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07 February 2014 No. 04 ANAESTHESIA AND RIGHT VENTRICULAR FAILURE CL Chellan Moderator: B Daya School of Medicine Anaesthetics and Critical Care CONTENTS INTRODUCTION ................................................................................................... 3 ANATOMY OF THE RIGHT VENTRICLE ............................................................. 5 PHYSIOLOGY OF THE RIGHT VENTRICLE ....................................................... 7 CAUSES OF RIGHT VENTRICULAR FAILURE................................................. 10 A. Pressure Overload ................................................................................... 11 Pulmonary Hypertension .................................................................................. 11 1. Volume Overload ..................................................................................... 13 2. Right Ventricular Dysfunction ................................................................... 14 PATHOPHYSIOLOGY ........................................................................................ 14 CLINICAL SYNDROME OF RIGHT VENTRICULAR FAILURE ......................... 17 DIAGNOSTIC TESTING ..................................................................................... 18 PERI-OPERATIVE MANAGEMENT ................................................................... 24 A. Pre-operative Assessment ....................................................................... 24 B. Anaesthetic Goals .................................................................................... 25 C. Choice of Anaesthetic .............................................................................. 26 D. Intra-operative Monitoring ........................................................................ 27 E. Management of peri-operative right ventricular failure .............................. 28 1. General Measures.................................................................................... 28 II. Preload Management ............................................................................... 28 III. Optimisation of RV Rate and Rhythm ....................................................... 29 IV. Pulmonary Vasodilators ........................................................................... 29 V. Vasopressors ........................................................................................... 31 VI. Inotropes .................................................................................................. 31 VII. Mechanical Support of the Right Ventricle................................................ 34 F. Post-operative considerations .................................................................. 34 CONCLUSION .................................................................................................... 35 Page 2 of 37 ANAESTHESIA AND RIGHT VENTRICULAR FAILURE INTRODUCTION For many years, the right ventricle (RV) of the heart has received little attention [1]; with the emphasis in cardiology being placed on the left ventricle (LV), overshadowing the importance of RV function. Before the 1970s, the RV was viewed as little more than a passive conduit for blood[2]; and the RV was thought to play a minor, sub-serviant role to the LV[3]. More recently, the importance of the RV in maintaining haemodynamic stability and organ function has been recognised. Since the RV has received much less interest in research, right ventricular failure (RVF) is less well understood, and there is limited outcomes data with regards to available therapy[1]. In contrast to left ventricular failure (LVF), there are no practice guidelines for its management[4]. The RV is different from the LV, and these differences may influence the assessment and treatment of patients with predominantly right, left or biventricular failure – hence RVF cannot be understood simply by extrapolating data and experience from LVF[5].RVF is a major public health problem[1]. It is estimated to account for 3% of all acute heart failure admissions, and may confer increased mortality compared to acutely decompensated LVF. It may also be an independent risk factor for morbidity and mortality in patients with left heart failure. Pulmonary hypertension (PH) in itself carries increased risk of adverse events (24%) and in-hospital deaths (9.7%); and PH and RHF is more common than previously thought[6]. In a retrospective study conducted by Ramakrishna and colleagues at the Mayo Clinic[7], RVF was found to be a contributing cause of death in 50% of patients with PH, with a mortality rate of 7% for patients undergoing non-cardiac surgery, during the study period 1991 – 2003. 1 in 2000 of the 10-15 million people with COPD will develop RVF[1], and RVF has been found to be the primary cause of death in most of the 50000 fatal cases of PE in the US each year[6]. Acute RV decompensation may be sudden and unpredictable and often responds poorly to treatment[8]. Unfortunately, it is becoming increasingly common, due to the growing prevalence of its predisposing conditions which include LV dysfunction, PE, PH, adult congenital heart disease and coronary ischaemia. In RVF, it has come to attention that RV function plays an important role in heart physiology. The importance of RVF in patients with cardiac and pulmonary disease and its impact in the peri-operative period and critical care is felt every day in clinical practice[9]. The aim of this talk is to provide an overview of the anatomy and physiology of the right ventricle, pathophysiology and diagnosis of RVF; and to discuss the treatment options that may be used when peri-operative RVF is encountered. Page 3 of 37 LIST OF ABBREVIATIONS RV: Right ventricle LV: Left ventricle RA: Right atrium LA: Left atrium RVF: Right ventricular failure LVF: Left ventricular failure RVEF: Right ventricular ejection fraction CO: Cardiac output LVEF: Left ventricular ejection fraction MAP: Mean arterial pressure PA: Pulmonary artery PAP: Pulmonary artery pressure RHC: Right heart catheterisation PV: Pressure-Volume mPAP: Mean pulmonary artery pressure RAP: Right atrial pressure PAC: Pulmonary artery catheter EDV: End diastolic volume PAWP: Pulmonary artery wedge pressure CVP: Central venous pressure SVR: Systemic vascular resistance AV: Atrio-ventricular PVR: Pulmonary vascular resistance IV: Interventricular TV: Tricuspid valve PV: Pulmonary valve PH: Pulmonary hypertension HPV: Hypoxic pulmonary vasoconstriction LVAD: Left ventricular assist device COPD: Chronic obstructive pulmonary disease PDE: Phosphodiesterase CPB: Cardio-Pulmonary Bypass PE: Pulmonary embolism iNO: Inhaled nitric oxide RVMI: Right ventricular myocardial infarction BNP: Brain natriuretic peptide Page 4 of 37 ANATOMY OF THE RIGHT VENTRICLE In the normal heart, the RV is situated anteriorly in the chest, lying behind the sternum; and is bordered by the annulus of the tricuspid and pulmonary valves and the IV septum. The anatomy of the RV has been described as being unique and complex[10]. The RV appears triangular when viewed laterally and crescentshaped in cross-section, in contrast to the ellipsoidal LV. The RV shape is influenced by the position of the IV septum, with the septum being concave toward the LV in normal loading conditions[11]. The RV is thin-walled, usually 1-3mm; hence RV mass is about 1/6th that of the LV in the mature child and adult. The RV volume is greater than that of the LV; the normal range of RVEDV (based on MRI) is 49 – 100 mL/m2 and LVEDV is 44 – 89 mL/m2 [12]. The RV is therefore well designed to accommodate increases in preload, but poorly designed to accommodate increases in afterload[13]. The RV can be divided into 2 components, the sinus or inflow region – extending from the TV and includes the trabeculated apical portion; and the conus or outflow tract (also called the infundibulum) – extending from the septo-marginal band to the PV. Three prominent muscular bands are present in the RV: parietal, septal and moderator bands. The parietal band and infundibular septum makes up the crista supraventricularis, which separates the sinus and conus regions [10, 11]. The septomarginal band extends inferiorly and becomes continuous with the