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Anaesthesia and right ventricular failure.

Before the 1970s, the right ventricle (RV) was considered to be little more than a passive conduit for blood. RV failure is generally less well understood by clinicians and has attracted much less research interest than left ventricular (LV) failure. Acute RV failure often responds poorly to treatment and there are no outcome data to support any of the available therapies. Additionally, in contrast to LV failure (1), there are no practice guidelines for the management of either acute or chronic RV failure.

Acute RV decompensation may be a sudden, unpredictable event and produces significant perioperative morbidity and mortality, particularly in patients with severe pulmonary hypertension.

The aims of this paper were to review the pathophysiology, assessment and treatment of perioperative RV failure.

CAUSES OF PERIOPERATIVE RV FAILURE

Right ventricular dysfunction may be primarily due to pressure overload, volume overload or impaired RV contractility.

RV pressure overload

RV pressure overload can result from any condition that impedes the passage of blood flow between the RV and the LV. This is usually caused by conditions that produce pulmonary hypertension, although it may also be caused by RV outflow tract obstruction or pulmonary valve stenosis.

Pulmonary hypertension (PHT) is defined as a mean pulmonary artery pressure (PAP) of >25 mmHg at rest (2) and may be further categorised as mild (25 to 40 mmHg), moderate (41 to 55 mmHg) or severe (>55 mmHg) (3).

Severe preoperative PHT is a significant independent risk factor for mortality in both cardiac (4) and non-cardiac surgery. In a study of 145 patients with a mean systolic PAP (sPAP) of 68 mmHg undergoing non-cardiac surgery, 16 patients developed congestive heart failure (11%) and five patients died from RV failure (3.5%) (5). In another study of 62 patients undergoing non-cardiac surgery with a mean sPAP of 79 mmHg, the cardiac mortality was 9.7% vs 0% for case-matched controls (6).

Pulmonary hypertension is caused by an increased pulmonary vascular resistance (PVR) or left atrial pressure (LAP), which are related to cardiac output (CO) by the following standard formula:

mean PAP=PVR x CO + LAP

Causes of elevated PVR

Perioperative causes of acutely elevated PVR include hypoxia, hypoventilation, atelectasis and high ventilating pressures. These may all contribute to the increase in PVR seen in acute respiratory distress syndrome (ARDS) (7). Other causes include cardiopulmonary bypass (CPB) (due to endothelial injury and secondary pulmonary vasoconstriction) (8), protamine reactions (9) and acute pulmonary embolism. While intraoperative pulmonary embolism is a rare event, it is a significant cause of intraoperative cardiac arrest, particularly during orthopaedic surgery (10).

Pulmonary vascular resistance is chronically elevated in pulmonary arterial diseases such as scleroderma, idiopathic pulmonary hypertension (IPAH--previously called primary pulmonary hypertension) and chronic thromboembolism. It is also chronically elevated in lung diseases such as chronic obstructive pulmonary disease.

The PAP is higher in chronic than in acute elevations of PVR, as the CO is better preserved due to the development of RV hypertrophy. While a falling PAP may be due to a reduction in PVR or LAP, it is also a sign of progressive RV failure. Conversely, an increase in CO in the face of a high, relatively fixed PVR will increase the PAP. Hence the functional state of the RV cannot be determined from the severity of PHT alone.

Causes of elevated LAP

Pulmonary venous hypertension due to elevated LAP increases the PAP and may produce secondary RV dysfunction. Causes include mitral valve disease, LV systolic failure and LV diastolic failure with preserved LV function (11).

RV volume overload

Acute RV volume overload is caused by conditions such as acute tricuspid regurgitation (TR), volume overload and ruptured Sinus of Valsalva aneurysm. The commonest causes of chronic RV volume overload are TR and atrial septal defect.

RV dysfunction

Right ventricular dysfunction is a common occurrence in cardiac surgical patients. Cardiac magnetic resonance imaging studies of patients undergoing coronary artery bypass grafts showed an immediate, modest fall in RV ejection fraction postoperatively. This was due mostly to RV diastolic dysfunction and was associated with abnormal interventricular septal motion, although it is not known whether this was a cause or a consequence of the RV dysfunction. These changes in RV performance also occur in patients undergoing off-pump coronary artery bypass grafts, suggesting that they are not necessarily due to the effects of CPB or cardioplegic arrest (12).

