BP), jugular vein distention with prominent ‘‘a’’ wave, left parasternal heave, loud P2 with split second heart sound, S3 and/or S4 of RV origin, crackles 3 on lung auscultation, and signs of R. heart failure (hepatomegaly, ascites, leg edema).2 The WHO has classified patients suffering from pulmonary hypertension based on their functional class into 4 classes. Class I patients are those in whom regular activity does not cause undue dyspnea, fatigue, or chest pain; class II patients have slight limitation of physical activity; class III patients have marked limitations of physical activity; and class IV patients are those who cannot carry out any physical activity without inducing any symptoms. A series of laboratory tests are needed to confirm the diagnosis and assess the severity of the disease and its underlying pathology. These include chest x-ray, electrocardiogram (ECG), complete blood count, urinalysis, coagulation profile, Echocardiogram (presence of RV hypertrophy and dilatation, severity of tricuspid regurgitation, flattening of the intraventricular septum), pulmonary function tests, ventilation/perfusion scan, chest computed tomography/magnetic resonance imaging, stress test, 6-minute walk test, right and left heart catheterization including acute vasodilator response test (administering NO at a concentration of 20–40 ppm if the PVR decreases by 20% and CO is unchanged or increased the patient is an acute responder),7 and liver function tests (LFTs; Table 1). TREATMENT Treatment of pulmonary hypertension consists of a general and a specific approach. General treatment for patients with PAHTN consists of supplemental oxygen to keep SaO2 . 90% at rest or during activity. It has been shown that supplemental O2 can improve survival in these patients. Diuretics are given to prevent volume overload and treat ascites and edema. Salt restriction is recommended. Digoxin is given to treat heart failure. Proper nutrition is required to Table 1. Diagnostic work-up.8 Diagnostic test Associated condition Echocardiogram Chest radiography Pulmonary function tests V/Q scan, pulmonary angiography, spiral CT scan Sleep study Blood tests (CBC, chemistry panel, serology, coagulation tests) LFTs Cardiac catheterization with vasodilator testing Electrocardiogram LV/RV dysfunction, valvular heart disease, CHD Underlying pulmonary disease COPD, restrictive lung disease Chronic thromboembolic disease Sleep apnea Connective tissue disease, hypercoagulable states Portopulmonary hypertension Arrhythmias, right axis deviation, heart block COPD, chronic obstructive pulmonary disease; LFTs, liver function tests. www.americantherapeutics.com American Journal of Therapeutics (2011) 0(0)
  4. 4. 4 maintain ideal body weight. Exercise is to be done as tolerated. Anticoagulation with warfarin is recommended to prevent in situ thrombi. Goal INR is 2–3, and its dose needs to be adjusted if used with prostacylin. Specific treatment includes the use of the different classes of pulmonary vasodilator medications. We review them briefly as follows: Calcium channel blockers These are only used in patients with a positive vasodilatory response. Their major side effects are hypotension and right heart failure. Nifedipine, Diltiazem, and Amlodipine are commonly used.2,4,7 Prostacycline analogs These are analogs of PGI2, a product of endothelial arachidonic acid, which causes smooth muscle relaxation via [cAMP. They improve outcome and long-term survival. The Most common drugs from this group are Epoprostenol a nonselective IV PGI2 analog with a half life of 4–6 minutes, unstable at room temperature with high pH requiring central access for administration. Iloprost is a selective inhaled PGI2 analog with a half life of 20–30 minutes. It has a simple delivery system and can be used in nonintubated patients. Treprostinil is a nonselective SQ/IV PGI2 analog with a half life of 3 hours. It was approved for use in 2002. It is stable at room temperature and has a neutral pH. Beraprost is an oral PGI2 analog, which is still under investigation.2,11 Inhaled nitric oxide Inhaled nitric oxide (INO) is a selective pulmonary vasodilator through activation of cGMP. It is delivered to the well-ventilated areas of the lung, thus improving the V/Q matching and decreasing intrapulmonary shunting. It has a half life of 2–6 minutes and is rapidly deactivated by oxyhemoglobin and haptoglobin– hemoglobin