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22June 2012 No.20 HIV related pulmonary hypertension in the obstetric patient A. Thotharam Commentator: S. Maharaj Moderator: M. Mudely Department of Anaesthetics CONTENTS INTRODUCTION ................................................................................................... 3 DEFINITION .......................................................................................................... 3 HAEMODYNAMICS .............................................................................................. 5 CLASSIFICATION ................................................................................................ 5 Venice .................................................................................................................. 6 Dana Point ........................................................................................................... 7 PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV)..................................................................... 8 Prevalence ........................................................................................................... 8 Pathogenesis ....................................................................................................... 8 HIV-related factors ........................................................................................... 9 Other viral factors ............................................................................................ 9 Host factors...................................................................................................... 9 Clinical presentation ......................................................................................... 10 Diagnosis ........................................................................................................... 10 Natural history ................................................................................................... 12 Therapy .............................................................................................................. 13 ANAESTHETIC MANAGEMENT ........................................................................ 16 Pre operative assessment ................................................................................ 16 Delivery .............................................................................................................. 17 Vaginal delivery ............................................................................................. 17 Caesarean section ......................................................................................... 17 Regional Anaesthesia ................................................................................... 17 General ........................................................................................................... 18 Peri-operative monitoring ................................................................................. 19 Post partum ....................................................................................................... 19 Has there been an improvement in mortality over the last decade? ............. 20 CONCLUSION .................................................................................................... 21 REFERENCES.................................................................................................... 22 Page 2 of 26 INTRODUCTION HIV, PULMONARY HYPERTENSION AND PREGNANCY : A FATAL TRIAD Pulmonary hypertension(PH) is a pathophysiological state characterized by elevated mean pulmonary arterial pressure and is found in a number of clinical conditions.31 It is a life threatening condition with poor prognosis if left untreated. Human immunodeficiency virus–related pulmonary hypertension (HIV-PAH) exists when pulmonary arterial hypertension (PAH) develops in patients who have human immunodeficiency virus (HIV) infection and an alternative cause cannot be recognized. 1-3 During pregnancy, physiologic cardiovascular and pulmonary changes worsen existing pulmonary hypertension and right ventricular dysfunction. Pulmonary hypertension is tolerated poorly in the parturient.4,5 Additional haemodynamic changes occur with labour, especially during uterine contractions. After placental extraction cardiac output and systemic vascular resistance increase dramatically. Therefore physiologic changes during pregnancy, during delivery and the postpartum period are critical for patients with severe PH.4-5 Deterioration in pregnancy typically occurs in the second trimester with symptoms of fatigue, dyspnoea, chest pain, when most pregnancy-induced haemodynamic changes have occurred4. During labour, uterine contractions add 500 ml of blood to the circulation. The pain and effort of labour increases right atrial pressure and cardiac output4,5, which may result in right heart failure and even death. Women with PAH are advised against pregnancy and a termination of pregnancy is considered if PH is identified early in pregnancy. When pulmonary hypertension is diagnosed late in pregnancy, the pregnancy is allowed to continue and an elective delivery is usually planned. Improved medical care of patients with PH has increased their life expectancy and has resulted in more women of childbearing age considering pregnancy. 