moderator band, which extends from the anterior papillary muscle to the IV septum. The moderator band was so named as it was initially thought to moderate RV distension, but it actually transmits the right branch of the AV bundle of the conduction system[13]. The RV can also be divided into anterior, lateral and inferior walls; as well as basal, mid and apical sections[11]. Both ventricles are composed of multiple muscle layers, that form a 3D network of fibres[11]. In the RV, the superficial layer fibres are arranged circumferentially – parallel to the AV groove – and continue into the superficial myofibrils of the LV. RV deep layers are aligned longitudinally from base to apex. The RV and LV are functionally bound due to the continuity of muscle fibres, IV septum and pericardium – these contribute to ventricular interdependence[11]; the concept that the size, shape and compliance of one ventricle can influence that of the other ventricle. The RV is supplied mostly by the right coronary artery – in a right dominant system. The lateral wall is supplied by the marginal branches, the posterior wall and infero-septal region by the posterior descending artery, the anterior wall and antero-septal region by branches of the left anterior descending artery, and the infundibulum by the conal artery[11]. The RV drains into the anterior cardiac veins which empty into the RA[14]. In the LV, myocardial perfusion occurs mostly in diastole, when intramyocardial tissue pressure is less than that of the aortic root. In the RV, under normal loading conditions, intramyocardial pressure remain low throughout the cardiac cycle, allowing continuous coronary flow. Page 5 of 37 Figure1. Segmental anatomy of the RV[10] Page 6 of 37 PHYSIOLOGY OF THE RIGHT VENTRICLE RV contraction is sequential- contraction starts with the inlet and trabeculated myocardium, and moves in a wave, ending with the infundibulum[6, 11]. The RV contracts by three mechanisms: - Inward movement of the free wall - Contraction of the longitudinal fibres which shortens the long axis, bringing the tricuspid annulus towards the apex - Traction of the free wall secondary to contraction of the LV – this may contribute up to 40% of systolic RV function due to ventricular interdependence This bellows like contraction (vs. the “wringing” motion of the LV) results in a greater ratio of RV volume change to RV free wall surface area change – producing a greater RVEF with little change in RV wall stretch[1]. This type of contraction is optimal for moving large, varying volumes of blood; but poorly adapted to generating high pressure – ie. the RV performs mainly volume, rather than pressure work[13]. RV systolic function is determined by preload, contractility and afterload[11]. RV performance is also influenced by rhythm, ventricular synchrony, RV free-interval relationship and ventricular interdependence. The relationship between preload and afterload is well demonstrated in the PressureVolume loops of the RV (illustrated in Figure 2) – where the triangular shape illustrates the short period of isovolumetric contraction and increased compliance[15]. Figure 2. Pressure-Volume loops of RV and LV[13] Page 7 of 37 One important finding from examination of PV loops is that the RV follows a timevarying elastance model[10, 11]; where ventricular elastance is the relationship between systolic pressure and volume under varying conditions. RV maximal elastance can be approximated by a linear relationship, and can be used as an index of contractility. Some limitations in the time-elastance model include nonlinearity, variability in slope values and afterload dependency[11] RV preload represents the load present before contraction. RV filling starts before and finishes after the LV, and RV filling velocities and the E/A ratio are lower[11]. Factors that influence RV filling are: intravascular volume status, ventricular relaxation, ventricular chamber compliance, heart rate, passive and active atrial characteristics, and pericardial constraint. The RV is able to accommodate dramatic alterations in venous return which may be caused by changes in volume status, position, and respiration. Despite these changes, the RV maintains a somewhat constant CO[1], largely due to its unique geometry. RV afterload is chiefly determined by the pulmonary circulation, which has a low pressure and resistance (1/10th that of SVR)[9] and is highly compliant.The cross-sectional area of the pulmonary vascular bed is large. The pulmonary vasculature is highly distensible, and is able to accommodate increases in flow because its vessels are recruitable. PVR can be regulated by many factors[4, 16]: hypoxia and hypercarbia ( vasoconstriction), cardiac output (distends open vessels and recruits previously closed vessels ↓PVR), gravity (influences distribution of blood flow in the pulmonary circulation), pulmonary volume (increased flow mechanical stress activation of endothelial cells) and pressure, and specific molecular pathways such as nitric oxide (vasodilatation), prostaglandins (vasodilatation), and the endothelin pathway (vasoconstriction). Under physiological conditions, pulmonary arterioles are thin walled, with thin media (only about 7% of wall thickness), and few smooth muscle cells, however endothelial dysfunction, chronic hypoxia, and inflammation can lead vascular remodelling which can cause and worsen pulmonary hypertension[16]. Page 8 of 37 Table 1 summarises the important anatomic and physiologic characteristics of the RV and LV. TABLE 1. COMPARISON OF NORMAL RV AND LV STRUCTURE AND FUNCTION[11] CHARACTERISTICS RV LV Structure Inflow region, trabeculated myocardium, infundibulum Inflow region and myocardium, no infundibulum Shape From the side: triangular Cross section: crescentic Elliptic EDV (mL/m2) 75 + 13 (49 – 101) 66 + 12 (44 – 89) Mass (g/m2) 26 + 5 (17 – 34) 87 + 12 (64 – 109) Thickness of ventricular wall (mm) 2–5 7 – 11 Ventricular pressures (mmHg) 25 / 4 [(15 – 30)/(1 – 7)] 130 / 8 [(90 – 140)/(5 – 12)] RVEF (%) 61 + 7 (47 – 76) 67 + 5 (57 – 78) Ventricular elastance - Emax (mmHg/mL) 1.30 + 0.84 5.48 + 1.23 Compliance at end diastole (mmHg-1) Higher than LV 5.0 + 0.52 x 10-2 Filling profiles Starts earlier and finishes later, lower filling velocities Starts later & finishes earlier, higher filling velocities PVR vs. SVR (dyne.s.cm-5) 70 (20 – 130) 1110 (700 – 1600) Stoke work index (g.m2/beat) 8 + 2 (1/6 of LV stroke work) 50 + 20 Exercise reserve ↑ RVEF > 5% ↑ LVEF > 5% Resistance to ischaemia Greater resistance More susceptible Adaptation to disease state Better adapted to volume overload Better adapted to pressure overload Page 9 of 37 CAUSES OF RIGHT VENTRICULAR FAILURE The common causes of RVF as illustrated in Table 2 are broadly divided based on the underlying pathophysiological mechanisms[4, 13, 14]: - RV pressure overload / RVF secondary to increased afterload - RVF secondary to volume overload - Intrinsic RVF (in the absence of PH) TABLE 2 : CAUSES OF RVF[13] 1. RVF with normal afterload Cardiomyopathy RV Infarction Sepsis Arrhythmogenic RV dysplasia 2. RVF secondary to increased afterload Mitral valve disease with PH Pulmonary embolus Obstructive sleep apnoea ARDS Pulmonary stenosis RV outflow tract obstruction Tetralogy of Fallot Double-chambered RV Transposition of great vessels Increased afterload following cardiac surgery - Inflammatory effects of CPB - Protamine Increased afterload following thoracic surgery - Excessive lung resection - LVAD 3. RVF secondary to volume overload Ventricular septal defect Atrial septal defect Pulmonary regurgitation Tricuspid regurgitation Anomalous pulmonary venous return Sinus valsalva rupture into the RA Coronary artery fistula to RA or RV Rheumatic valvulitis Page 10 of 37 Carcinoid syndrome A. Pressure Overload This is the most common cause of RVF, due to its anatomical and physiological properties[14]. RV pressure overload is caused by any condition impeding blood flow between the RV and LV such as PH, RV outflow tract obstruction and PV stenosis. Peri-operative causes of acutely elevated PVR include[4, 16]: hypoxia, hypoventilation, atelectasis, high ventilating pressures, CPB (due to endothelial injury), protamine reactions, acute pulmonary thromboembolism, CO2 or air