complexes. It produces methemoglobin in reaction to oxyhemoglobin, so its levels should be checked every q6 hours to keep it below 3–5%. It can be delivered via a nasal cannula, face mask, endotracheal tube. It has a complicated delivery system and is expensive. Its usual dose is 10–40 ppm. High flow rates should be used during its administration to prevent the accumulation of Nitrogen Dioxide (toxic byproduct of INO). INO should never be abruptly discontinued because it can result in rebound pulmonary hypertension.2,8,11 Endothelin receptor blockers ET-1 is a direct pulmonary vasoconstrictor by augmenting smooth muscle proliferation and fibrosis. It has 2 receptors, ETa responsible for SM proliferation and vasoconstriction and ETb responsible for clearance American Journal of Therapeutics (2011) 0(0) Salehi of endothelin and production of NO and PGI2 from the endothelium. This group of drugs has been shown to improve hemodynamics, exercise tolerance, and symptoms. Bosentan is a nonselective oral Eta blocker with a half life of 5 hours approved for patients with WHO functional classes III and IV. It can cause hepatotoxicity; therefore, monthly LFTs are recommended. Ambrisentan is a selective Eta antagonist approved for patients with WHO functional classes II and III. It is administered orally and can cause hepatic toxicity and birth defects. Sitaxsentan is under investigation in the United States. It is 6000 times more selective for Eta than bosentan is.8,11 Phosphodiesterase-5 inhibitors This group of drugs inhibits phosphodiesterase-5 and thus increases the cGMP levels leading to smooth muscle relaxation and vasodilatation. Sildenafil is approved for treatment of pulmonary hypertension regardless of functional class. It is safe to use with Eta blockers, PGI2 analogs, and INO. It prolongs INO effect and attenuates the rebound PAHTN when INO is discontinued. Sildenafil improves functional class and exercise tolerance in 12 weeks and 1-year follow-up with good safety profile.12,13 It is orally administered and can be given via a nasogastric tube intraoperatively. Its use is contraindicated with nitrates due to high risk of developing profound hypotension. Phosphodiesterase-3 inhibitors By inhibiting phosphodiesterase-3, these inhibitors increase the cAMP levels, which in return cause smooth muscle relaxation and nonselective vasodilatation. They also have a positive inotropic effect. Most important drugs from this group are Amrinone and Milrinone. Milrinone comes in both inhaled and IV forms. IV milrinone and INO have a more pronounced effect in reducing pulmonary artery pressure than when they are used alone. It also attenuates the rebound pulmonary hypertension when INO is being weaned. Inhaled milrinone has an additive effect with inhaled PGI2. Its most important side effect is hypotension.4,14 ANESTHETIC MANAGEMENT Assessment of patients with pulmonary hypertension undergoing anesthesia should include obtaining the history and performing a thorough physical examination, obtaining the recent ECG, chest x-ray, echocardiogram, right heart catheterization, and an arterial blood gas sample. All treatments need to be continued to the day of surgery with few considerations. Subcutaneous Trepostinil should be converted to IV Epoprostenol. Oral www.americantherapeutics.com
  5. 5. Pulmonary Hypertension: A Review Anticoagulation can be converted to short acting IV agents and be discontinued at the time of surgery. Any sign of worsening of pulmonary hypertension or RV function should necessitate further work up and treatment, and delay of the intended procedure if possible.8 MORTALITY AND MORBIDITY Noncardiac surgery in patients with pulmonary hypertension is associated with considerable morbidity and mortality even in patients that are stable and well managed. Ramakrishna et al15 showed a 7% mortality and 42% morbidity in patients undergoing major noncardiac surgery (Orthopedic, Thoracic, Vascular, Laparoscopic, etc). The risk is even higher with C-section and liver transplantation. Factors predicting perioperative morbidity risk include New York Heart Association class II or greater, history of PE, Surgery .3 hours, Intermediate to high risk surgery. Factors predicting perioperative mortality risk include right axis deviation on the ECG, RV hypertrophy, RV systolic pressure/Systolic BP $ 0.66, use of intraoperative vasopressors, and