Severe RV dysfunction following CPB may be due to inadequate myocardial protection (myocardial stunning) or intracoronary air embolism, however this is usually a transient phenomenon. Severe, refractory RV failure is a rare event following cardiac surgery. It may be caused by RV ischaemia or infarction (during coronary artery bypass grafting (13)) or decompensation of pre-existing RV dysfunction. Right ventricular infarction usually occurs in association with LV infarction, although it may be an isolated event in 3% of patients with acute myocardial infarction (14). Prolonged ischaemia may lead to severe RV failure in 2 to 3% of heart transplant cases and in 20 to 30% of patients requiring left ventricular assist device support. In this latter group of patients, this may be due to the reduction in the LV contribution to RV performance (15). The mortality in these patients may be up to 75% (16).

A variety of congenital heart diseases, such as atrial and ventricular septal defects, Ebstein's anomaly and tricuspid atresia (17), may also cause chronic RV dysfunction.

PATHOPHYSIOLOGY OF RV FAILURE

This was the subject of a recent review by Greyson (18), who defined right ventricular failure as "the clinical syndrome resulting from the right heart's inability to provide adequate blood flow to the pulmonary circulation at a normal central venous pressure" (18). The difficulty with defining RV failure more concisely is that the clinical signs of RV failure may occur in the absence of RV systolic dysfunction (e.g. severe TR) and RV dysfunction does not invariably lead to clinical evidence of RV failure.

Normal RV physiology

The RV is smaller and has a much more complex geometry than the LV. Although it ejects the same blood volume as the LV, the RV generates about one-sixth of its work and pressure, because the pulmonary vascular resistance is only about 15% of systemic vascular resistance (SVR). There is normally little variation in the PAP, as PVR decreases in response to an increase in cardiac output, because of dilatation and recruitment of pulmonary vessels (19).

The coronary blood flow to the RV differs significantly from the LV. The driving pressure for coronary blood flow is the aortic root pressure minus the intraventricular pressure for the respective ventricle. For the left ventricle, as the intraventricular pressure exceeds the aortic root pressure in early systole, there is no forward coronary blood flow. Most of the coronary blood flow to the left ventricle therefore occurs in diastole, when the driving pressure gradient between the diastolic aortic root and LV pressures is large. By contrast, blood flow in the right coronary artery occurs throughout the cardiac cycle, as there is a large driving pressure gradient between the aortic root pressure and RV systolic and diastolic pressures. However, this pressure gradient is decreased when RV systolic pressures are increased due to an increase in PVR (20). In some patients with chronic pulmonary hypertension, PVR may exceed SVR and RV systolic pressures may equal or exceed systemic levels. In these patients, the coronary blood flow to both ventricles will be predominantly diastolic.

The RV is normally crescent-shaped in cross section, while the LV is more circular.

RV contraction occurs as a bellows-like wave from the apex of the heart to the right ventricular outflow tract (21). RV systolic function is not purely dependent on contraction of the RV free wall, as the interventricular septum also augments RV output by bulging like a piston into the RV during systole (22) and maximal RV function is significantly reduced if the septum is dysfunctional (23).

[FIGURE 1 OMITTED]

RV response to increased volume

Large increases in RV volume work can be accommodated with relatively little increase in RV wall tension, as the thin-walled RV is much more distensible than the LV. Although the stroke volume of the RV increases in response to increased wall stretch (via the Frank-Starling mechanism), this response is normally minimal at baseline and is not important until the RV has dilated into a more circular shape (24). Large increases in RV volume work are accommodated at the expense of the LV, whose volume (and output) decrease due to interventricular septal shift (25).

Chronic RV volume overload is generally well tolerated, as it does not affect the contractility of the RV (26). While RV volume overload is considered a cause of chronic RV failure, acute RV decompensation does not generally occur unless the PVR becomes elevated. This is because the volume-overloaded RV has a limited ability to increase its contractility in response to the increased afterload (24).

RV response to increased afterload

The initial response of the RV to an acute increase in PVR is to rapidly increase its contractile state (homeometric autoregulation or Anrep effect). This is initially mediated by altered calcium dynamics (27) and subsequently by sympathetic nervous system activation (28). As PVR increases further, the RV dilates and its stroke volume increases via the Frank-Starling mechanism (heterometric auto-regulation). However, once the RV is at the limit of its compensatory reserve, further increases in after-load can lead to sudden haemodynamic collapse (29). This acute decompensation is associated with the onset of RV ischaemia (30,31).

Several mechanisms contribute to this downward haemodynamic spiral. Progressive RV dilation results in increased interventricular septal shift and to TR, both of which reduce LV preload. As LV preload falls, cardiac output and aortic root pressure also fall. Right coronary blood flow is decreased due to the combined effects of a reduced aortic root pressure and a raised RV intraventricular pressure, leading to RV ischaemia. Right ventricular ischaemia leads to further falls in RV stroke volume, LV preload and mean arterial pressure (MAP). These changes are summarised in Figure 1 (adapted with permission from Lualdi (32)).