embolism, bone cement and ischaemia-reperfusion syndromes. Pulmonary Hypertension [4, 15, 17-21] PH is defined as mPAP (mPAP = PVR X CO + LAP) of >25mmHg at rest, as assessed by RHC. Pre-capillary PH occurs in the setting of normal PAWP of <15mmHg, PVR of >3 wood units and normal or reduced CO; whereas in postcapillary PH, the PAWP is >15mmHg. The previous additional definition of mPAP>30mmHg during exercise is no longer used[20]. PH may be further classified as mild (mPAP 25 – 40mmHg), moderate (41-55mmHg), or severe (>55mmHg)[4]. The additional classification is useful as mild PH rarely impacts anaesthetic management[17] , whereas moderate and severe PH can precipitate acute decompensation of the RV, necessitating specific anaesthetic plans and therapy. The American College of Chest Physicians recommends that all patients who are suspected to have PH undergo RHC so that a precise diagnosis can be made [15]. RHC remains the gold standard for the diagnosis of PH as Echocardiography may have technical limitations, even under optimal conditions. Haemodynamic variables measured during RHC (which include RAP, PVR and RV performance) can also be used to assess prognosis and predict survival [15]. The diagnosis of PH relies on a high index of suspicion as symptoms are nonspecific and it may not be easy to differentiate them from symptoms of other pulmonary and/or cardiovascular disease – which may also co-exist. The mean interval from onset of symptoms to diagnosis has been noted to be around 2 years[19]. The classification of PH has undergone many changes since it was 1st proposed in 1973[20]. At the 4th World Symposium on Pulmonary Hypertension held in Dana Point, California in 2008; an updated clinical classification directed at the underlying clinical causes was developed – as illustrated in Table 3[18, 22]. Page 11 of 37 TABLE 3 : Clinical Classification of Pulmonary Hypertension developed by the 4th World Symposium on Pulmonary Hypertension at Dana Point, CA[22] 1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic (IPAH) 1.2 Heritable 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue diseases 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 1.6 Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary haemangiomatosis 2. Pulmonary hypertension owing to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3. Pulmonary hypertension owing to lung disease and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. Pulmonary hypertension with unclear multi-factorial mechanisms 5.1 Haematologic disorders: myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disease 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Page 12 of 37 PAH[20]: can occur in association with many other disorders. The incidence of PAH in HIV is approximately 0.5% - 6–12X higher than the general population, and this incidence is not decreased with ARV therapy. It is characterised by the presence of pre-capillary hypertension. Histological examination has demonstrated a panvasculopathy affecting predominantly small ‘resistance’ pulmonary arteries, involving intimal hyperplasia, medial hypertrophy, adventitial proliferation, thrombus in situ, varying degrees of inflammation and plexiform arteriopathy. PH due to LH Disease[6, 21, 23]: is a post-capillary PH, and includes LV systolic dysfunction, LV dysfunction with preserved EF and Valvular diseases. LH disease may cause passive backward transmission of increased LAP, leading to raised PAP. In some patients, the observed rise in PAP is out of proportion to the increased LAP, and the trans-pulmonary gradient is also increased – indicating remodelling of the pulmonary circulation or an abnormal vasoconstrictor response. PH due to LH disease, particularly LV systolic dysfunction is one of the most common causes of PH and these patients are at higher risk for morbidity and mortality. Therapy in this group is mainly directed toward the underlying condition. Although theoretical “reversal” of the PH may be possible if the underlying pathology is corrected, the increased PVR becomes irreversible in many conditions, PH due to lung diseases[18]: is mainly caused by alveolar hypoxia, impaired control of breathing, or high altitude. In most patients, the PH is modest. CTEPH: is a frequent cause of PH and occurs in up to 4% of patients after acute PE. Treatment goals in PH include[20]: improving symptoms and functional capacity, decreasing mPAP, normalising CO, and reversal or slowing down the rate of progression of the underlying disease. With the increasing availability of diseasemodifying therapies, median survival for patients with PH has increased – resulting in more of these patients undergoing anaesthesia and surgery. Factors predicting poor prognosis and increased risk of illness after non-cardiac surgery include[15, 18]: poor functional status (NYHA II or higher), elevated RAP, significant RV dysfunction (which may be more significant than the severity of PH) or evidence of RVF, increased BNP and CRP, underlying scleroderma, history of PE, intermediate or high risk surgery, and anaesthesia lasting longer than 3 hours. The overall mortality from massive PE is 6 – 8%, increasing to 30% if complicated by systemic hypotension. Total peri-operative mortality is about 30% with mortality rates approaching 60% in patients where pre-operative cardio-pulmonary resuscitation was necessary[24]. 1. Volume Overload[1, 4, 25] Acute volume overload may be caused by atrial or ventricular septal defects, acute tricuspid regurgitation, volume overload, and ruptured sinus of Valsalva aneurysm. Although volume overload is commonly considered as a cause, it generally will not cause acute RVF in the absence of increased PAP. Page 13 of 37 This is because the RV adapts better to volume than to pressure overload and may be able to tolerate volume overloaded states for a long time before significant decline in RV systolic function become evident. 2. Right Ventricular Dysfunction[1, 4, 13, 14, 25] RV ischaemia can be caused directly by RVMI, or indirectly by systemic hypotension. The RV is usually less prone to ischaemia due to its thin wall, continuous coronary perfusion, low oxygen extraction (about 50%) and consumption under resting conditions. RV infarction often occurs in association with LV infarction but can also occur as an isolated event. RVMI is often unrecognised. Most clinically evident cases occur in the setting of inferior MI, and although instability with hypotension occurs in less than 10% of patients, it is associated with high mortality – up to 75%. Acute RVF may be caused by RV myocardial injury itself, LV dysfunction, or loss of atrio-ventricular synchrony. RV dysfunction occurs commonly after cardiac surgery, and may be due to: myocardial stunning, intracoronary air embolism, decompensation of pre-existing RV dysfunction, as well as the effects of CPB or cardioplegic arrest. PATHOPHYSIOLOGY The most important factors determining RV adaptation to disease is the type and severity of myocardial injury or stress, the time-course of the disease (acute/chronic), and the time of onset of the disease(newborn/paediatric/adult)[25]. Other factors that may have a role include: neuro-hormonal activation, altered gene expression, and the pattern of ventricular remodelling; with interactions occurring between the factors. A. Response of the RV to increased volume[1, 4, 6, 14] Generally, RV volume overload is well tolerated because it is optimised to accommodate large changes in volume[6]. Indeed, the RV may tolerate longstanding volume overload, as seen in ASD and TR, without significant decreases in RV systolic function[25].Like the LV, the RV uses the Frank Starling Mechanism to increase stoke volume in response to increased wall stretch[1]. Thus, RV dilatation leads to greater recruitment of function. This response is usually minimal at baseline, but once the RV has dilated into a more circular form, a steeper relationship between volume and stretch develops[4]. Global function of the RV is dependent on its free wall and IV septum, with both the RV and LV making a contribution towards RV output. In isolated volume overload, the RV can still use ventricular interaction. Although the IV septum is shifted towards the left in diastole, it