history of PE. (Table 2). ANESTHETIC GOALS Formulating an appropriate anesthetic plan requires a clear vision into the general and hemodynamic goals for these patients. General goals include avoiding hypoxia, hypercarbia, acidosis (respiratory or metabolic), Hypo or Hypervolemia, hypothermia, providing adequate anesthesia and pain control. Hypoxia, hypercarbia and acidosis directly or indirectly increase PVR, which in turn can cause a rapid rise in the PA pressures leading to a pulmonary hypertensive crisis and RV failure. Hypovolemia leads to systemic hypotension and impairment of RV perfusion and RV failure. Hypervolemia depending on the presence or absence of left ventricular (LV) dysfunction can result in pulmonary congestion, RV overload, elevation of central venous pressure, and end organ congestion (Liver, Kidney). Providing adequate anesthesia and 5 pain control are essential because pain leads to sympathetic stimulation, which in the context of increased pulmonary vascular tone in these patients can result in pulmonary hypertensive crisis. Hemodynamic goals include maintenance of preload to maintain ventricular filling, maintaining afterload to sustain adequate ventricular perfusion pressure, normal to high contractility to preserve cardiac output and forward flow, maintaining sinus rhythm and normal heart rate (avoiding extremes) to sustain adequate ventricular filling and preserving stroke volume and cardiac output. PREMEDICATION Control of anxiety is important in these patients. Benzodiazepines should be titrated carefully to prevent oversedation and hypoventilation, which can be detrimental. Bronchodilators should be considered if indicated. All pulmonary hypertension specific treatments should be continued in the perioperative period. Specific changes may be needed as mentioned before. MONITORING In addition to standard American Society of Anesthesiologists monitors, selection of invasive monitors depends on the severity of the disease and the risks associated with the procedure (fluid shifts, blood loss, acidosis, and swings in BP). Patients with mild pulmonary hypertension usually do not need invasive monitoring. In patients with moderate to severe pulmonary hypertension, an arterial line is indicated to monitor beat to beat BP changes and blood gas monitoring to detect acid/base imbalances and oxygenation. Central venous pressure monitoring usually is adequate to guide fluid management in the setting of normal RV function. Pulmonary artery catheters are usually indicated when the procedure is associated with significant fluid shifts, BP swings or in patients with compromised RV function. It should be noted that floating PA catheters is associated with higher risk of Table 2. Perioperative considerations.8 Predictors of morbidity Predictors of mortality History of PE NYHA class II or greater Intermediate to high risk surgery Surgery duration . 3 hrs History of PE Right axis deviation Right ventricular hypertrophy RV systolic pressure/systolic blood pressure $ 0.66 Intraoperative vasopressor use NYHA, New York Heart Association. www.americantherapeutics.com American Journal of Therapeutics (2011) 0(0)
  6. 6. 6 PA rupture, and arrhythmias in this patient population.8 Transesophageal echocardiography can also be used to assess RV and LV function, calculate PA pressures, and cardiac output. It could be an alternative in patients with high risk of PA rupture or arrhythmias. Its use depends on the practitioner’s comfort in obtaining and interpreting images. ANESTHETIC TECHNIQUES A Specific Anesthetic technique is less important than the attention to the anesthetic goals and prevention of triggers that cause PAHTN crisis. An appropriate anesthetic technique should be based on the type of procedure, risks associated with the procedure, patients’ comorbidities, and severity of disease. Because any airway instrumentation can precipitate pulmonary hypertensive crisis in patients with moderate to severe PAHTN, local anesthesia or conscious sedation may be preferred considering that the procedure allows the use of such techniques. If conscious sedation is chosen, end tidal carbon dioxide (ETCO2) administered via a nasal cannula should be carefully monitored because it reflects adequate pulmonary blood flow and RV function, Sudden drop in ETCO2 can be a sign of increase in PVR and RV failure. Anesthesiologists should be ready to assist