Some patients with acute RHS may benefit from specific therapies, such as thrombolysis for acute pulmonary embolism (see Chap. 27). In most patients, however, the two basic aims of treatment are supportive: to reduce systemic oxygen demand while improving oxygen delivery (Table 26-5). Oxygen demand can be lowered by treating fever, sedating the patient, instituting mechanical ventilation, and in severe cases, using therapeutic muscle relaxation. Oxygen delivery can be enhanced by correcting hypovolemia, transfusing red blood cells, relieving alveolar hypoxia, infusing vasoactive drugs, and avoiding detrimental ventilator settings. The goals of oxygen therapy in RHS are to enhance arterial saturation (SaO2) and to block alveolar hypoxic vasoconstriction (AHV). Using a sufficient oxygen concentration to achieve 88% SaO2 is advocated in ARDS and other alveolar flooding diseases (see Chap. 38), but in RHS not associated with intrapulmonary shunt, we target SaO2 to >96% to ensure alveolar oxygen values sufficient to block AHV (PaO2 >55 mm Hg). It may be useful to correct anemia with red blood cell transfusion, raising the arterial oxygen content, and reducing the necessary cardiac output. The resulting increased blood viscosity (and its tendency to raise pulmonary vascular resistance) probably does not outweigh the reduced demand for forward flow.
Fluid therapy, ventilator management, and vasoactive drug infusion are discussed below and have been the subject of a recent review.58
In most patients with shock it is appropriate to administer fluid, often in massive quantities, to restore left ventricular diastolic filling and boost cardiac output. Despite the recognition that the right heart becomes extremely preload dependent during ischemia and infarction,56 excessive fluid administration is likely to worsen hemodynamic stability. In many of these patients the right-sided pressures are already well above normal, signaled by neck vein distention. Data from animal models of pulmonary embolism, as well as from studies of patients with right ventricular infarction, demonstrate that fluid therapy may be unhelpful or even detrimental.
In a canine autologous clot model of pulmonary embolism, the effects of fluid loading were studied before embolism, then following embolism.59 Before embolism, fluid loading significantly raised the right atrial pressure, the transmural left ventricular end-diastolic pressure (LVEDP), and the left ventricular end-diastolic area index (a measure of left ventricular volume using sonomicrometry). Following multiple emboli, fluid loading raised right atrial pressure, but transmural LVEDP fell significantly as did the left ventricular end-diastolic area index. These findings indicate that fluid loading following embolism causes further leftward displacement of the interventricular septum, further compounding LV diastolic dysfunction. In a canine glass bead embolization model, fluid loading was found to precipitate right ventricular failure, even when relatively small volumes were infused.60
Similar results have been shown in human right ventricular infarction.61,62 Despite raising the right atrial and wedge pressures, fluid loading failed to increase the cardiac index, blood pressure, or left and right ventricular stroke work. These findings should serve as a caution regarding fluid administration to patients with shock due to acute RHS. Since some patients may be volume depleted at presentation, a fluid challenge is reasonable, especially if the neck veins are flat or right heart filling pressures are low. Nevertheless, fluid should be given with a healthy degree of skepticism and careful attention to the consequences. We recommend that a discrete crystalloid fluid bolus of no more than 250 mL be administered while assessing relevant indicators of perfusion such as blood pressure, heart rate, pulsus paradoxus, cardiac output, central venous oxyhemoglobin saturation, or urine output. If no benefit can be detected, further fluids should not be given, and attention should shift to vasoactive drugs.