returns to normal position in systole – adding to RV systolic function[14]. With severe RV dilatation, minimal increase in RV free wall contraction can occur in response to further increases in volume, leading to increasing RV pressure; further increases in RV volume then occurs at the expense of the RV[6], and this may have a negative effect on CO. Page 14 of 37 B. Response of the RV to increased pressure[6] In comparison to the LV, the RV has limited ability to produce elevated pressure work[6]: RV functions worsens parallel to increases in PAP[9]. The thinner free wall faces higher rise in wall tension with increased pressure (LaPlace relation). There also appears to be biochemical differences allowing the RV to be optimised more for rapid contraction[6]. Two examples of well tolerated pressure overloaded states include Eisenmenger Syndrome and Congenital Pulmonary Stenosis. The initial response to modest pressure overload is accomplished by homeometric autoregulation – The Anrep Phenomenon[1, 4]. This rapidly increases contractile function to maintain CO, and is mediated through alterations in calcium dynamics. Although RV hypertrophy may initially be adaptive, it is also the initial step in the process of remodelling, which is ultimately damaging[5]. As afterload increases, endogenous catecholamines may allow further increases in inotropy. With further increases in PVR, the EDV increases and functional recruitment via the Frank Starling mechanism occurs – heterometric autoregulation[14]. Once the mechanisms of contractile reserve are exhausted, further increases in afterload can lead to sudden haemodynamic collapse, which is often associated with the onset of RV ischaemia[4]. Progressive RV dilatation leads to increased IV septal shift and tricuspid regurgitation, causing decreased LV compliance and preload, which causes decreased CO and systemic hypotension. The dynamics of RV coronary perfusion is also altered due to increased RV pressure and decreased aortic root pressure[1]. RV ischaemia leads to further decreases in RV stroke volume, LV preload and MAP a catastrophic downward spiral – as illustrated in figure 3[14]. Page 15 of 37 C. Response of the RV to decreased contractility[1, 4] If the pulmonary driving pressure can be maintained, and the PVR remains low, decreases in RV contractility may not result in RVF. In this situation, an elevated CVP can provide enough driving force to maintain flow across the pulmonary circulation. When PVR or LAP is elevated, ie. when RV demand increases; RVF will occur. Ischaemia caused by RCA occlusion can lead to varying degrees of RV ischaemia, which explains why there may be varying degrees of haemodynamic instability[9]. Grade 1: necrosis of <50% of the posterior wall Grade 2: necrosis limited to, but not involving >50% of the posterior wall Grade 3: necrosis of the posterior wall and <50% of the anterolateral wall Grade 4: necrosis of the RV posterior wall and >50% of the anterolateral wall RV MI has been reported to occur more in the setting of previous RV hypertrophy. D. The RV in LVF[5] The hypothesis that LV enlargement can lead to RV dysfunction was first made in 1910. RVF may develop in association with LV dysfunction or failure through many different mechanisms: LVF causes increased RV afterload due to increased pulmonary venous and ultimately pulmonary arterial pressure. This is illustrated in Figure 4[26] If LV dysfunction is due to cardiomyopathy, the same process may also affect the RV Myocardial infarction may affect both ventricles LV dysfunction may cause decreased aortic root pressure, decreasing RV coronary perfusion which may lead to significant RV dysfunction Ventricular interdependence may play a role LV dilatation may cause RV diastolic function by a limited pericardial component Page 16 of 37 CLINICAL SYNDROME OF RIGHT VENTRICULAR FAILURE The American College of Cardiology/American Heart Association guidelines[27] define Heart Failure as “a complex clinical syndrome that can result from any structural of functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.” In these guidelines, the RV is barely mentioned. In patients with an LVAD, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) proposes an inclusive definition for RVF as[1]: “symptoms and signs of persistent RV dysfunction (RAP >18mmHg with cardiac index <2.0l/min/m2) [in the absence of elevated LAP/PCWP (greater than 18mmHg), tamponade, ventricular arrhythmias or pneumothorax]; any RVF requiring Right ventricular assist device implantation; or any RVF requiring iNO or inotropic therapy for a duration of more than 1 week at any time after LVAD implantation.” For the peri-operative period, no consensus definition of RVF has yet been established. Greyson CR suggests that RVF be defined as[1]: “the clinical syndrome resulting from the rights heart’s inability to provide adequate blood flow to the pulmonary circulation at a normal central venous pressure.” The symptoms of RVF are non-specific and they may vary depending on the severity of and the underlying precipitant of RVF[8]. Patients with conditions causing increased afterload, may complain of dyspnoea, presyncope, syncope or fatigue. In both RV infarction and PE, chestpain or discomfort may be an important presenting symptom. In acute on chronic RVF, lower limb swelling, and RUQ discomfort may be present. Signs of RVF include: systemic hypotension, tachycardia, tachypnoea, cyanosis, elevated jugular venous pressure, a parasternal heave, right sided 3rd heart sound, TR, hepatomegaly and peripheral oedema. The signs of PH may also be present: increased splitting of the 2 nd heart sound, loud pulmonary component of the 2nd heart sound – although these may be lost as RVF worsens and PAP decreases. The signs and symptoms of acute RVF may be superimposed on those of chronic RVF, and may also co-exist with LVF, valvular lesions, and chronic pulmonary diseases.No single sign or symptom can perfectly identify all episodes of RVF, but in general, decompensated RVF is not present if the JVP is normal – this may be a predicament in the setting of RVF with intravascular volume depletion. The absence of pulmonary congestion with raised CVP + hypotension has often been quoted as being the most specific findings in isolated RVF[1]. Peri-operative limitations of these key elements in diagnosing RVF include: - Co-existence of RVF with LV systolic or diastolic failure - Increased RAP from increased intrathoracic or intraabdominal pressure without any RV dysfunction.PH – is a risk factor for developing RVF (initial PAP will be high, but will pseudonormalise in RVF due to decreased CO) Page 17 of 37 DIAGNOSTIC TESTING The current options for diagnosis include ECG, CXR, cardiac biomarkers, ECHO, cardiac MRI and RHC. Figure 5 illustrates an integrated approach to the assessment in a patient with acutely decompensated RVF. Page 18 of 37 Electrocardiograph[8, 13]: is often normal. Patients may have evidence of infarction or signs suggestive of PE. Possible changes include: - Sinus tachycardia - T wave inversion in leads III and aVF or leads V1-4 - RBBB – incomplete or complete - QRS axis >90 or indeterminate - SIQIIITIII pattern - Qr pattern in lead VI - S waves in lead I and aVL >1.5mm - Q waves in lead III and aVF but not in lead II - Transition zone shifted to V5 - Low limb lead voltage - Atrial fibrillation Chest Radiograph (CXR)[8]: has limited ability to identify RVF. Once signs suggestive of RVF are shown, it is usually advanced. Due to its anatomic location, the RV is poorly visualised on conventional CXR. PE may be suggested by enlargement of the main PAs, distended azygous vein, and oligaemia of a lobe. RV dilatation may be suggested by changes in heart position, cardiac silhouette (filling of retrosternal space), and adjacent structures. RA dilatation may be suggested by increased curvature of the right heart border. Cardiac Biomarkers: will aid in the diagnosis of RVF, and suggest possible causes[8]. Elevated levels of serum troponins, BNP and pro-BNP have been seen in RV dysfunction, especially in the setting of underlying PE. Troponins may be elevated due to ischaemia or micro-infarction secondary to increased wall tension, increased oxygen demand and decreased