5 DEFINITION The definition of pulmonary hypertension is based upon right heart catheterization measurements. PH is defined as a mean pulmonary artery pressure greater than or equal to 25mmHg at rest6,7 associated with a pulmonary capillary wedge pressure lower than 12mmHg . A mean pulmonary artery pressure of 8 to 20 mmHg at rest is considered normal, while the significance of a mean pulmonary artery pressure of between 21 to 24 mmHg at rest is unclear.9 Patients presenting with pulmonary artery pressures in this range need further evaluation in epidemiological studies. Page 3 of 26 Two previous definitions that were acknowledged are no longer used. They include a mean pulmonary artery pressure greater than 30 mmHg with exercise (this is similarly measured by right heart catheterization)7 and a systolic pulmonary artery pressure greater than 40mmHg (derived from Doppler 8 echocardiography) . The latter corresponds to a tricuspid regurgitant velocity of 3.0 to 3.5 m/sec. Table 1.Haemodynamic definitions of pulmonary hypertension31 Definitions Characteristics Clinical groups Pulmonary hypertension MAP > 25 mmHg All Pre capillary PH MAP > 25 mmHg 1. Pulmonary arterial Hypertension PWP <15mmHg CO normal/reduced 3. PH due to lung Disease 4. Chronic thromboembolic PH 5. PH with unclear and/or multifactorial mechanisms Post capillary PH Mean PAP 2. PH due to left heart >25 mmHg Disease PWP >15 mmHg CO normal/reduced TPG >12 mmHg TPG <12 mmHg MAP= Mean Arterial pressure, PWP= pulmonary wedge pressure, CO= cardiac output, TPG= transpulmonary gradient, PH = pulmonary hypertension Page 4 of 26 HAEMODYNAMICS Haemodynamic variables that contribute to pulmonary arterial pressure can be identified using a variation of Ohm’s Law.9 Change in pressure = flow x resistance Ppa - Ppv = Q x PVR Ppa = (Q x PVR) + Ppv Where Ppa is mean pulmonary arterial pressure, Ppv is mean pulmonary venous pressure, Q = right sided cardiac output , PVR is pulmonary vascular resistance . Ppv is estimated by the pulmonary capillary wedge pressure (PCWP). Ppa = (Q x PVR) + PCWP From this equation, it is apparent that mean pulmonary arterial pressure is determined by the pulmonary vascular resistance, right sided cardiac output and mean pulmonary venous pressure. The primary cause of significant PH is almost always increased pulmonary vascular resistance as in the case with HIV infection.9 Regardless of the cause of PH, a known series of events occur. The right ventricle hypertrophies in response to the pressure. If severe enough, the right ventricle dilates and cardiac output falls.9 CLASSIFICATION Just as the definition of PH has changed, so has the classification. PH was previously classified as either idiopathic pulmonary arterial hypertension (IPAH, previously known as primary pulmonary hypertension) or secondary PH. Nevertheless, it became apparent that some forms of secondary PH closely resemble IPAH in their histopathological features , natural history and response to treatment. In an attempt to organize PH on a mechanistic basis, the World Health Organization (WHO) classified PH into five groups based on aetiology.31 Page 5 of 26 Venice Table 1: Venice clinical classification of pulmonary hypertension (2003) 76 Group 1 PAH 1.Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH 1.2 Familial (FPAH) 1.3 Associated with APAH 1.3.1 Collagen vascular disease 1.3.2 Congenital systemic-to-pulmonary shunts 1.3.3 portal hypertension 1.3.4 HIV infection 1.3.5 Drug and toxins 1.3.6 Other (thyroid disorders, glycogen storage disease, Gaucher disease, Haemorrhagic telangiactasia, haemoglobinopathies, myeloproliferative disorders, splenectomy 1.4 Associated with significant venous or capillary involvement 1.4.1 Pulmonary veno-occlusive disease 1.4.2 Pulmonary capillary haemangiomatosis 1.5 Persistent pulmonary hypertension of the newborn Group 2 PH 2. Pulmonary hypertension due to left heart disease 2.1 Left sided atrial or ventricular heart disease 2.2 left sided valvular heart disease Group 3 PH 3. Pulmonary hypertension owing to lung disease &/or hypoxaemia 3.1 COPD 3.2 interstitial lung disease, 3.3 Sleep disordered breathing 3.5 Alveolar hypoventilation disorders , 3.6 Chronic exposure to high altitude, 3.7 Developmental disorders Group 4 PH 4.Chronic thromboembolic pulmonary hypertension 4.1 Thromboembolic obstruction of proximal pulmonary arteries 4.2 Thromboembolic obstruction of distal pulmonary arteries 4.3Nonthromboembolic pulmonary embolism (tumour,parasite,foreign material) Group 5 PH 5.Miscellaneous Sarcoidosis, histiocytosis X, Lymphangiomatosis, compression of pulmonary vessels(adenopathy, tumours, fibrosing mediastintis) Page 6 of 26 Dana Point Table 2: Dana Point classification of pulmonary hypertension based on aetiology (2008)31 Group 1 PAH 1.Pulmonary arterial hypertension (PAH)10 1.1 Idiopathic PAH 1.2 Heritable PAH, 1.2.1 BMPR2 1.2.2 ALK1, endoglin (With or without hereditary haemorrhagic