RV response to decreased contractility

Severe, chronic RV failure may be surprisingly well tolerated if the pulmonary driving pressure can be maintained and the PVR remains low. The RV may even be bypassed completely--for example, in the Fontan repair for univentricular heart.

The pulmonary driving pressure is the mean pulmonary artery pressure (mPAP) minus the LAP. The mPAP is normally only about 15 mmHg: hence in the absence of any RV contraction at all the pulmonary driving pressure can be maintained with a moderately increased CVP, provided that both the PVR and LAP remain low. However, a small increase in PVR in this situation will lead to severe haemodynamic decompensation (33).

[FIGURE 2 OMITTED]

In summary, RV failure is the result of inadequate contractility, volume or pressure overload. All of these mechanisms contribute to the progression of RV decompensation.

ANAESTHETIC CONSIDERATIONS

Preoperative assessment

Perioperative risk factors for RV decompensation include:

1. Pre-existing RV dysfunction (due to congenital 1. heart disease, RV infarction or secondary to raised PVR), and

2. Severe PHT, without RV dysfunction. 2.

The symptoms of RV failure are non-specific: progressive dyspnoea occurs most frequently and the signs include an elevated jugular venous pressure, peripheral oedema and hepatomegaly.

In patients at risk, echocardiography is the screening investigation of choice to assess RV function and sPAP. Right ventricular systolic impairment decreases tricuspid annular systolic motion. Other characteristic echocardiographic findings of RV failure include right atrial and ventricular dilatation, reduced LV preload, interventricular septal shift (Figure 2) and TR. The velocity of the TR jet is used to estimate the sPAP (34).

Right heart catheterisation is performed in patients with PHT and heart failure as part of the assessment of their suitability for cardiac transplantation. In addition to the measurement of pulmonary haemodynamics, the patient's response to pulmonary vasodilators can be evaluated (35).

In patients with PHT, RV dysfunction may be a more significant perioperative risk factor than the severity of PHT, as the degree of adaptation of the RV varies widely among patients with similar pulmonary arterial pressures.

Other investigations that may be clinically indicated include pulmonary function testing, arterial blood gases and liver function tests (36).

Table 1 contains a summary of perioperative recommendations that are based on the following sections.

Preoperative preparation

The merits of surgery have to be carefully assessed in patients with significant RV dysfunction and a perioperative management plan should be developed between the relevant attending physicians prior to surgery.

Premedication should be individualised, with the aim of providing anxiolysis without respiratory depression. Anxiolysis may be particularly important in patients with IPAH. The most common sequence of events leading to death in these patients is minor stimulation resulting in tachycardia or increased PVR, followed by refractory cardiovascular collapse (37).

With severe PHT, there should be a plan for the management of pulmonary vasodilator therapy. Chronic therapy should be maintained perioperatively. In previously untreated patients, preoperative pulmonary vasodilator treatment should be considered, as it may limit the adverse impact of perioperative factors on the PVR. Sildenafil, bosentan (38) or intravenous prostacyclin (39) may be commenced in the months or weeks prior to planned surgery, while the response to inhaled iloprost may be assessed immediately prior to anaesthetic induction. A therapeutic response (reducing the PVR) will cause a fall in CVP and an increase in CO. In patients with severe RV dysfunction, the PAP may not decrease significantly (because of the increase in CO).

Warfarin therapy (e.g. for chronic pulmonary thromboembolism) should be ceased several days preoperatively and substituted for intravenous heparin or subcutaneous enoxaparin.

Ventilation

There are no outcome data to support any management strategy for the prevention of perioperative decompensation in patients at risk of RV failure. However, ventilatory factors that increase PVR should be avoided:

* Avoid hypoventilation: Hypercapnia will increase the PAP (40). This occurs independently of the presence of hypoxia (41). sPAP may increase by up to 1 mmHg per 1 mmmHg increase in alveolar PC[O.sub.2] in patients with normal lungs (42), and similar increases are seen in patients with chronic obstructive pulmonary disease (43). While hypercarbia increases the CO, its effect on PAP is predominantly due to an increase in PVR. By contrast, hypocarbia produces pulmonary vasodilation (42).

* Avoid hypoxia: Alveolar hypoxia induces localised pulmonary vasoconstriction, which diverts blood to better-ventilated alveoli. In normoxic subjects, hypoxic pulmonary vasoconstriction (HPV) is minimally active and becomes active when the alveolar P[O.sub.2] falls below about 60 mmHg (44). PVR will not increase until a critical proportion of alveoli are hypoxic. For example, while lobar pneumonia may have minimal effect on PVR, it may be tripled by one-lung ventilation (45). Stimulation of HPV also occurs in response to a fall in the mixed venous [P.sub.a][O.sub.2], although this response is not as potent as the response to alveolar hypoxaemia (46).