coronary perfusion. BNP is secreted by the myocardium secondary to increased RV shear stress. In general, the cut-off values for troponins and prognostication in PE are similar to those used in diagnosing MI. In PE, troponins and BNP have negative predictive values for in hospital death between 97-100%. In acute PE and RVF though, the positive predictive value is low, there is a wide range of sensitivities, and specificity is also low for adverse events, including inhospital deaths[8]. In a study by Nagaya and colleagues[28], in patients with volume overload secondary to ASD and pressure overload secondary to PAH or thromboembolic PH; rising BNP levels correlated with increases in mPAP, PVR, mRAP, RVEDP and RV mass, and decreases in CO and RVEF. In another study, the same authors showed that elevated baseline and post treatment BNP were independent prognostic markers of mortality, in patients with PAH[29]. Echocardiography (ECHO/Echo) [8, 14, 30-32] This is quoted by some as being the preferred diagnostic tool due to its availability at the bedside and non-invasive nature; and by others as being inferior to RHC due to intrinsic and operator dependent limitations. Page 19 of 37 ECHO can be useful in determining RV dimensions and function, PAPs, and allows for real-time analysis of RV shape – with particular attention to septum, convexity, RV dimension and TR[9]. It may also help diagnose the cause of RV dysfunction, and diagnose other conditions such as valvular heart disease, congenital heart disease, LV outflow tract obstruction, LV systolic or diastolic dysfunction, acute PE, pulmonary disease and pericardial diseases. Although Trans-Thoracic Echo (TTE) provides direct visualisation of the RV, technical and anatomic limitations may decrease its sensitivity and reproducibility; and TransOesophageal Echo(TOE) may then provide better assessment[8]. Echocardiography assessment of the RV may be more challenging than that of the LV because of its complex shape, difficulty in endocardial surface recognition, and marked dependence on loading conditions[33]. Although challenging, it remains the mainstay of peri-operative RV functional assessment. Because RV dysfunction is associated with morbidity and mortality, especially after cardiac surgery, its assessment during intra-operative TOE is vital[33]. In the near future, 3D technology may enable better assessment of RV volumes. Echocardiographic findings associated with RVF include[8]: - RV dilatation (ratio of RVEDV:LVEDV of >0.6, if severe then >1.0) - RV hypokinesis - Change to a more concentric RV morphology - Paradoxical septal motion - Impaired LV diastolic function (suggested by alterations in Doppler mitral flow such that A wave> E wave) - RA enlargement - TR - PAP as estimated by the modified Bernoulli equation (p=4V2) - PA dilatation - Lack of inspiratory collapse of the IVC - Pericardial effusions Other useful Echo derived measures of RV loading conditions and performance are[13]: - RV free wall motion - Thickness of free wall >15mm at end-diastole hypertrophy - Dilatation: as assessed by examining the apex in long-axis view – when the RV forms the apex then dilatation is present - Tissue Doppler tissue velocity: quantitative index of RV free wall motion and function - Hepatic venous flow pattern: demonstrates systolic flow reversal - occurs in severe RVF - Doppler echo: allows assessment of severity of PH Page 20 of 37 Figure 6 Views used to perform comprehensive evaluation of the right heart [34] Page 21 of 37 In 2010, the American Society of Echocardiography published their guidelines for the assessment of the Right Heart in adults[34]. The purposes of their guidelines are to: - Describe acoustic windows required to evaluate the right heart (14 views are described and illustrated – as in Figure 6) - Describe echo parameters required to assess RV size and function - Present advantages and disadvantages of each measure/technique described by critical assessment of the literature - Recommend measures to be included in the standard echo report - Provide reference values of right-sided measurements based on literature reviews Table 4 gives a summary of the echocardiograph indices of the RV. Table 4: Echocardiographic indices of the right ventricle[33] FUNCTIONAL PARAMETER NORMAL VALUE LOAD DEPENDENCY RV Fractional Area Change (RVFAC) (%) 32 – 60 +++ RVEF (%) 45 – 68 +++ >15 +++ 1.4 + 0.5 + Systolic Performance Variables Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm) Isovolumetric Acceleration using Doppler tissue imaging (IVA) (m/s2) Tricuspid annular plane maximal systolic velocity (using spectral pulsed wave tissue Doppler) (cm/s) >12 ++ Diastolic Parameters IVC dimension (cm), collapse index (%) Tricuspid early (E) to late (A) filling velocity ratio < 1.7, CI > 50 +++ 1.5 + 0.3 +++ S/D velocity ratio >1 no S reversal atrial reversal< 50% S Hepatic vein profile (S: systolic, D: diastolic) +++ Isovolumetric Relaxation Time (IVRT) (ms) < 60 +++ Rapid myocardial filling velocity (E1) (cm/s) E1: 15.6 + 3.9 +++ Late diastolic myocardial filling velocity, A1 (cm/s) A1: 15.4 + 4.5 +++ 0.28 + 0.04 ++ Combined Systolic and Diastolic Parameter RV myocardial performance index The severity of RV systolic dysfunction may be graded using RVFAC and RVEF Using RVFAC: mild dysfunction: 25-31%, moderate dysfunction 18-24%, severe dysfunction <17% Using RVEF: mild dysfunction: 35-44%, moderate dysfunction 26-34%, severe dysfunction <25% Page 22 of 37 Radionuclide Ventriculography[9, 35]: allows for non-invasive assessment of RV function. In this procedure, RBCs are radiolabeled and ECG-gated cardiac scintigraphy is obtained. Alternative names for this technique includes gated cardiac blood pool imaging, multigated acquisition (MUGA), and gated equilibrium radionuclide angiography (RNA). This method can be used to assess regional and global wall motion, cardiac chamber size and morphology, ventricular systolic and diastolic function – including LVEF and RVEF. An RVG may be acquired at rest, during exercise, and after therapeutic interventions. Cardiac Magnetic Resonance Imaging (MRI)[14, 30]: allows measurements of RV mass and volume. With the use of gadolinium, it can detect ischaemia vs. infarction. It is particularly helpful in patients with complex congenital lesions, for planning complex cardiac surgery, and for research purposes. Currently, its use is limited. Right Heart Catheterisation (RHC): with end-expiratory measurements of PA, right-sided and left-sided pressures, is the gold standard for the diagnosis of PH. Although it has not been shown to affect outcomes, RHC provides essential haemodynamic information in acute RVF[32], especially in combination with Echo, or in cases where Echo studies are technically limited; or when continuous haemodynamic monitoring is required[8]. Thermodilution using the PAC allows RV output to be determined: 𝐸𝐹 = 𝐸𝐷𝑉−𝐸𝑆𝑉 × 100%. It also allows measurement of right-side pressures, RVEF and 𝐸𝐷𝑉 RV volumes – providing valuable information into RV function or dysfunction and allows for risk stratification as well. It can also be used to evaluate response to pharmacological therapy and allows drugs to be titrated to specific end-points[32]. Important limitations include unreliable measuring of CO using thermodilution in the face of significant TR, the risks associated with balloon inflation in patients with severe PH, and the potential complications associated with central venous catheterisation. Page 23 of 37 PERI-OPERATIVE MANAGEMENT A. Pre-operative Assessment[4, 14, 18] A pre-operative management plan should be formulated in association with the relevant attending physicians and the surgeons. The pre-operative assessment[18] should include: o Type of surgery: o Thoracic surgery: changes in intrathoracic pressures, lung volumes and oxygenation may cause acute increases in PVR and decreased RV function o Laparascopic procedures: pneumoperitoneum is usually poorly tolerated due to decreased preload and increased afterload o Procedures with rapid blood loss: poorly tolerated especially in patients with RV systolic and diastolic dysfunction o Other high risk surgeries: include those with significant perioperative systemic inflammatory response (eg. CPB); and those