telangiactasia) 1.2.3 unknown 1.3 Drug and toxins 1.4 Associated with PAH (APAH) 1.4.1 connective tissue disease 1.4.2 HIV infection 1.4.3 portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.4.6 Chronic haemolytic anaemia 1.5 Persistent pulmonary hypertension of the newborn 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary haemoangiomatosis Group 2 PH 2. Pulmonary hypertension due to left heart disease 2.1 systolic dysfunction, 2.2 diastolic dysfunction 2.3 valvular heart disease9 3. Pulmonary hypertension owing to lung disease &/or hypoxaemia 3.1 COPD 3.2 interstitial lung disease, 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.2 Sleep disordered breathing 3.3 Alveolar hypoventilation disorders , 3.6 Chronic exposure to high altitude, 3.7 Developmental disorders 4. Chronic thromboembolic pulmonary hypertension 5.Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Haematological disorders: myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis, vasculitis. 5.3 Metabolic disorders: glycogen storage disease,Gauchers disease . 5.4 Others: tumoural obstruction, fibrosing mediastinitis,chronic renal failure on dialysis Group 3 PH Group 4 PH Group 5 PH Page 7 of 26 PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) HIV infection is an independent risk factor for pulmonary hypertension (PAH)11-13, which may occur irrespective of the mode or stage of HIV infection, and degree of immunodeficiency1, 14 . Mortality in patients with PAH-HIV is usually related to pulmonary vascular disease rather than other complications of HIV infection. PAH is considered and independent predictor of death.1, 14, 15 Prevalence The initial prevalence of PAH in HIV patients was found to be 0.1–0.5%15-17 with an estimated incidence of 0.1% per year. This is 6-12 times greater than the prevalence of PAH in individuals without HIV infection . The largest study was a prospective cohort study of 7648 consecutive patients (done in France- 2004 to 2005) with HIV which found a prevalence of HIV PAH of 0.5%17. Studies likely underestimate the true prevalence of HIV-PAH because the disease often exists prior to the onset of symptoms and diagnosis. Asymptomatic disease is not included in the prevalence estimate. It was suggested that the use of highly active antiretroviral therapy could decrease the rate of PAH associated with HIV infection18, but a population study recently conducted in France contradicts this hypothesis because the calculated minimal prevalence of HIV-related PAH was 0.46%, very similar to before the highly active antiretroviral therapy era.17 Pathogenesis The pathogenesis of HIV-related PAH remains unclear. Both host and viral factors are likely to play important roles. 1 The contributions of viral and host factors are difficult to distinguish as many patients with HIV infection have coexisting conditions that are associated with PAH (eg Hepatitis B/ Hepatitis C infection)1 Plexiform lesions are the hallmark histopathologic finding in patients with severe PAH including HIV PAH.9 Plexiform lesions are characterized by abnormal endothelial cells, intima disruption , medial hypertrophy , thrombosis and luminal obliteration with recanalization19. HIV infection probably does not directly cause the plexiform lesions since HIV is not known to infect endothelial cells. However HIV infection may affect the same pathways that produce plexiform lesions in other types of PAH. Supporting this theory,the plexiform lesions of HIV-PAH are indistinguishable from the lesions seen in patients who have idiopathic PAH (IPAH) 20,21. Page 8 of 26 HIV-related factors HIV proteins may contribute to the development of HIV-PAH, as suggested by the data that follows:73 gp 120- gp 120 is an HIV surface protein that facilitates the binding of HIV to CD4 –positive T lymphocytes. It stimulates in vitro secretion of endothelin-1, a molecule which is known to contribute to IPAH by causing vasoconstriction as well as smooth muscle cell proliferation22. Endothelin-1 may contribute similarly to HIV-PAH . This theory is supported by the observation that circulating monocytes from patients with HIV infection have increased endothelin-1 gene expression.73 Tat- Tat is an HIV transactivator that is essential for viral replication . It downregulates a molecule (BMPR2- Bone morphogenic protein receptor type II) whose function is to induce apotosis in a variety of cell types 23. A deficiency of BMPR2 function will allow excess endothelial cell growth and proliferation in response to injury, which may contribute to PAH 24,25. Nef- Nef is an HIV adaptor protein that is essential for the maintenance of high levels of HIV RNA. Nef predominates in the alveolar mononuclear cells and the endothelial cells of patients who have HIV-PAH 19. In animals , infection with Nef-positive virus induces plexiform lesions , whereas infection with a Nef-negative virus does not.73 Hence this data suggest that Nef may contribute to formation of these plexiform lesions in patients with HIV-PAH. Other viral factors Another co-infection in patients with HIV is Human Herpes virus or HHV8 which is the virus responsible for Kaposi’s