HPV is stimulated by atelectasis and acidosis and inhibited by metabolic and respiratory alkalosis (47).

The normal pulmonary circulation is virtually unresponsive to high concentrations of inspired oxygen. However, pulmonary vasodilation was observed in response to the administration of 100% inspired oxygen in non-hypoxic patients with PHT (48), due to the inhibition of HPV.

* Avoid atelectasis: The PVR is minimal at the functional residual capacity and increases as it falls toward the residual volume. This is thought to be due to stimulation of HPV or compression of corner vessels (which lie at the junction of three or more alveoli) (49).

Atelectasis occurring during anaesthesia due to a reduction in the functional residual capacity may be prevented by the use of positive end-expired pressure (PEEP) (50), although high levels of PEEP must be avoided, as it will increase PVR.

* Avoid high ventilating pressures: Valsalva manoeuvres, high inflating pressures and high levels of PEEP (>15 cm[H.sub.2]O) should be avoided in patients with pulmonary hypertension, as high intrathoracic pressures produces RV dilation, interventricular septal shift and reduced RV output (51).

In patients with poor respiratory function, it may be difficult to prevent hypoxia, hypoventilation and atelectasis while minimising ventilating pressures.

If controlled ventilation is necessary, the 'best' PEEP can be obtained from the lower inflection point of the respiratory pressure-volume loop and the patient ventilated with a low tidal volume and a high respiratory rate. Low ventilating pressures may be easier to achieve with spontaneous ventilation, however PEEP and pressure support should be used to prevent atelectasis and hypoventilation (respectively).

Choice of anaesthetic

The choice of anaesthetic is predicated on the requirements to maintain RV preload and contractility, minimise the PVR and to avoid RV hypoperfusion due to reduced MAP. Hence if a neuraxial technique is performed, it should be introduced slowly, using invasive monitoring and with vasopressor agents immediately available.

The depth of anaesthesia and postoperative analgesia should be sufficient to avoid large sympathetic haemodynamic responses to pain and surgery, especially in patients with severe PHT and RV dysfunction. Both general and regional techniques have been used successfully in patients at high risk of RV decompensation; for example, patients with severe PHT undergoing caesarean section (24,37,52-54).

Inhaled anaesthetics

All of the volatile anaesthetics may worsen RV dysfunction by reducing preload, afterload and contractility. Halothane (55), enflurane (56), isoflurane and sevoflurane (57) do not adversely affect PVR. However, PVR is increased by both desflurane (58,59) and nitrous oxide (60,61), hence these agents should be avoided in patients who are at risk of RV decompensation.

Intravenous anaesthetics

Etomidate has been advocated as the induction agent of choice in patients with RV dysfunction, although there are no comparative data (62).

Thiopentone reduces RV contractility and SVR, but does not affect PVR (63). Ketamine increases PVR in adults (64,65), though this has not been observed in either infants (66) or children (67) with PHT.

There have been conflicting findings on the effects of propofol on RV function. In patients with respiratory failure, propofol infusion significantly reduced RV contractility, which was reversed with dobutamine (68). Right ventricular function was better preserved with propofol than isoflurane in patients underdoing cardiac surgery (69), whereas the opposite was found in patients during one-lung anaesthesia (70). Part of the explanation for these conflicting findings is that propofol attenuates the effects of endogenous pulmonary vasodilators under certain conditions. For example, while propofol has no effect on PVR normally, in the presence of [alpha]-adrenoreceptor activation it produces pulmonary vasoconstriction (71).

Opiates

Fentanyl and sufentanil have minimal effects on pulmonary haemodynamics (72). Remifentanil produces minor pulmonary vasodilation, which is mediated by histamine release and opiate receptor pathways (73).

Monitoring RV function

Acute RV failure should be suspected in any patient who has the characteristic haemodynamic signs of a high CVP and a low CO. Other possible causes of these findings (such as tension pneumothorax or excessive PEEP) should be excluded clinically. Echocardiography is required to differentiate RV dysfunction from other possible causes, such as pericardial tamponade.

Arterial blood pressure

Invasive blood pressure monitoring facilitates the haemodynamic management of patients with RV dysfunction, as systemic hypotension must be avoided. Severe RV dysfunction will increase the systolic pressure variation due to respiration, because of the presence of a low LV preload.

Central venous pressure

In the absence of hypovolaemia, acute RV failure from any cause will produce an increased CVP (and jugular venous engorgement). The onset of TR is heralded by the development of a prominent V-wave in the CVP waveform. The clinical detection of RV dysfunction in a hypovolaemic patient is more difficult, as the CVP may be within normal limits. Echocardiography should therefore be considered in any patient who has unexplained hypotension in the presence of a normal CVP.