A wide variety of vasoactive drugs has been tried in patients or animal models for the treatment of acute RHS due to pulmonary embolism, ARDS, or right ventricular infarction, with variable success. These include nonspecific vasodilators (hydralazine
63 and nitroprusside
61,64,65), vasoconstrictors (norepinephrine,7,60,66
dopamine,69 and vasopressin
70,71), inotropes (dobutamine,61,62,72–74 amrinone,75
isoproterenol,7 epinephrine,67 and levosimendan
77), and pulmonary vasodilators (prostaglandin E1,78,79 prostaglandin I2,35 and nitric oxide
35,65,70,80–86). Predicting the response to any of these drugs a priori is complicated by their tendency toward opposing effects. Conflicting data from studies of an agent in different animal models suggest that the interspecies variation and prevailing pulmonary vascular tone are important in determining if a particular agent has a predominantly pulmonary vasodilatory or vasoconstricting effect.73,74 Thus the choice of vasoactive drugs cannot be based solely on the presumed pathophysiology, but also must be based on the results of human and animal studies summarized below. We contend that a vasoactive drug is effective in RHS when it significantly raises cardiac output without significantly worsening systemic hypotension, SaO2, or RV ischemia. Dobutamine is our preferred positive inotrope, inhaled NO (and perhaps aerosolized prostacyclin) have salutary short-term physiologic effects as pulmonary vasodilators, and norepinephrine may provide added benefit as a systemic vasoconstrictor and positive inotrope by raising coronary perfusion pressure to an ischemic RV.
In massive pulmonary embolism, dobutamine and norepinephrine appear superior to other vasoactive drugs.7,72 In human PE, dobutamine has been most intensively studied. For example, of 10 patients with shock due to massive PE treated with dobutamine, 1 rapidly died, but 9 showed impressive hemodynamic improvement (Table 26-6). These results show that dobutamine improves cardiac output by improving right ventricular function or reducing pulmonary vascular resistance. Although fewer data are available regarding norepinephrine in human embolism, animal studies and limited human data support its use.7,6672 In a canine model of pulmonary embolism, dobutamine and dopamine had essentially identical hemodynamic effects.69 Data from a separate canine study suggest that at doses less than 10 μg/kg per minute, dobutamine-induced pulmonary circulatory changes are exclusively flow dependent.74 At higher doses, changes in pulmonary vascular resistance are variable and may depend on the prevailing pulmonary vascular tone. These drugs should be titrated according to clinical measures of the adequacy of perfusion, such as renal function, mentation, thermodilution cardiac output, or central venous oxyhemoglobin saturation, rather than to blood pressure alone. We begin dobutamine at 5 μg/kg per minute, raising the dose in increments of 5 μg/kg per minute every 10 minutes. If the patient fails to respond to dobutamine (or the response is incomplete), we substitute (or add) norepinephrine infused at 0.4 to 4 μg/kg per minute. In patients with hypoperfusion due to right ventricular infarction, dobutamine is superior to nitroprusside
61 (and to fluid infusion61,62), significantly improving right ventricular ejection fraction and cardiac output. Therefore dobutamine is the drug of first choice in all cases of RHS. We avoid the use of dopamine because of its highly variable pharmacokinetics and concern for disproportionate splanchnic vasoconstriction, even in relatively low doses.
Table 26–6. Dobutamine for Shock Due to Massive Pulmonary Embolism in 10 Patients |Favorite Table|Download (.pdf)
Table 26–6. Dobutamine for Shock Due to Massive Pulmonary Embolism in 10 Patients
|Pao (mm Hg)||81||86|
|Ppa (mm Hg)||32||31|
|Pra (mm Hg)||13||11|
|Ppw (mm Hg)||12||11|
|CI (L/min per m2)||1.7||2.3|
The role of vasopressin (and its longer acting congener, terlipressin) remains controversial and incompletely evaluated. Vasopressin clearly functions as a systemic vasoconstrictor at high doses. In patients with septic shock, replacement of acutely depleted endogenous vasopressin with a low-dose infusion (0.04 U/min) is thought to improve catecholamine sensitivity via the functionally vasoconstricting V1 receptor. The pulmonary vasculature has been shown by some investigators to express V1 receptors, but that vasopressinergic stimuli may paradoxically mediate pulmonary vasodilation.87,88 This might suggest a salutary potential for vasopressin therapy in acute right heart syndromes. In a canine model, however, vasopressin caused both systemic and pulmonary vasoconstriction while impairing RV contractility.71 Our present practice is to avoid vasopressin for acute right heart syndromes unless catecholamine-dependent septic shock is present.