or control ventilation.14 If it is determined that the patient may not be able to maintain adequate ventilation (morbid obesity, sleep apnea, high anesthetic requirements) under sedation or the procedure will not permit spontaneous ventilation, general anesthesia with laryngeal mask airway or endotracheal intubation should be considered. Carmosino et al16 showed that Incidence of complications in children with pulmonary hypertension is independent of the method of airway management. If mechanical ventilation is considered, moderate tidal volumes and low PEEP should be considered to optimize lung recruitment and pulmonary blood flow and minimize atelectasis.8 Neuraxial anesthesia and regional blocks can be used in this patient population if not contraindicated (anticoagulation). Spinal anesthesia should be avoided due to profound sympathetic blockade, decrease in venous return, and bradycardia. Lumbar epidural anesthesia with careful titration is the method of choice if neuraxial anesthesia is considered, although the successful use of combined spinal epidural anesthesia during delivery has been reported.17 Thoracic epidural anesthesia should be considered with caution because it blocks the efferent cardiac sympathetic nerve fibers, which results in negative inotropic response to sudden rise of PA pressures and RV failure.18 American Journal of Therapeutics (2011) 0(0) Salehi ANESTHETIC AGENTS There is conflicting evidence in the literature regarding the effects of anesthetic agents on the pulmonary vasculature. IV anesthetics have little effect on PVR. They cause less intrapulmonary shunting than inhalational agents do because they do not blunt the hypoxic vasoconstriction in the lungs.19,20 Propofol and Thiopental decrease PVR and pulmonary artery pressure (PAP) and mean arterial pressure and myocardial contractility, which are not desirable. The effect of Etomidate on pulmonary vasculature is not well studied. It has minimal effect on the systemic hemodynamics. Benzodiazepines and Narcotics have minimal systemic and pulmonary hemodynamic effect. There is no consensus on the pulmonary effects of Ketamine. It can increase PVR and PAP depending on their baseline values with the most profound effect when baseline PVR and PAP are high.21 Ketamine does not increase PVR when used with pulmonary vasodilators while maintaining its systemic effects [maintenance of systemic vascular resistance (SVR) and BP] which makes its use desirable in this setting.4 Inhalational agents impair hypoxic vasoconstriction in the lungs and hence increase intrapulmonary shunting. They cause dose-dependent depression of myocardial contractility and decrease SVR, which may cause RV dysfunction. Desflurane augments vasocontrictive response to a1 adrenergic activity and increases PVR and PAP. Isoflurane and Sevoflurane are acceptable components of a balanced anesthetic technique. NO increases PVR in adults but has little effect in infants with pulmonary hypertension.22 Pulmonary vascular response to N2O is dependent on the perioperative degree of PVR.23 A balanced anesthesia technique is preferred for general anesthesia. Combination of Midazolam, Fentanyl, low-dose Propofol, or Etomidate/low concentration of Sevoflurane can be used for induction. Anesthesia can be maintained with low-dose inhalational agents and intermittent doses of narcotics. If Neuromuscular relaxation is desired, agents with low hemodynamic effects are preferable (Rocuronium, Vecuronium). POSTOPERATIVE CARE These patients need a monitored bed or an intensive care unit postoperatively to provide adequate ventilation and oxygenation, pain control, fluid management and to monitor hemodynamics. Pulmonary vasodilatory therapies should continue in the postoperative period. In most patients, morbidity and mortality occur several days after surgery due to progressive [PVR, RV dysfunction, and sudden death. www.americantherapeutics.com