The presence of a low CO is also suggested by measuring a fall in central venous oxygen saturation or Pv[O.sub.2].

Pulmonary artery pressures

The pulmonary artery catheter (PAC) is a useful monitor of RV function. An acute increase in PAP provides early warning of a rising PVR, while acute RV failure is signalled by a rising CVP and a falling cardiac output. In addition, it is a useful monitor of the effects of therapeutic interventions on RV function.

PAC: role in RV failure due to pressure overload

An increased PVR increases PAP, as the contractility of the RV will increase to maintain a constant output. However, once the contractile reserve of the RV is exhausted, a decreasing PAP and an increasing CVP signals the onset of RV failure. Hence the key haemodynamic sign of a therapeutic response to inhaled pulmonary vasodilators is not a reduction in PA pressures, but a decrease in CVP and an increase in CO.

Although the preload to the LV will be reduced in acute RV failure, the pulmonary capillary wedge pressure may be unchanged or even increase. This is because the compliance of the LV is also reduced, due to the leftward displacement of the intraventricular septum (74).

PAC: role in RV contractile failure

A small elevation in PVR may lead to acute RV decompensation in patients with reduced RV contractility. Cardiac output and PAP will fall, while the CVP will increase.

Pulmonary hypertension is a risk factor for catheter-induced PA rupture (75), although the design of modern PA catheters has been improved to minimise this risk.

Echocardiography

Echocardiography is currently the only practical investigation available for confirmation of the diagnosis of perioperative RV failure. This may be either transoesophageal (TOE) or transthoracic echocardiography. However, technical limitations may adversely affect the assessment of RV function by both techniques. The entire RV may not be well visualised by transoesophageal echocardiography, as it is in the far field of the scanning sector, while obtaining good transthoracic echocardiography imaging windows may be difficult in the supine, ventilated patient.

In summary, the key haemodynamic signs of RV failure are an increased CVP and a decreased CO. These variables better reflect RV function than does PAP.

Management of perioperative RVF

In patients with suspected perioperative RV failure, general supportive measures should be introduced immediately while urgent echocardiography is organised. These supportive measures should include 100% oxygen, optimisation of ventilation (correct hypoventilation/minimise airway pressures) and treatment of hypotension with vasopressors. Intravenous fluid administration should be ceased.

In patients with acute or pre-existing perioperative RV failure, the goals of subsequent therapy are to prevent RV ischaemia, optimise RV preload, afterload and contractility, without compromising systemic haemodynamics. Table 2 summarises the drug therapies that are effective for acute perioperative RV failure.

Preload management

Because RV failure results in a high RV and a low LV preload, determining the 'optimal' preload may be problematic. Hypovolaemia will reduce RV output, while a fluid challenge may worsen RV dysfunction caused by an acute increase in PVR (74). One approach to this problem is to assess the haemodynamic response to raising the patient's legs. If the CVP is <10 mmHg and this produces an increase in MAP, intravenous fluids are indicated76. Conversely, if the CVP is <20 mmHg and there is no increase in MAP, the use of diuretics may be more appropriate (51).

Pulmonary vasodilators

Perioperative RV failure is usually associated with an elevated PVR, either as the underlying cause (pressure overload) or as the precipitating event in patients with RV volume overload or RV dysfunction.

Although the perioperative evidence is limited, the efficacy of pulmonary vasodilators may be related to the severity of pulmonary vasoconstriction. For example, the administration of inhaled nitric oxide (iNO) after mitral valve surgery significantly reduced the PVR in patients with pre-existing pulmonary hypertension, but had no effect on patients with normal PVR (77). While this suggests that iNO may not be indicated for RV failure, it produced a significant reduction in PVR and an improvement in cardiac output in patients with RV infarction and cardiogenic shock (77). In these patients, the PVR was moderately elevated (mean 243 dyn.s.[cm.sup.-5]). It was postulated that the increase in PVR was due to the effects of mechanical ventilation, pulmonary oedema and activation of HPV (due to low CO).

* Intravenous pulmonary vasodilators: Intravenous pulmonary vasodilators may be used to reduce RV afterload, but excessive systemic vasodilation must be avoided due to the risks of reducing right coronary blood flow. Calcium channel blockers, adenosine, magnesium, nitroglycerine and phosphodiesterase inhibitors all reduce PVR (79,80). Prostacyclin is an endogenous pulmonary vasodilator that is derived from endothelial cells. Intravenous prostacyclin has been shown to improve survival in the management of patients with IPAH (81) and is effective in reducing PVR in ARDS and following mitral valve surgery (82). However, intravenous prostacyclin produces systemic vasodilation and is also a potent inhibitor of platelet aggregation (83), hence neuraxial anaesthesia is contraindicated during its administration.