with a high possibility of venous air, CO2, fat, or cement emboli - Functional status of the patient - Severity of PH - RV function - Co-morbidities - Pregnancy: even though mortality has decreased from 38 to 25% with current therapies, it is still high; and pregnancy is still discouraged in patients with severe PH, and RV dysfunction Merits of surgery must be carefully assessed and discussed with the patient, especially in a patient with significant RV dysfunction as this may be a significant peri-operative risk factor. In patients with unacceptably high risk, consideration should be given to chronic treatment or corrective surgery (eg. Valve repair or thrombectomy/pulmonary endarterectomy); prior to elective or non-urgent surgery, in order to decrease PH and improve RV performance[4]. Pre-operative assessment of RV dysfunction can be aided by the investigations described earlier. Other investigations that may be clinically indicated include: arterial blood gases, lung function tests and liver function tests[4]. In certain cases - ie. moderate to severe RV dysfunction with severe PH, RHC may be performed to evaluate the patients response to pulmonary vasodilators[14]. This aids with the planning for intra-operative pulmonary vasodilator therapy. Premedication[4]: should be individualised. It is aimed at providing anxiolysis without respiratory depression. Chronic therapy should be continued perioperatively (with a few exceptions such as warfarin). Pre-operative pulmonary vasodilator therapy (oral sildenalfil, Ca-channel blockers, iNO, and nebulised iloprost) should be considered as they may decrease the adverse effect of perioperative factors that increase PVR. Page 24 of 37 B. Anaesthetic Goals[12, 20, 32] Acute decompensation in the perioperative period is relatively common. No algorithms exist, but principles of management include: - Optimisation of RV rate and rhythm - Augmentation of cardiac output o Optimisation of RV preload o Optimisation of RV systolic function (Categorisation of interventions aimed at improving RV performance is depicted in Figure 7) o Reduction in afterload by decreasing PVR Treat reversible factors that increase PVR Use pulmonary vasodilators - Avoiding RV hypoperfusion o Maintenance of aortic root pressure to ensure adequate RCA filling pressure o Prevention of systemic hypotension Page 25 of 37 C. Choice of Anaesthetic Both general and regional anaesthesia has been safely conducted in patients with high risk of RV decompensation[4], eg. patients with severe PH secondary to valvular heart disease undergoing Caesarean section. Large sympathetic haemodynamic responses to pain, surgery, and laryngoscopy should be avoided, as they will increase PVR. If a neuraxial technique is performed, it should be introduced slowly (such as in a graded epidural or intrathecal catheter), invasive monitoring should be used and vasopressor agents must be immediately available. If general anaesthesia is performed, ventilator factors that increase PVR should be avoided: - Avoid hypoventilation: as hypercapnia will increase the PAP independently of the presence of hypoxia – SPAP increases up to 1mmHg for every 1mmHg increase in PCO2 - Avoid hypoxia: which leads to localised pulmonary vasoconstriction. HPV usually becomes active when the alveolar PO2 decreases less than 60mmHg, and in response to decrease in mixed venous PaO2 - Avoid atelectasis: Decreased FRC may be prevented by using PEEP, but high levels of PEEP must also be avoided as it will also increase PVR - Avoid high ventilating pressures: including Valsalva manoeuvres, high inflating pressures and high PEEP. These cause RV dilatation which leads to IV septal shift, and decreased RV output. In patients with poor respiratory function, it may be difficult to achieve these goals and if possible and not contraindicated, neuraxial anaesthesia is recommended[4]. Influence of anaesthetic drugs on PVR and RHF Anaesthetic drugs can cause changes in PVR, RV afterload, and intracardiac shunting[16]. Many agents have direct and indirect agents on PVR. IV Agents: Many authors advocate Etomidate as the IV induction agent of choice [4, 18] – but there are no comparative data to support this. Ketamine increases PVR in adults, but this has not been observed in infants or children with PH[4]. There have been conflicting findings regarding the effects of Propofol: some studies showing decreased RV contractility[4, 16] and others showing increased PaO2 and lower shunt fraction values with Propofol vs. Iso/Sevoflurane in onelung-ventilation, and another showed decreased mean cardiac index and RVEF[36]. Inhalational Agents[16]: All volatiles may worsen RV dysfunction due to decreased preload, contractility and afterload. Halothane, Isoflurane and Sevoflurane do not adversely affect PVR, but Desflurane and Nitrous Oxide cause increases in PVR. Opiates[4]: Fentanyl and Sufentanil have minimal effects on pulmonary haemodynamics. Remifentanyl produces minor pulmonary vasodilatation. Page 26 of 37 D. Intra-operative Monitoring[4, 14] An individualised approach is important, and choice of monitors should be dictated by the severity of RV dysfunction and PH, intra-operative mode of ventilation, and type of procedure[14]. - Invasive arterial blood pressure: facilitates haemodynamic management as systemic hypotension can be detected earlier and vasopressor/inotropic therapy can be initiated. Frequent sampling of blood gases can also be undertaken, especially in cases where ventilation is difficult and hypoventilation may be a problem. - Central Venous Pressure: In the absence of hypovolaemia, acute RVF will cause an increase in CVP and jugular venous engorgement. The onset of TR can also be detected by prominent CV waves on the CVP waveform. - Pulmonary Artery Catheter: is a useful monitor of RV function. It can aid with assessing severity or worsening of PH and RVF; monitor the effects of PH and RVF; and monitor the effects of interventions that may be undertaken, especially in cases of acute deterioration. An acute increase in PAP – provides a warning that PVR may be increasing and acute RVF may be suspected if this is concurrent with increasing CVP and decreasing CO. It should be kept in mind that pressure measurements alone provide less information than measurement of PVR and that severe PH is a risk factor for catheter induced rupture of the PA. - Trans-Oesophageal Echocardiograph: is quoted as being mandatory by some authors[4,8]. It is a practical investigative tool that can be used to confirm the intra-operative diagnosis of acute decompensated RVF. Technical limitations may adversely affect intra-operative assessment of RV function. Page 27 of 37 Table 5 summarises the anaesthetic recommendations for patients at risk of RV decompensation as illustrated by Forrest and colleagues[4]. TABLE 5. Recommendations for patients at risk for intra-operative RV decompensation[4] INTERVENTION - PH, + RVF Severe PH, - Severe PH, + RVF RVF Premedication and Pre-induction + Sildenafil 25 – 50mg po +/+ Iloprost 10mcg via neb Monitoring CVP : Spontaneous Ventilation IPPV IABP: Spontaneous Ventilation IPPV CO: Spontaneous Ventilation IPPV TOE Neuraxial Anaesthesia Ventilation High FiO2 Mild Hyperventilation Low Ventilating Pressures Anaesthetic Agents + + +/+ + + + + + + + +/+ + + + + + + + + + Ketamine: Children Adults Thiopentone / Etomidate Propofol N2O Isoflurane/Sevoflurane/Halothane Desflurane + +/+ + + - + + + + - + + + - Fentanyl/Sufentanyl/Remifentanil + + + E. Management of peri-operative right ventricular failure 1. General Measures Supportive measures should be instituted immediately; usually while urgent ECHO is being organised[4]. - Ensure adequate oxygenation: use of high FiO2 and mild hyperventilation may decrease RV afterload[14] - Optimize ventilation: correct hypoventilation, recruitment manoeuvres and PEEP can help to minimise atelectasis - Treat hypotension II. Preload Management Determining optimal preload in the face of RVF can be problematic[4]. Hypovolaemia will decrease RV output and an inappropriate fluid challenge or volume overload will worsen RV dysfunction by resulting in acute RV distension, increased TR, IV septal shift, impairment of LVED filling, systemic hypotension Page 28 of 37 