sarcoma . The endothelial abnormalities in patients with Kaposi’s sarcoma closely resemble the plexiform lesions that are characteristically found in HIV-PAH.26 Whether Human Herpes Virus 8 has a role in the pathogenesis of HIV-PAH is not been fully elucidated. Host factors Patients with a certain human leukocyte antigen (HLA) may also be predisposed to HIV-PAH. In a case-control study , the frequency of HLA class II DR52 and DR6 was higher in patients with HIV-PAH when compared with healthy subjects and a racially diverse group of patients with HIV infection who did not have PAH.27 A number of host cytokines are much higher in patients with HIV infection . These cytokines may play a role in the development of HIV-PAH. Such cytokines include interleukin-6, IL1 beta, tumour necrosis factor alpha and platelet derived growth factor which can induce a procoagulant state, increase the expression of endothelial adhesion molecules and increase the accumulation of inflammatory cells in the pulmonary arteries28 ,29. Page 9 of 26 These cytokines are unlikely thought to be the sole cause of HIV-PAH because they are elevated in all patients with HIV infection, only a fraction of whom develop HIV-PAH.73 Clinical presentation HIV-related PAH shares a similar clinical presentation with IPAH. These findings may not be as straight forward to recognise as being due to PH if the PH is due to another underlying condition like HIV infection as the presentation of the underlying disease may obscure those of PH.1 History Patients with PH initially experience exertional dyspnoea, lethargy, and fatigue ,which are a result of inability to increase cardiac output with exercise 30. Symptoms at rest are reported in advanced cases. As PH advances and right ventricular failure develops, exertional chest pain, exertional syncope and peripheral oedema may develop. In many circumstances, angina occurs due to subendocardial hypoperfusion which is due to increased right ventricular wall stress and myocardial oxygen demand. Physical examination The initial physical finding of PH is usually increased intensity of the pulmonary component of the second heart sound. This second heart sound may even be palpable. The second heart sound is narrowly split or may be single in patients with preserved right ventricular function. Splitting of the second heart sound widens as the right ventricle fails or if a right bundle branch block develops. Auscultation of the heart may also reveal a systolic ejection murmur and in more severe disease, a diastolic pulmonary regurgitant murmur(pulmonary insufficiency) .The right sided regurgitant murmurs and gallops are augmented with inspiration. Right ventricular failure results in systemic venous hypertension. This can lead to a variety of findings such as elevated jugular venous pressure, a right ventricular third heart sound as well as a prominent ‘V’ wave in the jugular venous pulse if tricuspid regurgitation is present. Inaddition hepatomegaly, a pulsatile liver, peripheral oedema, ascites and pleural effusions may be present. Diagnosis Diagnosis of Human immunodeficiency virus-induced PAH requires confirmation of PAH, confirmation of HIV infection and exclusion of other causes of pulmonary hypertension. Tests used in the diagnosis include: Page 10 of 26 Chest radiograph Abnormal findings encompass: central pulmonary arterial dilatation, which contrasts with “pruning” of the peripheral blood vessels. Right atrial and right ventricular hypertrophy may be appreciated in advanced cases. The chest radiograph allows associated lung diseases or pulmonary venous hypertension caused by left heart disease to be excluded. The severity of PH does not co-incide with the extent of radiographic abnormalities.31 Electrocardiogram This may offer indicative or supportive evidence of PH by showing RV hypertrophy, strain and right atrial dilatation. RV hypertrophy on ECG is present in 87% and right axis deviation in 79% of patients with IPAH30. The absence of these findings does not exclude the presence of PH neither will it eliminate severehaemodynamic abnormalities. The ECG has insufficient sensitivity(55%) and specificity (70%) to be a screening tool for detecting significant PH. Ventricular arrhythmias are rare. Supraventricular arrhythmias may be present in advanced stages, in particular atrial flutter, but also atrial fibrillation, which almost invariably leads to further clinical deterioration.32 Myat Tun Lin Nyo et al, Case report, CVJA 2012 ECG trace of a parturient with HIV-PAH :sinus tachycardia,right ventricular hypertrophy,right axis deviation , T inversionV1-V4 Page 11 of 26 wave Echocardiography This is the screening method of choice. Anatomic and functional data including ventricular function , valvular abnormalities and intracardiac shunts can be assessed. Echo may show RVH, dilatation of the right heart chamber with impairment of left ventricular filling and paradoxical motion of the interventricular septum. Doppler studies provide an estimate of pulmonary artery systolic pressure by measuring peak velocity of the jet of tricuspid regurgitation or by directly measuring systolic flow velocity across pulmonary valve. 