Sildenafil is a potent pulmonary vasodilator. It acts by inhibiting the breakdown of cyclic guanine monophosphate by the phosphodiesterase type V isoenzyme. In children and infants undergoing congenital heart surgery, intravenous sildenafil produced significant pulmonary vasodilation (84,85). However, this was associated with an increase in intrapulmonary shunt and impaired oxygenation. Sildenafil should therefore be avoided in patients with marginal oxygenation.

* Inhaled pulmonary vasodilators: Both inhaled prostacyclin and iNO produce selective pulmonary vasodilation in well-ventilated lung regions, which reduces PVR and ventilation-perfusion inequality (86,87). They are effective in the treatment of PHT due to pulmonary vascular disease (88-90), ARDS (91-93), following cardiac surgery (94-96) and in patients with IPAH or Eisenmenger's syndrome undergoing caesarean section (37,97-100).

Inhaled prostacyclin produces a greater reduction in PVR than iNO in patients with IPAH (101-102) and has an equivalent effect on PVR in ARDS (86). Iloprost is a stable analogue of prostacyclin. It has comparable efficacy to inhaled prostacyclin, but has a longer half-life (20 to 30 minutes vs six minutes) and a longer clinical duration of action (about 60 vs 15 minutes) (103). Iloprost is therefore more convenient to administer than inhaled prostacyclin, as continuous nebulisation is not required.

In patients undergoing mitral valve replacement, iloprost produced a greater reduction in PAP and a greater improvement in RV function than intravenous nitroglycerine (104). In a randomised trial of 46 patients with a mean PAP of 34 mmHg undergoing cardiac surgery who received either iloprost (20 [micro]g) or iNO (20 ppm), iloprost produced a significantly greater reduction in PVR and PAP and a significantly greater increase in CO than iNO (105).

Both iNO and inhaled prostacyclin inhibit platelet aggregation. Inhaled nitrous oxide prolonged bleeding time in patients with ARDS (106) and inhaled prostacyclin inhibited platelet function following cardiac surgery, although chest tube drainage and transfusion requirements were not significantly increased (107). Inhaled nitroprusside and inhaled nitroglycerine produce dose-dependent pulmonary vasodilation, although there is little clinical evidence to support their use (108). There is more evidence to support the use of inhaled milrinone. In heart transplant patients with PHT, inhaled milrinone (2 mg) produced selective pulmonary vasodilation (109). In an audit of 73 high-risk cardiac surgical patients, inhaled milrinone (5 mg) given before CPB was associated with a higher rate of successful weaning than when given after CPB (1 vs 9 patients required return to CPB respectively, P <0.05) (110).

Several combinations of pulmonary vasodilators have been shown to produce greater effects than single agents alone. These include: inhaled iloprost and iNO (111), inhaled milrinone and inhaled prostacylin (112) and oral sildenafil and inhaled iloprost (113). While specialised delivery systems and monitoring are required for iNO delivery, the advent of ultrasonic nebulisers has simplified the delivery of other inhaled agents. Ultrasonic nebulisers are more efficient than jet nebulisers in delivering drugs to alveoli (114) and are better suited for use in ventilated patients as they do not require an external oxygen supply.

* Selective oral pulmonary vasodilators: Oral sildenafil and bosentan (an endothelin II antagonist) produce selective pulmonary vasodilation. Bosentan is effective in the management of IPAH (115), chronic pulmonary thromboembolism (116,117), congenital heart disease (118,119) and Eisenmenger's syndrome (120). Bosentan was effective in the perioperative management of a patient with severe PHT associated with liver transplantation (121) and in a patient following bariatric surgery (122). The use of bosentan is contraindicated in pregnancy, because of potential teratogenic side-effects (123).

There is more experience with the perioperative use of sildenafil. In eight patients with PHT following cardiac surgery, oral sildenafil (25 to 50 mg) produced a 49% reduction in PVR within 30 minutes of administration. There was a small fall in MAP (7 mmHg) due to a 25% fall in SVR index (124).

Oral sildenafil either alone (125,126) or in combination with bosentan (127) also facilitates weaning from iNO therapy.

In summary, inhaled iloprost, iNO and oral sildenafil are all effective pulmonary vasodilators for perioperative use. Inhaled iloprost is more convenient to administer than iNO and produces a synergistic reduction in PVR when combined with inhaled milrinone.

Vasopressors

The function of an ischaemic RV due to pressure overload may be improved by increasing the MAP. Although this is partly due to an increase in right coronary blood flow, changes in interventricular septal function may also contribute. Increasing the LV afterload increases LV diastolic pressures, which shifts the interventricular septal back towards the RV. This results in improved LV output and allows the RV to increase its output if some functional reserve is present (128).