and decreased RV perfusion a progressive downward spiral[20]. CVP and Pulse pressure variation cannot be used reliably in patients with RVF[25]. Echo guided volume assessment (eg. IVC diameters) and response to challenges may be useful. Optimal filling can be assessed with cautious fluid boluses or by elevation of the patient’s legs. Vigorous fluid administration is discouraged[32], and liberal transfusion strategies are associated with increased morbidity and mortality[25]. Forrest and colleagues suggest that if the CVP is < 10cmH20 and raising the legs produces an increase in MAP – then IV fluids are indicated; if the CVP is <20 and there is no increase in MAP – then diuresis may be more appropriate[4]. RV volume overload may also be recognised by a rising V wave on CVP, increasing TR seen at ECHO, or pulmonary oedema – Fluid withdrawal with diuretics or ultrafiltration is then indicated[32]. III. Optimisation of RV Rate and Rhythm[20, 25] Sinus rhythm and ventricular synchrony are important for optimal filling of the RV. AV block or atrial fibrillation may have profound haemodynamic effects, and may require sequential AV pacing or cardioversion. A study of RV synchronisation is still in its early stages and further studies are still needed to determine optimal site of pacing, optimal outcome variables and long term effects[25]. Because of the association between RV and TR, slightly increased heart rate (80 – 100bpm) are advantageous, in order to decrease EDV. Bradycardia causes decrease in CO as SV is already limited by the increased afterload. Tachycardia may increase RV ischaemia. IV. Pulmonary Vasodilators Perioperative RVF is usually associated with increased PVR, either as the underlying cause or the precipitant. Since the RV is poorly adapted to tolerate acute changes in afterload, vasodilator therapy aims to decrease RV afterload, thereby improving physiological coupling between the RV and pulmonary circulation and leading to increased CO[12]. Pulmonary vasodilators have been described as being the cornerstone of RVF treatment[32]. Specific pulmonary vasodilators help by decreasing afterload, and contain HPV. In the chronic setting, they may also influence remodelling of pulmonary vessels[12]. These beneficial effects may come at the expense of decreased SVR, hypotension and can potentially worsen RV preload and ischaemia – especially with non-selective agents and in unstable patients. Pulmonary vasodilators should therefore be used after optimisation of RV perfusion and CO, or in conjunction with vasopressors/inotropic agents[12]. - Intravenous Pulmonary Vasodilators [4, 16]: such as Ca channel blockers, adenosine, Mg, Nitroglycerin and PDE inhibitors reduce PVR. Besides the potential haemodynamic side effects, their non-selective actions may also worsen ventilation/perfusion matching. - Prostanoids [4, 8, 12]: include prostaglandin I2 (Prostacyclin, PGI2) and its analogues – iloprost, and prostaglandin E1 (Alprostadil). An important difference between the different preparations is their half-lives. Prostacyclin is derived from Page 29 of 37 endothelial cells and is a potent systemic and pulmonary vasodilator, with antiplatelet and antiproliferative effects. It has been shown to improve survival in patients with Idiopathic PAH and is effective in decreasing PVR and ARDS and following mitral valve surgery[4]. - These agents may worsen ventilation/perfusion mismatching or increase PAWP in patients with severe LV dysfunction. Their potent anticoagulant effects must also be kept in mind, especially in patients post-surgery, those on heparin infusions, and those in whom neuraxial anaesthesia is planned. - PDE5 Inhibitors [12, 13, 30]: including Sildenafil, inhibit breakdown of cyclic GMP by the PDE V isoenzyme, potentiating the beneficial effects of Nitric Oxide (NO), ie. Pulmonary vasodilatation – thereby acutely decreasing PVR, increasing CO, and decreasing PAWP. PDE5 inhibitors may also exert Milrinone like effects through PDE3 inhibition, augmenting RV function[12]. Adverse effects include decreased SVR and hence decreased RV performance. - Inhaled Pulmonary Vasodilators [4, 12, 30, 32]: Inhaled prostacyclin and iNO cause selective pulmonary vasodilatation in well ventilated areas, decreasing PVR and improving ventilation/perfusion matching. iNO is a potent pulmonary vasodilator with a short half-life due to inactivation by haemoglobin – which decreases its systemic effects. It does require continuous delivery into the ventilator circuit, which is practically difficult. Other limitations include: accumulation of toxic metabolites leading to methaemoglobinaemia and rebound PH after weaning. iNO decreases PVR and improves CO in PAH, secondary PH, acute PE, ischaemic RV dysfunction and postsurgical PH[12]. It has also been shown to benefit patients with acute RVF secondary to ARDS, and to decrease inflammatory cytokine production[32]. The use of iNO prophylactically in patients with PH undergoing cardiac surgery is controversial. Inhaled Iloprost is more convenient to administer due to its longer half-life and comparable efficacy. Continuous nebulisation is not required. It has been shown to be more effective than NO in decreasing PVR and improving CO in patients with PH after CPB, and in PAH[12]. Other advantages include decreased systemic effects and no need for additional equipment or monitoring. Selective Oral Pulmonary Vasodilators [4, 12]: Sildenafil as already mentioned is a potent pulmonary vasodilator and leads to decreased PVR. It maintains SVR and improved myocardial perfusion and has been used effectively in selected patients -eg. post CABG, and children undergoing congenital heart surgery. It has lusitropic and inotropic effects in the hypertrophied RV and decreases RV mass in patients with PAH. It can also be used to improve pulmonary haemodynamics and exercise capacity in patients with systolic LV dysfunction. It may improve myocardial perfusion, reduce platelet activation, and decrease endothelial dysfunction post CPB[12]. In one study, 25-50 mg was shown to produce a 49%decrease in PVR within 30min of administration[4], and some authors quote that even a single dose may facilitate weaning from NO[12]. Page 30 of 37 Bosentan – an endothelin II antagonist, also produces selective pulmonary vasodilatation and is effective in management of Primary PPPH, CTEPH, Congenital heart disease and Eisenmengers syndrome[4]. Its use is contraindicated in pregnancy and there is still limited experience in its peri-operative use[13]. Several combinations of pulmonary vasodilators have been shown to produce greater effects than single agents, eg. Inhaled iloprost + iNO; oral sildenafil + inhaled iloprost. V. Vasopressors Vasopressors increase coronary perfusion pressure by increased SVR. This may also benefit ventricular interdependence by shifting the IV septum back towards the RV. This leads to improved LV output, and may improve and even reverse RV ischaemia[4]. Vasopressors may also be initiated to compensate for systemic hypotension caused by systemic side effects of pulmonary vasodilators or inodilators. The ideal agent would increase SVR without affecting PVR and without causing a tachycardia. Vasopressin has been shown in animal studies to cause vasoconstriction and pulmonary vasodilatation due to stimulation of NO release. In humans, the effects have been variable, and it should be considered especially in refractory cases[4]. Phenylephrine is a direct alpha-1 agonist and improves right coronary perfusion without causing tachycardia. It may cause increased PVR and hence worsen RV function. It may be less effective than noradrenaline in treating hypotension post induction of anaesthesia in patients with RVF[4]. Noradrenaline exerts its vasopressor effects through alpha-1 agonism and is also positively inotropic through beta-1 stimulation – it can therefore improve RV-PA coupling, CO, and RV performance; but it may have adverse effects on PVR at high doses (ie. >0.5mcg/kg/min) [12]. VI. Inotropes Inotropes are indicated in patients with acute RVF and decreased CO, as it improves myocardial function. There is limited data available to guide which agent is best. Adrenaline decreases PVR, PAP, and the PVR/SVR ratio. Dobutamine at