Prostaglandin E1 (PGE1) is a potent pulmonary vasodilator that exhibited promise in the treatment of ARDS. When infused at a dose of 0.02 to 0.04 μg/kg per minute to patients with severe ARDS and mean PA pressure greater than 20 mm Hg, PA pressure fell 15% despite an increase in cardiac output. At the same time, however, systemic blood pressure fell to a similar degree, and intrapulmonary shunting rose significantly.78 In an oleic acid model of porcine ARDS, PGE1 lowered pulmonary artery pressure, but stroke volume and stroke work did not improve significantly.79 In patients with ARDS given prostacyclin (4 ng/kg per minute), pulmonary artery pressure fell, RV ejection fraction rose, and cardiac output increased significantly.35 A small series of patients with chronic pulmonary hypertension have been given aerosolized prostacyclin, and they demonstrated pulmonary vasodilation, increased cardiac output, and improved arterial oxyhemoglobin saturation.89 Systemic blood pressure fell somewhat, but to a much lesser degree than when prostacyclin was infused intravenously (for similar degrees of pulmonary vascular effect). When compared for acute hemodynamic effects in patients with primary pulmonary hypertension (PPH), aerosolized prostacyclin (approximately 14 ng/kg per minute over 15 minutes) was demonstrated to be a pharmacologically more potent acute vasodilator than inhaled NO (NO 40 ppm for 15 minutes).90
In a similar comparison in ARDS patients, gas exchange parameters were comparably improved when inhaled prostacyclin (7.5 ± 2.5 ng/kg per minute) was compared with inhaled NO at a dose lower than that in the PPH study (17.8 ± 2.7 ppm).91 This may suggest that in patients with right heart syndromes and long-standing pulmonary hypertension, inhaled prostacyclin may afford greater efficacy.
Although not conclusively demonstrated, inhaled prostacyclin has been used with some success in perioperative acute RHS.
Adenosine is an endogenous vasodilator that has a very short half-life (less than 10 seconds) due to rapid metabolism by adenosine deaminase. When used following cardiac surgery, adenosine lowered pulmonary artery pressure, raised cardiac output, and did not cause hypotension.46,92 Adenosine was infused centrally at a dose of 50 μg/kg per minute.
Phosphodiesterase Inhibitors: Amrinone, Milrinone, Dipyridamole, and Sildenafil
Amrinone is an inotrope and vasodilator with potential in the acute right heart syndromes. In a canine model of massive embolism, amrinone (0.75 mg/kg bolus followed by 7.5 μg/kg per minute) lowered pulmonary artery pressure, raised cardiac output, and raised systemic blood pressure.75 Limited data are available for the use of milrinone in acute RHS and its use is limited by a long half-life and limited ability of titration.76 Additionally, milrinone has been shown to be less efficacious than inhaled NO in treating pulmonary hypertension post–cardiac surgery.82 Another phosphodiesterase inhibitor, dipyridamole, has been evaluated as an adjunct to NO in pediatric patients with acute RHF, and shown to have some additional pulmonary vasodilatory effects.93,94
Significant interest has arisen in the therapeutic potential of the selective type 5 PDE inhibitor sildenafil, presently approved for male erectile dysfunction. Impressive acute reductions in pulmonary arterial pressures have been demonstrated with oral and intravenous administration in animal models of acute lung injury95 and RHS, in patients with established pulmonary hypertension,96 and in 93 patients with pulmonary hypertension complicating pulmonary fibrosis.97 Additionally, synergistic effects of selective PDE inhibitors in combination with inhaled and intravenous vasodilators has been demonstrated in acute lung injury–associated right heart syndromes.98–100
Nitric oxide brings together the potential for hemodynamic as well as gas exchange improvement. When patients with ARDS and pulmonary hypertension were given NO via endotracheal inhalation at a dose of 18 ppm, PA pressure fell, right ventricular ejection fraction rose, and RV end-systolic and end-diastolic volumes fell.35 There was no detectable change in mean arterial pressure, and arterial oxygen pressure rose significantly. Increasing the dose of NO to 36 ppm had no incremental effect. These findings have been confirmed in similar patients with ARDS who were managed with permissive hypercapnia (mean arterial carbon dioxide pressure = 71 mm Hg) and given a lower dose of NO (5 ppm), although the effect was more modest.80 Disappointingly, survival has not been improved in four large randomized controlled studies of NO in ARDS patients.83–86
Both prostacyclin and the newer nonselective endothelin receptor antagonists (ETRA) have been demonstrated to have antiproliferative activity on the pulmonary vasculature. This mechanism has been suggested to account for the modest functional improvement in patients with chronic pulmonary hypertension.101,102 Although single case reports suggest beneficial effects of the orally administered nonselective ETRA bosentan, this agent has not been subjected to rigorous evaluation in patients with acute right heart syndromes, and it may have limited potential in critically ill patients because of significant associated hepatic toxicity.