The ideal vasopressor in patients with RV dysfunction would increase SVR without affecting PVR. However the effects of vasopressors on PVR are complex and vary, depending on their relative [alpha]- and [beta]-adrenoreceptor properties and also on the degree of RV dysfunction. For example, in an isolated normal lung model, adrenaline and noradrenaline produce dose-dependent pulmonary vasoconstriction due to their [[alpha].sub.1]-adrenoreceptor effects (129). However, this is offset by their [[beta].sub.1]-adrenoreceptor actions in vivo, which increase the CO and thereby reduce the PVR.

In patients with chronic PHT, phenylephrine, methoxamine (130) and noradrenaline all increase the MAP and right coronary blood flow. However, phenylephrine may worsen RV function (131) and is less effective than noradrenaline in the treatment of hypotension following induction of anaesthesia in these patients (132). While noradrenaline was found to increase PVR in chronic PHT (133), it reduced (74,133) or did not alter PVR (134) in acute RV failure due to pressure overload. These differing effects on PVR can be explained by the observation that noradrenaline significantly increased the CO in acute RV failure due to pressure overload, but not in patients with chronic PHT.

Vasopressin may also be a useful vasopressor in patients with PHT. From animal models, vasopressin had been shown to produce potent systemic vasoconstriction and pulmonary vasodilation, due to stimulation of NO release from the pulmonary endothelium (135). However, the effect of vasopressin on PVR in human studies has been variable, and may depend on whether PVR is low (mild increase in PVR (136), normal (no effect on PVR (137)) or acutely elevated (increases PVR (138)). In a study of patients with milrinone-induced hypotension who were undergoing coronary artery bypass grafts, both noradrenaline and low-dose vasopressin increased SVR. However, vasopressin had a relatively greater effect on the systemic circulation than on the pulmonary circulation, as it decreased the PVR/ SVR ratio significantly more than noradrenaline (136). Vasopressin reversed acute RV failure following delivery in two patients with IPAH who were undergoing caesarean section, one of whom was already receiving intravenous dobutamine, noradrenaline and prostacyclin (139).

In summary, noradrenaline is superior to methoxamine and phenylephrine for the treatment of RV dysfunction due to PHT, while vasopressin should be considered for refractory cases.

Inotropes

The limited animal and human data available support the use of adrenaline, noradrenaline, dobutamine, levosimendan and milrinone in RV failure.

In an animal experiment, adrenaline reduced the PVR, PAP and the PVR/SVR ratio significantly more than dopamine, both when the PVR was normal and when it was elevated. Increasing doses of adrenaline (but not dopamine) also decreased the PVR/SVR ratio (140). In patients with severe RV dysfunction, adrenaline (141), noradrenaline (142) and dobutamine (143) may be effective.

Dobutamine has been considered the drug of choice in patients with RV infarction (144,145). Dobutamine is useful in the management of RV failure due to acute pressure overload as it increases RV contractility without affecting PVR (146). In other animal experiments on RV pressure overload, dobutamine produced a greater increase in RV contractility than noradrenaline (147), while levosimendan (a newer inotrope that sensitises myocardial troponin to calcium) produced a similar increase in RV contractility to dobutamine, but produced a greater reduction in PVR (148).

Phosphodiesterase-III inhibitors increase contractility and produce both systemic and pulmonary vasodilation. In patients with PHT following mitral valve replacement, amrinone produced a greater increase in cardiac index and RV ejection fraction than dobutamine (149). Amrinone and milrinone produce similar haemodynamic effects (150). In children undergoing congenital heart surgery, the combination of intravenous milrinone and iNO produced a greater reduction in PAP than either agent alone (151). In experimental acute pulmonary hypertension in pigs, the combination of intravenous milrinone and oral sildenafil reduced PVR significantly more than either agent alone. Although milrinone also reduced SVR, there was no further reduction in SVR when it was combined with sildenafil (152).

Dobutamine, adrenaline, noradrenaline, milrinone and levosimendan are all effective inotropes for RV failure. However, as levosimendan and milrinone both produce systemic vasodilation, vasopressors may need to be co-administered to prevent reduced right coronary blood flow. The combination of RV dysfunction and PHT should be treated with a combination of inotropes and pulmonary vasodilators.

Mechanical support of the RV

Mechanical support of the RV should be considered in patients with severe RV failure that is refractory to medical therapy, provided that it is either potentially reversible or if the patient is a candidate for heart-lung transplantation. The efficacy of an intra-aortic balloon pump for RV failure following cardiac surgery is unknown. The use of an intra-aortic balloon pump improved RV perfusion in an experimental model of RV infarction, but had little effect on RV function (153).