73 Confirm PAH Right heart catheterization is necessary to confirm PAH, which occurs when the following criteria are met.33 Mean pulmonary artery pressure >25 mmHg at rest. Pulmonary capillary wedge pressure < 15mmHg Supportive data include an elevated pulmonary vascular resistance and transpulmonary gradient. The transpulmonary gradient is defined as the difference between the mean pulmonary arterial pressure and the pulmonary capillary wedge pressure. Confirm HIV This is done by detecting antibodies to the virus. Exclude alternatives Groups 2, 3, 4, and 5 PH (Dana Point classification) must be excluded before a patient who has HIV infection and pulmonary arterial hypertension can be diagnosed with HIV-PAH. Hence further diagnostic testing such as echocardiography, chest radiography, computed tomography, pulmonary function testing, polysomnography, ventilation-perfusion scanning or pulmonary angiography, autoantibody testing or spirometry should be carried out. 73 Natural history Mortality appears to be high in patients with HIV related pulmonary arterial hypertension A systematic review of 131 patients with HIV-PAH found that 50% of patients died during a median follow up of eight months1. The median duration from the diagnosis of HIV-PAH until death was six months. The data however needs to be interpreted with caution as not all the patients received the same management in these studies and many studies included patients who were managed before Highly Active Anti-Retroviral Therapy (HAART) became common. Page 12 of 26 An observational study of 35 patients with HIV-PAH found that 23 patients died (66%) with a median survival duration of 2.7 years after diagnosis34. HIV infection was accountable for 52 % of deaths, with 32% due to PAH or undetermined (16%) An observational study of 82 patients with HIV-PAH demonstrated a one, two and three year mortality rate of 27, 40 and 53% respectively14. A more recent series of 77 patients with HIV-PAH in the modern therapeutic era suggests that mortality has improved35. The one and three year survival rates were 88 and 72 % respectively, which shows an improvement from previous studies. All of these patients received HAART and 50 patients (65%) received advanced therapy for their PAH. Therapy The treatment discussed here is unique to HIV-PAH however the treatment of HIV-related PAH is less well established in comparison with other forms of PAH. The treatment of PAH can be divided into primary therapy and advanced therapy. Primary therapy is aimed at factors contributing to the PAH and consequences of the PAH. Advanced therapy includes treatment with agents with more complex mechanisms of action including vasodilatation and decreased vascular growth. Primary and advanced therapy for HIV-PAH are essentially very similar to that of the other types of PAH. Antiretroviral therapy HAART is effective at suppressing HIV replication and restoring immune function in patients who meet the criteria for treatment. However its initiation for the sole purpose of treating HIV-PAH is not indicated due to conflicting data regarding its effectiveness.73 In one retrospective cohort study of 35 patients with HIV-PAH, results were compared among patients who received combination antiretrovirals (ARVs) (n=14) , a single nucleoside analogue reverse transcriptase inhibitor (n=12) or no ARV (n=9)34. Only the patients treated with combinationARVs had an improvement in haemodynamics, as assessed by Doppler echocardiography. In addition there seemed to be fewer PAH associated deaths among patients who received combination ARVs. However, the patients receiving combination therapy were also receiving PAHdirected therapy (epoprostenol) , hence the results need to be reviewed with concern. Another cohort study of 82 patients with HIV-PAH found that survival deteriorated when patients received HAART without advanced therapy with epoprostenol.14 Bruno et al performed a retrospective review to determine variables affecting survival in patients with HIV-PAH on HAART. They concluded that HAART was unable to improve haemodynamic variables in these patients.35 From a South African perspective a randomized controlled trial of HAART vs placebo needs to be performed to establish whether HAART is effective in decreasing the incidence of HIV-PAH. Page 13 of 26 Calcium channel blockers These agents are not recommended for the treatment of HIV-PAH because efficacy has not been documented and unbearable adverse effects can develop 12 .These comprise considerable hypotension as a result of systemic vasodilation and decreased right ventricular filling. Diuretics Are can be included in therapy if fluid retention exists35. They should be used with concern to prevent a drop in cardiac output( due to decreased right and/or left ventricular preload), arrhythmias induced by hypokalaemia, and metabolic acidosis. Anticoagulation is not routinely recommended in HIV- PAH alone,because of an increased risk of bleeding, anticipated compliance issues, and drug interactions6,66.In essence : each patients treatment should be individually tailor made. Advanced