part0017

Positive airway pressure has a beneficial effect on left ventricular function by reducing both preload and afterload (the transmural pressure across the left ventricle). At the same time, however, positive airway pressure can worsen right ventricular function—the normally low-pressure pulmonary vascular circuit now is subjected to significant pressure from the ventilator. Hypoxic pulmonary vasoconstriction also increases the workload on the right ventricle. Most of the time, this doesn't affect hemodynamics too much, and fluid loading is sufficient to maintain right ventricular output. In some patients, though, pulmonary hypertension and right ventricular dysfunction can have a notably adverse effect on both cardiac and pulmonary function.

Right ventricular (RV) dysfunction and even overt RV failure can be seen with severe ARDS. It is also seen with massive or submassive pulmonary embolism, right ventricular infarction, and in patients with preexisting pulmonary hypertension (chronic obstructive pulmonary disease, obstructive sleep apnea, connective tissue diseases, primary pulmonary hypertension, etc.). RV failure can be particularly difficult to treat—the right ventricle is normally a thin-walled structure that operates best in conditions of low vascular pressure and resistance. A sudden increase in pulmonary vascular resistance is hard for the RV to deal with—it just doesn't have the muscle mass of the left ventricle. Inotropes like milrinone and dobutamine can be used to "whip the heart," but an increase in cardiac output is often neutralized by a corresponding rise in myocardial oxygen consumption. In this situation, a selective pulmonary arterial vasodilator may prove to be helpful.

The most commonly used pulmonary arterial dilator in critical care medicine is inhaled nitric oxide (iNO). iNO can be delivered by mask or through the endotracheal tube and has a rapid vasodilatory effect on pulmonary arterioles and capillaries. One particular advantage of iNO is that it will only cause vasodilation in the alveolar-capillary beds that it reaches. This has the effect of improving ventilation-perfusion matching in patients with severe hypoxemia. Inhaled prostacyclin can also be used and has the same physiologic effect. Intravenous pulmonary vasodilators like prostacyclin and alprostadil can be used, but tend to have a much more potent effect on hemodynamic function and often cause hypotension.

There have not been many clinical trials of inhaled prostacyclin, and the evidence base is limited. iNO has been studied much more extensively, and so further discussion will center on the use of iNO. This does not mean that inhaled prostacyclin is not effective, and it may work just as well as iNO in similar clinical settings. It is important to note that neither iNO nor inhaled prostacyclin are FDA-approved for use in adults with ARDS or right ventricular failure, and any use is off-label.

The allure of inhaled pulmonary vasodilators is that they cause selective vasodilation only in the lung units that they can reach; they have a rapid onset and offset; that they have minimal adverse hemodynamic effects; and that there are no downstream metabolites. For years, this was thought to be the case. iNO was believed to be inactivated immediately by reacting with hemoglobin in the pulmonary capillaries. Recent research has shown that this is not the case. iNO reacts with hemoglobin and leads to formation of nitrite and S-nitrosohemoglobin. Nitrite can be recycled in downstream tissues to nitric oxide, which can cause systemic capillary vasodilation. S-nitrosohemoglobin also induces nitric oxide production, particularly in the setting of tissue hypoxia. This couples vasodilation and deoxygenation, which may lead to mitochondrial dysfunction. This has been demonstrated in clinical trials, where use of iNO is associated with a higher rate of renal failure. 33 Presumably, the toxic effects of these metabolites are not limited to the kidneys, which means that the metabolites of iNO could contribute to multisystem organ dysfunction.

In patients with ARDS, iNO may improve oxygenation via selective pulmonary vasodilatation. No studies have shown a survival benefit with this therapy, however, and a recent meta-analysis 34 of nine clinical trials concluded that, "Nitric oxide does not reduce mortality in adults or children with acute respiratory distress syndrome, regardless of the degree of hypoxemia." The reason for the lack of benefit seems to be in line with other therapies that have been shown to improve oxygenation but not survival—very few patients with ARDS die of refractory hypoxemia. The majority die of multisystem organ failure, and the potentially toxic metabolites of iNO may potentiate this. Therefore, iNO should only be used in ARDS as a true rescue therapy. It may be helpful in patients with a PaO 2 /FiO 2 ratio less than 55 despite optimal care and who are not candidates for other rescue therapies that have been proven to be beneficial (prone positioning, veno-venous ECMO).

Acute right ventricular failure is primarily treated with fluid loading and inotropic support. Dobutamine and milrinone are inotropes that increase right ventricular contractility. Milrinone, a phosphodiesterase-III inhibitor, also has vasodilatory properties on the pulmonary circulation. Levosimendan is another calcium-sensitizing inodilator, but it is not commercially available in the United States.

RV failure is often associated with moderate-to-severe hypoxemia and pulmonary dysfunction. Conventional ventilator strategies that use high levels of PEEP or increase the mean airway pressure (like APRV) can worsen right ventricular function and increase pulmonary vascular pressures. Inhaled nitric oxide or prostacyclin can be used to lower the pulmonary vascular resistance, thereby improving right ventricular function and improving gas exchange.