doses up to 5mcg/kg/min, has been considered the drug of choice in patients with RV infarction[4]. It is also useful in patients with RVF due to acute pressure overload as it increases myocardial contractility, decreases PVR and SVR. It has been shown to have synergistic effects when used with NO in patients with PH[12]. It can induce tachycardia, especially at higher doses, and is therefore not ideal in patients with tachyarrhythmia[30]. PDE3 Inhibitors increase intracellular cAMP and augment myocardial contractility[12]. It also produces systemic and pulmonary vasodilatation. Page 31 of 37 The selective agents include enoximone, milrinone and amrinone. Milrinone[12] is most frequently used and has been shown to decrease pulmonary pressures and augment RV function. Nebulised milrinone has been used to manage PH crises – through pulmonary selectivity, it causes less systemic hypotension and less V/Q mismatching compared to intravenous use. When combined with iNO, it produces greater decrease in PAP than either agent alone. In animal studies, when combined with oral sildenafil, it was also shown to decrease PVR significantly more than either agent alone, without causing any further decrease in SVR[12]. Due to the side effects of systemic hypotension, it is often co-administered with vasopressors: Milrinone+Vasopressin is superior to Milrinone+Noradrenaline in RV dysfunction[12]. Levosimendan sensitises troponin C in the myocardium to calcium, leading to improved diastolic function and myocardial contractility. It also has global vasodilatory and anti-ischaemic properties - through K+ channel opening in vascular smooth muscle cells and endothelin1 inhibition; and specific pulmonary vasodilatory properties - through PDE3 inhibition[32]. By decreasing PVR, it appears to improve RV-PA coupling, hence overall improving RV function[12]. Most of the studies have been conducted on animals in an experimental RVF setting and although there is some evidence of the benefits of Levosimendan in clinical situations – such as RV ischaemia, ARDS and post mitral valve replacement, further studies in acute RVF are needed[32]. In a systematic review and analysis of research from 1980-2010, Price and colleagues make recommendations based on the GRADE method, to guide the management of pulmonary vascular and pulmonary dysfunction[12]. The breakdown of articles incorporated into the systematic search is shown in Table 6. Page 32 of 37 Table 6. Breakdown of Clinical Articles in Systematic review by Price and Colleagues[12] Subtype of treatment Number of studies in initial search Number of suitable studies included in the review Volume therapy 113 5 Vasopressors 388 28 Sympathetic Inotropes 565 8 Inodilators 280 17 Levosimendan 172 12 Pulmonary Vasodilators 586 121 Mechanical Devices 47 19 Their recommendations based on the quality of evidence (STRONG/WEAK) were: - WEAK: Close monitoring of fluid status according to effects on RV function - WEAK: Noradrenaline may be an effective systemic pressor in patients with acute RV dysfunction and RV failure - WEAK: Low dose Vasopressin may be useful in difficult cases that are resistant to usual treatments - WEAK: Low dose Dobutamine improves RV function, it may reduce SVR - STRONG: Dopamine may increase tachyarrhythmias, and it is not recommended - WEAK: Levosimendan may be considered for short term improvements in RV performance - STRONG: Pulmonary vasodilators decrease PVR, improve CO, and oxygenation - STRONG: Consideration should be given to use of inhaled rather than systemic agents when systemic hypotension is likely, and concomitant vasopressor use should be anticipated - STRONG: Give consideration for use of NO as a short term therapy - WEAK: Oral Sildenafil may decrease PVR and facilitate weaning from NO in selected patients, without adverse effects on systemic blood pressure. Page 33 of 37 VII. Mechanical Support of the Right Ventricle Mechanical support of the RV can be considered in patients with severe RVF refractory to medical therapy: if there is a potentially reversible cause, if the patient is awaiting corrective surgery, or if the patient is a candidate for heart-lung transplantation. An intra-aortic balloon pump may improve RV perfusion by augmenting right coronary artery perfusion, but this does not necessarily mean that RV function will improve[4], and it is generally only used for short term support. It may also be used to allow for weaning of vasopressors[8]. Extracorporeal Membrane Oxygenation has been used in severe PH as a bridge to transplantation, and after endarterectomy or massive PE[32]. Atrial Septostomy: has evolved from the observation that patients with PH and a patent foramen ovale survived longer than those without[24]. In this surgical procedure, a shunt is created between the atria, allowing for decompression of the right side, a decrease in RVEDP, decrease wall tension, and increased contractility. The resulting desaturation caused by the right to left shunt can be controlled with supplemental oxygen[8]. This procedure is generally only considered when all other interventions have failed – it is considered palliative[25]. It may also be used as a bridge to transplantation. F. Post-operative considerations [37] Understanding of the impact that PH and RV dysfunction have on peri-operative outcome in non-cardiac surgery is still incomplete[38]. Post-operative complications include: heart failure, respiratory failure (delayed extubation, re-intubation), myocardial ischemia or infarction, stroke, dysrrhythmias, and in-hospital death. In a study investigating postoperative outcomes in non-cardiac surgery by Lai and colleagues[38], most post-operative deaths were preceded by refractory hypoxaemia and cardio-pulmonary failure. The authors suggest that surgical stress, pain, fluid shifts, nutritional insufficiency, sympathetic activation and potential infection; compromise pulmonary oxygenation and CO. Therefore, careful postoperative management is necessary to prevent worsening RV dysfunction and failure. Attention should be paid to volume status, ventilation and oxygenation levels, acid-base status, blood pressure, and heart rate. Continued administration of vasopressors/pulmonary vasodilators/inotropes may be necessary. Adequate analgesia is important to prevent sympathetic stimulation – which worsens PH; but this must be balanced against the negative effects of analgesics (especially opioids) on cardiopulmonary function. Good postoperative management depends on: - A thorough preoperative assessment (to risk stratify the patient) - Communication between the surgeon, anaesthesiologist, physician, and intensivist - Prior planning for postoperative care including level of care (ICU vs. high care vs. general ward) Page 34 of 37 CONCLUSION The peri-operative management of patients with RV dysfunction is complex and requires multiple steps: - Recognising the disorder - Diagnosing the cause - Assessing disease severity - Evaluating risks and benefits of anaesthesia and surgery - Formulating an anaesthetic plan and - Managing the peri-operative complications that may arise Minimizing PVR and maintaining MAP, ie. “RV Protection,” are of major importance in the prevention of decompensated RVF – which is characterised by rising CVP and falling CO. Thus, the anaesthesiologist must have knowledge of RV physiology, the underlying pathophysiology of perioperative RV dysfunction, and the potential treatment strategies available including optimising physiological parameters, use of selective pulmonary vasodilators, and vasopressor and inotropic support. . Improved understanding of the complex RV may also increase interest in the neglected disorder of RVF and may facilitate research. This need for further research has been highlighted by the National Heart, Lung and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure [5], as they recognise the pivotal impact that the right ventricle has on the outcome of various disease states, both common and rare. They state that further research should be a high priority. Page 35 of 37 REFERENCES 1. Greyson, C. Pathophysiology of right ventricular failure. Crit Care Med. 2008; 36(1(Suppl)): S57-65. 2. Haddad F, et al. 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