therapy Advanced therapy includes management with prostanoids, endothelin receptor antagonists and phosphodiesterase 5 inhibitors. It is usually used for patients who show continuing PH and a WHO functional class II,III or IV despite adequate primary therapy. Both intravenous and inhaled epoprostenol improve haemodynamics and symptoms in patients with HIV-PAH.14,37-39 Prostanoids may be used pre/post partum as they are considered teratogenic74 and have negative effects on uterine blood flow75. Intravenous epoprostenol was evaluated in an uncontrolled clinical trial of 6 patients. Acute infusion of epoprostenol decreased the mPAP (mean Pulmonary artery pressure by 8.5mmHg) and PVR (pulmonary vascular resistance - mean 216 dyn/sec per cm-5) while increasing the cardiac output (mean 2L/min) and increasing cardiac index (mean 1.1L/min) 39. Repeat catheterization of five patients after one year of IV epoprostenol therapy showed greater haemodynamic function. Ongoing haemodynamic benefit was seen after two years in three patients and after four years in two patients. Furthermore the New York Heart Association functional class improved in all of these patients. Epoprostenol must be infused via an infusion pump and a central venous catheter. Dose : 1-2 ng/kg per min and increased by 1-2 ng/kg every one to two days as tolerated. Maximum dose has not been established. Doses as high as 150-200 ng/kg per min have been used. Complications include jaw pain, diarrhoea, arthralgias, thrombosis, pump malfunction, central venous catheter infection can also occur. Page 14 of 26 Inhaled epoprostenol was evaluated in two patients with HIV-PAH38. Seven months of inhaled epoprostenol showed improved walking distance, NYHA functional class, mPAP, and PVR. Trepostinil- can be given intravenously or subcutaneously. Intravenous route is preferred as it is associated with less pain on injection. Treprostinil may improve the symptoms and haemodynamics of HIV-PAH. This was shown in an uncontrolled clinical trial in which three patients with HIV-PAH were treated with trepostinil40. The six minute walk distance and NYHA functional class improved at one year in all patients. In addition the systolic pulmonary artery pressure (estimated by echo) improved in two of these patients. Iloprost- Is an inhaled prostanoid that may improve the symptoms and haemodynamics of patients with HIV-PAH. Another uncontrolled clinical trial demonstrated that the eight patients treated with iloprost ,had acute improvement of the pulmonary vascular resistance and cardiac index.41 Among the four patients who continued with long term iloprost the six minute walking distance increased and the haemodynamic improvement persisted.41 There are case studies successfully describing the use of iloprost for PAH in pregnancy49 albeit its association with teratogenicity50. Bosentan- is an oral non selective endothelial receptor antagonist that blocks endothelin-1, a vasoconstrictor and smooth muscle mitogen. Bosentan also may improve the symptoms and haemodynamics of patients with HIV-PAH. However, endothelial receptor antagonists are contraindicated in pregnancy as they are teratogenic42 Sildenafil - Is a phosphodiesterase (PDE5) inhibitor thereby increasing cyclic GMP, and prolonging the vasodilatory effects of nitric oxide. Sildenafil appears to improve symptoms and haemodynamics in patients with HIV-PAH, according to many case reports43-46. Clinical trials have shown that oral sildenafil is effective in the treatment of both acute and chronic pulmonary hypertension 47 48 Drug interactions however occur between sildenafil and protease inhibitors. Protease inhibitors can increase levels of sildenafil and sildenafil can decrease levels of protease inhibitors.43 Nitric oxide(NO) – May be used as an inhaled gas. It is a selective pulmonary vasodilator and acts by stimulating soluble guanylate cyclase and increasing cyclic guanosine monophosphate. Inhaled NO is currently cumbersome, expensive, and needs a sophisticated system because it is administered only during the initial part of the inspiration phase. Patient mobility is also limited. Rebound pulmonary hypertension may occur with withdrawal. The experiences with NO in pregnancy are limited to few case studies. Page 15 of 26 ANAESTHETIC MANAGEMENT Pre operative assessment Preoperative assessment consists of the history, physical examination, and laboratory studies. Assessment of risk and coexisting diseases during preoperative evaluation should focus on the patient’s status, anaesthesia, CD4 cell count, the coexistence of opportunistic infections ,malignancies, concurrent treatments with antiretroviral or anti-opportunistic drugs. This will allow a good prediction for the peri-operative risk of the HIV-patient to be construed. Advanced HIV infection, when accompanied with opportunistic infections or malignancies, may complicate the perioperative course and management. The CD4 count/mortality relationship is useful in risk assessment. Physical examination must include a comprehensive neurological exam together with the other systems, including a difficult airway. The laboratory