When initiating inhaled pulmonary vasodilators for right ventricular failure, a pulmonary artery catheter is strongly encouraged. Echocardiography can also be used to evaluate contractility and to measure pulmonary artery pressure, but it isn't available continuously and is not ideal for titrating medications. The pulmonary artery catheter can continuously measure pulmonary artery pressure, cardiac output, and SvO 2 . It can also be used to calculate the pulmonary vascular resistance. This is very useful for differentiating between conditions that cause pulmonary arterial hypertension and those associated with pulmonary venous hypertension. Selective pulmonary vasodilators tend to be more effective for the former.

Pulmonary vascular resistance (PVR) can be calculated by measuring the mean pulmonary artery pressure and the pulmonary artery occlusion pressure at end-expiration. The difference between the two measurements is then divided by the cardiac output (in L/min).

A patient with a normal mean pulmonary artery pressure (20 mm Hg), pulmonary artery occlusion pressure (10 mm Hg), and cardiac output (5 L/min) would have a pulmonary vascular resistance of 2 mm Hg-min/L, or Wood units. Normal PVR is 2-3 Wood units. * Conditions that elevate both the mean PAP and the PAOP (most commonly left ventricular dysfunction, but also mitral and aortic valvular disease) are characterized by pulmonary hypertension and a normal PVR. This is often referred to as pulmonary venous hypertension. The high pressure in the left atrium leads to high right-sided pressures in order to keep the blood flowing. Caution should be used with any kind of pulmonary vasodilator—lowering the mean PAP, while the PAOP remains elevated, often leads to pulmonary edema.

Consider a patient who has severe systolic CHF. He has a mean PAP of 40 mm Hg and a PAOP of 30 mm Hg. The PAOP (a.k.a. the wedge pressure) represents left atrial pressure. Left atrial pressure equals left ventricular pressure at the end of diastole, when blood stops flowing from the atrium to the ventricle. The left ventricular end-diastolic pressure is elevated due to severe CHF. The only way that blood can flow from the right ventricle through the pulmonary vasculature and into the left ventricle is if the pulmonary artery pressure is higher than the left ventricular pressure. Now, this patient is started on iNO. The mean PAP falls, as predicted. iNO is a selective pulmonary vasodilator, which means that it will not reduce the left ventricular afterload. The left atrial pressure remains the same. If the mean PAP is now 28, and the left atrial pressure is 30, you can see where this is going. Blood flow will reverse, leading to pulmonary edema and hypotension.

Pulmonary arterial hypertension, on the other hand, is characterized by an imbalance between the mean PAP and the PAOP. Thromboembolic disease, connective tissue disease, and chronic hypoxemia are common causes. A patient with a mean PAP of 45 mm Hg, PAOP of 15 mm Hg, and a cardiac output of 6 L/min has PVR of 5 Wood units, suggesting pulmonary arterial hypertension. Right ventricular dysfunction with a PVR ≥ 4 Wood units may improve with a pulmonary vasodilator.

It is important to remember that inhaled nitric oxide or prostacyclin is an adjunctive therapy, and not a treatment in itself. The underlying condition leading to right ventricular failure should be treated aggressively. Pulmonary embolism should be treated with anticoagulation and thrombolysis. Acute chest syndrome in patients with sickle cell disease should be treated with antibiotics and exchange transfusion. Acute myocardial infarction should be treated with reperfusion therapy. Attention to volume status is crucial—while hypovolemia will certainly lead to hypotension, volume overload will cause bowing of the interventricular septum and compromise left ventricular filling. Euvolemia, guided by echocardiography and/or pulmonary artery catheter monitoring, should be achieved by diuresis or renal replacement therapy.

iNO is available with a commercial delivery system that has a long track record of reliability and safety. Using an unapproved, self-made delivery system has the risk of unreliable dosing of iNO and potentially toxic exposure of the patient and staff to nitrogen dioxide. Use the commercial system!

Inhaled prostacyclin can be reconstituted in saline and delivered by a jet nebulizer system modified for use with mechanical ventilation. This requires an aerosol delivery device that can be coordinated with the ventilator's inspiratory cycle, which has been described in the literature . 3 5

iNO should be started at 20 parts per million (ppm). A successful response is a reduction in the mean pulmonary artery pressure by at least 10%, and usually an improvement in the PaO 2 by at least 20 mm Hg. If the patient does not respond within 5-10 minutes, then a higher concentration (40 ppm, or even 80 ppm) can be tried. Most patients who are going to respond will do so at 20 ppm. iNO should be stopped in those patients who do not have an initial response to therapy.

In patients who respond, the dose of iNO should be lowered in 5-10 ppm increments every 15-30 minutes, to a floor of 5 ppm. An increase in the mean PAP by ≥ 5 mm Hg, or a fall in the SpO 2 by ≥ 5%, should be treated by increasing the dose of iNO back to the level where it was effective.