Ventilator manipulation has the potential to dramatically affect the circulation in patients with shock, including those with acute RHS. For example, in animal models of shock, institution of mechanical ventilation significantly prolongs survival, an effect much greater than that seen with fluid therapy or vasoactive drugs. Of particular interest in patients with RHS is the maintenance of oxygenation, the role of hypercapnia (including permissive hypercapnia), and the effects of tidal volume and positive end-expiratory pressure (PEEP).
Hypercapnia increases pulmonary artery pressure. In patients with ARDS, reducing minute ventilation as part of the strategy of permissive hypercapnia leads to small but real increases in mean pulmonary artery pressure.103–105 In most patients with ARDS who do not exhibit right heart limitation, this effect of hypercapnia is probably unimportant. However, in the subset of patients with severe pulmonary hypertension, permissive hypercapnia may lead to unacceptable hemodynamic deterioration.
The effect of PEEP on right ventricular function is complex, controversial, and highly variable from patient to patient.106,107 Many studies are limited by the failure to correlate hemodynamic pressures to juxtacardiac pressure. The effect of PEEP can be expected to differ depending on whether atelectatic or flooded lung is recruited, or whether relatively normal lung is overdistended. In a study of patients with ARDS, PEEP had little effect on RV function when given in amounts up to that associated with improving respiratory system compliance.106 At higher levels of PEEP, the dominant effect was to impair RV systolic function.
The dominant effect of mechanical ventilation is related to its effect on preload. Sustained airway pressure increases in volume-repleted patients with normal RV function result in a mild increase in right atrial pressure that is offset by increases in abdominal pressures that sustain venous return. However, it remains to be determined if this is true for patients with acute RHS and elevated right heart pressures.108 Large-tidal-volume breathing impairs RV systolic function, presumably by increasing pulmonary vascular resistance in alveolar vessels. In a canine model with normal lungs, raising the tidal volume above 10 mL/kg caused a detectable rightward and downward shift of the RV function curve.109
These effects of mechanical ventilation on right ventricular function suggest the following strategy in patients with critical compromise of the RV: (1) give sufficient oxygen to reverse any hypoxic vasoconstriction; (2) avoid hypercapnia; (3) keep PEEP at or below a level at which continued alveolar recruitment can be demonstrated and seek to minimize self-controlled PEEP (Auto-PEEP); and (4) use the lowest tidal volume necessary to effect adequate elimination of carbon dioxide. Of course, the acute effects of each intervention should be measured to confirm that cardiac output increases. These principles are consonant with the goals of ventilation in most patients with ARDS, except that when there is an RHS, hypercapnia should be avoided if it leads to further hemodynamic deterioration.
In contrast to the now well-defined role for mechanical assist devices in decompensated left heart failure,110 there remains relatively little experience with mechanical therapy for the failing right heart. Notably, progressive right ventricular dysfunction complicates left ventricular assist device implantation or orthotopic heart transplantation for decompensated left heart failure111,112 and is associated with progressive end-organ dysfunction.113 The presently available approaches include extracorporeal and paracorporeal pulsatile and centrifugal pump ventricular assist systems.75,76 An alternative approach uses a right atrial catheter to draw blood into a centrifugal pump and a percutaneously placed pulmonary artery catheter as the outflow cannula.114 Small implantable centrifugal pumps are under development.