work-up should include complete blood count .Check for toxic effects or possible interaction of antiretrovirals ( anaemia/ thrombocytopaenia), clotting functions, and glucose, liver (use of Bactrim), and renal function tests (use of protease inhibitors). Verification of the immunological status, i.e., the CD4 lymphocyte cell count and viral load during the previous 3 months, is important. Chest radiograph and electrocardiogram should be performed in all patients. Patients with a history or signs of cardiac or pulmonary dysfunction should undergo a more thorough evaluation (blood gases, pulmonary function tests, echocardiography, cardiac effort test, and radioactive cardiac scanning or even cardiac catheterization. One must remember that these patients have often been subjected to cardiotoxic antiretroviral drugs, may be in a hypercoagulable state, may have accelerated coronary arteriosclerosis, and often have decreased left ventricular contractility. They will require appropriate preoperative work-up and therapy before any anaesthetic or surgical procedure. Another consideration is that acute or prolonged pre op treatment with NO or inhaled prostacyclins may inhibit platelet aggregation hence pre op thromboelastogram should ideally be performed to exclude clotting abnormalities. Page 16 of 26 Delivery The optimal mode of delivery (vaginal vs. caesarean section) and anaesthetic management in patients with PAH remains a matter of debate. Vaginal delivery, however, is related to smaller shifts in blood volume, less clotting or bleeding complications, and a lower risk of infection.67 Vaginal delivery Regional anaesthesia for vaginal delivery is an acceptable technique. Low dose epidural analgesia is imperative.51,52. It has no deleterious haemodynamic effect by itself and significantly lowers the adverse haemodynamic consequences of labour53. However careful timing is important if patients are receiving anticoagulation. Caesarean section As mentioned, the choice of anaesthetic for these patients remains debatable. Whatever the choice may be, the risk of right sided heart failure is markedly increased. Elective caesarean section is often used 52,54,55,56, as it takes place during the day to avoid the risk of emergency deliveries with the haemodynamic instability that could occur under these conditions. Before anaesthesia , chronic medical treatment already being given for pulmonary hypertension and right sided heart failure should be continued. Patient positioning intraoperatively is also very important. Regional Anaesthesia Epidural anaesthesia has been used successfully for caesarean sections in patients with HIV-PAH. There are now more case reports highlighting the successful use of regional anaesthesia with positive outcome52,55,59,60 61. Nevertheless the dense and extended block required for analgesia during caesarean section may have haemodynamic consequences. Specifically single shot spinal anaesthesia is considered a contraindication in these patients62,63. . Hence, graded epidural anaesthesia is often regarded as the best regional technique52,60,61. Some authors prefer using combined spinal-epidural anaesthesia because it provides a superior sensory block than epidural anaesthesia and is associated with an unlikely risk of hypotension when used in very low doses, spinally.62,63 Regional anaesthesia also has the advantage of not interfering with the immune system or with antiretroviral drugs. Contraindications however must be noted. Several haemodynamic goals should be reached: maintain the pulmonary pressure as low as possible and the systemic pressure within 15% above and below the basal level (the systemic pressure should always be higher than the pulmonary pressure). Avoid arrhythmias , tachycardia and maintain sinus rhythm. Page 17 of 26 General Some authors have described the use of general anesthesia with good maternal outcome57,58.In these patients, pulmonary complications can exist due to opportunistic infections. This may lead to respiratory distress and hypoxaemia, worsened by a lowered functional residual capacity seen in pregnancy. Although some authors have described the use of general anaesthesia with good outcome57,58, others have reported higher pulmonary arterial pressure during laryngoscopy and tracheal intubation , and the adverse effects of PEEP may result in cardiac failure62,63. Potent inhalational agents have the ability to drop systemic vascular resistance, contractility, and heart rate, thereby producing hypotension and low cardiac output. The reduction in contractility and the increased incidence of dysrhythmias that occur with halothane are poorly tolerated. Isoflurane, sevoflurane, and desflurane have less effect on contractility and may result in beneficial pulmonary vasodilation, but, the marked reductions in systemic vascular resistance may result in systemic hypotension.69 In patients with adequate functional reserve sevoflurane can be used as it is shorter-acting and more readily titratable than isoflurane and unlike desflurane does not produced tachycardia during rapid increases in concentration.69 Nitrous oxide increases pulmonary