  7. 7. Pulmonary Hypertension: A Review MANAGEMENT OF PULMONARY HYPERTENSIVE CRISIS Management of pulmonary hypertensive crisis is based on the principles discussed before: administration of 100% O2 to increase PAO2 and PaO2 and decrease PVR; hyperventilation to induce a respiratory alkalosis; reduction of PAP by YPaCO214; correction of metabolic acidosis. PVR is directly related to the H+ concentration. Management also involves starting INO or other pulmonary vasodilators; supporting myocardial contractility and cardiac output with inotropic support. Epinephrine and Milrinone are preferred. If systemic hypotension and vasodilatation occur, the use of vasopressors is recommended. Norepinephrine is preferred because of its wider ratio of systemic to pulmonary effects (more systemic vasoconstriction than pulmonary). Adequate pain management to eliminate noxious stimuli, which can cause an increase in PAP.14 CONCLUSIONS In managing patients with pulmonary hypertension, anesthesiologists face many challenges. One should carefully assess these patients, obtain all the necessary studies, consult with the surgeon and other specialties involved in the care of these patients, and devise a wellthought anesthetic plan. REFERENCES 1. Rubenfire M, Bayram M, Hector-Word Z. Pulmonary hypertension in the critical care setting: classification, pathophysiology, diagnosis, and management. Crit Care Clin. 23:801–834. 2. Subramanian K, Yared JP. Management of pulmonary hypertension in the operating room. Semin Cardio Vascul Anesth. 2007;11:119–136. 3. Zamanian R, Haddad F, Doyle RL, et al. Management strategies for patients with pulmonary hypertension in the intensive care unit. Crit Care Med. 2007;35:2037–2050. 4. Fischer LG, Aken HV, Burkle H. Management of ¨ pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists. Anesth Analg. 2003;96:1603–1616. 5. Rudolf AM, Yuan S. Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest. 1966;45:399–411. 6. Remolina C, Khan AU, Santiago TV, et al. Positional hypoxemia in unilateral lung disease. N Engl J Med. 1981; 304:523–525. 7. Berger S, Konduri GG. Pulmonary hypertension in children: the twenty-first century. Pediat Clin N Am. 2006;53:961–987. www.americantherapeutics.com 7 8. Mac Knight B, Martinez EA, Simon BA. Anesthetic management of patients with pulmonary hypertension. Semin Cardio Vascul Anesth. 2008;12:91–96. 9. Gaine S. Pulmonary hypertension. JAMA. 2000;284: 3160–3168. 10. Weitzenblum E, Chaouat A. Pulmonary hypertension due to chronic hypoxic lung disease. In: Peacock AJ, Rubin LJ, eds. Pulmonary Circulation: Diseases and Their Treatment. 2nd ed. New York, NY: Oxford University Press; 2004:376. 11. Adamali H, Gaine SP, Rubin LJ. Medical treatment of pulmonary arterial hypertension. Semin Resp Crit Care Med. 2009;30:484–492. 12. Galie N, Ghofrani HA, Torbicki A, et al; and Sildenafil use ` in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157. 13. Pepke-Zaba J, Gilbert C, Collings L, et al. Sildenafil improves health related quality of life in patients with pulmonary arterial hypertension. Chest. 2008;133: 183–189. 14. Friesen RH, Williams GD. Anesthetic management of children with pulmonary arterial hypertension. Pediatr Anesth. 2008;18:208–216. 15. Ramakrishna G, Sprung J, Ravi BS, et al. Impact of pulmonary hypertension on the outcomes of non cardiac surgery; predictors of perioperative morbidity and mortality. J Am Coll Cardiol. 2005;45:1691–1699. 16. Carmosino MJ, Friesen RH, Doran A, et al. Perioperative complications in children with pulmonary hypertension undergoing non cardiac surgery or cardiac catheterization. Anesth Analg. 2007;104:521–527. 17. Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology. 2005;102:1133–1137. 18. Rex S, Missant C, Segers P, et al. Thoracic epidural anesthesia impairs the hemodynamic response to acute pulmonary hypertension by deteriorating right ventricular-pulmonary arterial coupling. Crit Care Med. 2007;35: 222–229. 19. Kellow NH, Scott AD, White SA, et al. Comparison of the effects of Propofol and Isoflurane anesthesia on RV function and Shunt fraction during thoracic surgery. Br J Anesth. 1995;75:578–582. 20. Bjertnaes LJ. Hypoxia induced vasoconstriction in isolated perfused lungs exposed to injectable or inhalational anesthetics. Acta Anaesthesiol Scand. 1977;21:133–147. 21. Morray JP, Lynn AM, Stamm SJ, et al. Hemodynamic effects of Ketamine in children with congenital heart disease. Anesth Analg. 1984;63:895–899. 22. Hickey PR, Hansen DD, Strafford M, et al. Pulmonary and systemic effects of nitrous oxide in infants with normal and high pulmonary vascular resistance. Anesthesiology. 1986;65:374–378. 23. Schulte-Sasse U, Hess W, Tarrow J. Pulmonary Vascular response to nitrous oxide in patients with normal and high pulmonary vascular resistance. Anesthesiology. 1982; 57:9–13. American Journal of Therapeutics (2011) 0(0)