Successful outcomes have been reported with the use of rescue veno-arterial extracorporeal membrane oxygenation in patients with RV failure due to massive pulmonary embolism (154-158). In a series of 21 patients with massive pulmonary embolism who were supported with extracorporeal membrane (eight of whom were in cardiac arrest), 13 patients (62%) survived (159). Extracorporeal membrane oxygenation was also used to support a patient with RV decompensation due to IPAH for 10 days until a heart-lung transplant could be performed (160). New, percutaneous RV assist devices may be a bridge either to recovery or to transplantation (161,162).

CONCLUSION

The key aspects of 'RV protection' in patients who are at risk of perioperative decompensation are prevention, detection and treatment aimed at reversing the underlying pathophysiology. Minimising PVR and maintaining MAP are of central importance in the prevention of RV decompensation, which is characterised by a rising CVP and a falling CO. Although there are no outcome data to support any therapeutic strategy, combinations of inhaled iloprost or intravenous milrinone with oral sildenafil produce a synergistic reduction in PVR, without affecting SVR. Levosimendan is a promising new inotrope for the treatment of RV failure, although its role in comparison to older agents such as dobutamine, adrenaline and milrinone has yet to be determined. This is also the case for the use of vasopressin as an alternative pressor to noradrenaline. Finally, if all else has failed, mechanical support of the RV should be considered in selected cases.

ACKNOWLEDGEMENTS

I would like to thank Professor Peter Kam (Nuffield Professor of Anaesthetics, Sydney University, Camperdown, New South Wales) for his constructive criticism of this paper.

Accepted for publication on November 12, 2008.

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P. FORREST *

Department of Anaesthetics, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

* M.B., Ch.B., F.A.N.Z.C.A., Senior Staff Specialist.

Address for reprints: Dr P. Forrest, Department of Anaesthetics, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW 2050.
TABLE 1
Summary of anaesthetic recommendations for patients at risk of right
ventricular decompensation. The level of monitoring recommended is
patient-specific and not procedure-specific.

Intervention No PHT: Severe PHT:
 RVF no RVF

Premedication
 sildenafil 25-50 mg po - -
Pre-induction
 iloprost (10 [micro]g) neb - +/-
Monitoring
 CVP: spontaneous ventilation - -
 IPPV + +
invasive BP: spontaneous ventilation - -
 IPPV + -
PAC (or other cardiac output monitor)
 spontaneous ventilation - -
 IPPV - -
 TOE +/- -
Neuraxial anaesthesia + +
Ventilation
 high Fi[O.sub.2] + +
 mild hyperventilation + +
 low ventilating pressures + +
Anaesthetic agents + +
 ketamine: children + +
 ketamine: adults +/- -
 thiopentone/etomidate + +
 propofol + +
 [N.sub.2]O - -
 isoflurane/halothane/enflurane + +
 desflurane - -
 fentanyl/sufentanil/remifentanil + +

Intervention Severe
 PHT: RVF

Premedication
 sildenafil 25-50 mg po +
Pre-induction
 iloprost (10 [micro]g) neb +
Monitoring
 CVP: spontaneous ventilation -
 IPPV +
invasive BP: spontaneous ventilation +
 IPPV +
PAC (or other cardiac output monitor)
 spontaneous ventilation +
 IPPV
 TOE +/-
Neuraxial anaesthesia +
Ventilation
 high Fi[O.sub.2] +
 mild hyperventilation +
 low ventilating pressures +
Anaesthetic agents +
 ketamine: children +
 ketamine: adults -
 thiopentone/etomidate +
 propofol -
 [N.sub.2]O -
 isoflurane/halothane/enflurane +
 desflurane -
 fentanyl/sufentanil/remifentanil +

RVF=right ventricular failure, PHT=pulmonary hypertension,
NO=nitric oxide, [N.sub.2]O=nitrous oxide, PEEP=positive end-expired
pressure, CVP=central venous pressure, TOE=transoesophageal
echocardiography, PAC=pulmonary artery catheter, BP=blood
pressure, IPPV=intermittent positive pressure ventilation,
BP=blood pressure, +=recommended, - =not recommended.

TABLE 2
Summary of recommended pharmacologic therapies for
perioperative right ventricular failure

 PVR normal PVR high

Pulmonary vasodilators
 NO (10 ppm) - +
 iloprost (10 [micro]g neb) - +
 milrinone (2-5 mg neb) - +
 sildenafil (50 mg po) - +
Vasopressors
 phenylephrine + +/-
 noradrenaline + +
 vasopressin + +
Inotropes
 dobutamine + +
 adrenaline + +
 milrinone + +
 levosimendan + +

PVR=pulmonary vascular resistance, NO=nitric oxide,
+=recommended, - =not recommended.
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Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:8AUST
Date:May 1, 2009
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