resistance in patients with pulmonary hypertension and should be avoided69. Decreased venous return compromises right ventricular preload and pulmonary blood flow. When mechanically ventilating a patient, decreased venous return can occur from positive intrathoracic pressure, such as positive-end-expiratory pressure (PEEP). High PEEP also evokes alveolar overdistension and compression of the capillary network in the alveolar wall and interstitium. This increases PVR and decreases pulmonary blood flow . High PEEP can shift the interventricuar septum producing paradoxical motion , causing right heart dilatation and a smaller left ventricle chamber size72. Decreased systemic vascular resistance (as in post induction) may depress systemic arterial pressure. Hypotension decreases coronary perfusion pressure , which can result in myocardial ischaemia resulting in right sided heart failure. Drugs: Protease inhibitors inhibit CYP 450 thereby impairing metabolism of fentanyl, amiodarone, quinidine. Nevirapine is an inducer of CYP 450 therefore higher doses of anaesthetic drugs may be essential. Etomidate, atracurim, remifentanil and desflurane are not dependent on CYP 450 hepatic metabolism , and hence are the drugs of choice. Avoid ergometrine and nitrous oxide, as both increase PVR. Page 18 of 26 Many haemodynamic goals should be reached: keep pulmonary pressure low. Systemic pressures must be within 15% of the starting pressures (the systemic pressure should always be higher than the pulmonary pressure) and maintain sinus rhythm. Avoidance of hypercarbia, hypoxia, hypothermia and acidosis is also imperative. Also avoid increase in PVR, maintain RV preload, maintain LV afterload, and right ventricular contractility. In case of persistent hypotension, the use of vasoconstrictors such as phenylephrine and norepinephrine can augment coronary perfusion pressure and avoid right ventricular ischemia. Norepinephrine also provides inotropic support. Norepinephrine is metabolized by the pulmonary vascular endothelium. Therefore, its metabolism is reduced in PPH, and its concentrations increase.68 Other agents such as dobutamine and milrinone, which increase cardiac output, maintain systemic blood pressure, and decrease pulmonary vascular resistance, are indicated69. Peri-operative monitoring Monitoring at delivery with electrocardiograpy, pulse oximetry, and invasive arterial blood pressure monitoring is always advocated. However pulmonary artery catheter insertion is debated due to the increased risk of pulmonary artery rupture and thrombosis in pulmonary hypertension.62,64. Standard vascular access includes a central venous line, and a large venous catheter for rapid fluid administration. Post partum Oxytocin infusions must be slow as direct boluses can be fatal in high risk, haemodynamically unstable patients65 The postpartum period is often the commonest period for acute PH decompensation 58. Probable causes include a progressive increase in pulmonary vascular tone , acute pulmonary vasospasm, cardiac arrhythmias, pulmonary thromboembolism, heightened sympathetic tone and fluid shifts. All precautions should be taken to avoid hypoxaemia, hypotension and hypovolaemia, hypothermia and hypercarbia. Postoperative control of pain should be efficient. Any therapy to decrease PVR and improve pulmonary blood flow should be weaned with caution. Patients should be monitored in an intensive care setting. Page 19 of 26 Has there been an improvement in mortality over the last decade? BEDARD ET AL , EUROPEAN HEART JOURNAL (2009) 30 ; 256-265 Mortality rates among parturients with PAH remain high, although they seem to have decreased in the last decade compared with previous era70,71 . Pregnancy should, therefore, continue to be discouraged in patients with PAH.70,71 Page 20 of 26 CONCLUSION HIV-PAH is a serious clinical problem associated with significant morbidity and mortality. Despite the most modern treatment efforts, the maternal mortality as around 36%70,71. Scheduled caesarean delivery during combined spinal-epidural anaesthesia seems to be an attractive approach, but there is no evidence of actual benefit.Hence pregnancy must still be discouraged in patients with severe PH. HIV-associated PAH has almost been exclusively studied in the US and European countries, with just a few case reports from African countries. My experience or observation is that HIV–associated pulmonary hypertension is actually underdiagnosed or misdiagnosed , with patients being investigated for other conditions, hence a diagnosis of pulmonary hypertension is not an early one, often with no treatment been advocated. Although HAART has become widely accessible in developed countries, it is less accessible in our government sector . However, early diagnosis, supportive treatment, and HAART are steps that can considerably advance the quality of life of patients with HIV related PAH. The optimal management of these potentially fatal condition involves interaction with a multidisciplinary approach, with an individually, tailor made anaesthetic plan for each patient. 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