Modulating the Pulmonary Circulation: Nitric Oxide and Beyond

Thomas Schilling, Astrid Bergmann

Abstract

One-lung ventilation is required for thoracic surgery interventions; however, it can impair ventilation/perfusion (V_A/Q) matching, thus putting the patient at increased risk for hypoxemia that might compromise the overall outcome. Both anesthetic and surgical management may influence the pulmonary and systemic reaction. Concerning the anesthetic management, plenty of research has been undertaken to highlight the impact of anesthetic drugs and ventilatory settings, especially the use of pressures and volumes. Intraoperative hypoxia and its consequences have been widely elucidated, opening the way for V_A/Q matching to reach the focus of interest. Several drugs that affect the vasculature and/or the respiratory system have been analyzed, as they might lead to dilation or constriction within the pulmonary vessels and therefore impact on V_A/Q relation. One of the key issues in anesthetic management is to impede a rise in pulmonary vascular resistance and a rise in cardiac oxygen demand. Inhalational agents, such as nitric oxide or prostacyclin analogs, act as potent vasodilators that do not compromise systemic vascular resistance, as they act locally in the ventilated areas. Phosphodiesterase inhibitors have promising effects on V_A/Q matching, as well as the chemoreceptor agonist almitrine. Even though calcium channel blockers and endothelin receptor antagonists do not play a role within the intraoperative setting, they will be frequently encountered in patients suffering from pulmonary hypertension. Pulmonary vasculature and perfusion distribution are also affected by several vasoconstricting agents, such as catecholamines or by different vasodilators and inotropes. All of them impact on V_A/Q relation depending on their site of action and can thus influence management in thoracic anesthesia.

Keywords

one-lung ventilation; hypoxemia; pulmonary circulation; pharmacologic intervention; nitric oxide; prostacyclin; phosphodiesterase inhibitors

Introduction

Thoracic surgery commonly requires the separation of the patient’s airway, followed by exclusion of one lung from ventilation (i.e., one-lung ventilation [OLV]) to facilitate surgical interventions.¹ However, ventilation of one lung will result in an increased intrapulmonary shunt because of continuous perfusion in the nonventilated collapsed lung. In addition, insufficient oxygenation of pulmonary blood through the atelectatic regions of the ventilated lung will increase venous admixture and ventilation/perfusion (V_A/Q) mismatching.² In fact, in the lateral position, the blood flow that is delivered to the ventilated lung can comprise more than 60% of the cardiac output as compared with less than 40% in the nonventilated collapsed lung.

During OLV in lateral position, because of the absence of any ventilation in the nondependent lung, accompanied by persistent perfusion in the collapsed region, the percentage of cardiac output that will participate in gas exchange becomes even less, and an increase in total intrapulmonary shunt of 30% to 35% can occur.

Other factors may disturb the distribution of pulmonary perfusion, resulting in a more pronounced V_A/Q mismatch. These may include a decrease in cardiac output and an increase in pulmonary vascular resistance (PVR), augmented by the effects of different volatile or intravenously administered anesthetics. In addition, blood loss, or an impaired alveolar ventilation (e.g., because of double-lumen-tube misplacement or bronchial blocker malposition), development of pulmonary edema, or absorption atelectasis may increase the transpulmonary shunt.³

As a result, hypoxemia, reported in about 10% of patients undergoing thoracic surgery, is defined as a decline of arterial oxygen saturation below 90%, despite the use of high inspiratory fractions of oxygen (FiO₂) during OLV.⁴ The hypoxemia during OLV is usually not severe; however, in some cases, life-threatening conditions may occur that respond poorly to corrective maneuvers.⁵ These therapeutic approaches may include application of positive end-expiratory pressure (PEEP) to the ventilated lung, continuous positive airway pressure (CPAP), as well as pure oxygen insufflation/apneic oxygenation⁶ into the nonventilated lung. Besides, the use of relatively high tidal volumes (6–8 mL/kg) and assurance of normal blood hemoglobin concentrations are advised.³

In addition, alveolar recruitment maneuvers are recommended to recruit poorly aerated alveoli in the ventilated lung and to minimize blood shift to the nondependent lung during OLV.⁷^,⁸ However, this strategy may reinforce mechanical stress applied to the lungs, including higher driving pressures, alveolar stretching, and shear stress secondary to cyclic recruitment/derecruitment of alveoli.⁹ Subsequently, OLV can result in significant diffuse parenchymal injury.¹⁰

The simple manipulation of respiratory parameters often fails to improve oxygenation, especially in patients who additionally suffer from obstructive or restrictive pulmonary diseases¹¹ or pulmonary hypertension.¹² Different attempts have therefore been made to manage life-threatening complications of OLV intraoperatively and have encouraged the search for coadjuvant or alternative pharmacologic treatments.

An important concept seems to accelerate the onset of hypoxic pulmonary vasoconstriction (HPV) by reduction of perfusion in the nonventilated lung and to increase distribution of perfusion to the dependent, ventilated lung regions,¹³ thereby improving V_A/Q matching and to decrease hypoxemia. HPV is an important physiologic defensive mechanism by which pulmonary blood flow is diverted from nonventilated hypoxemic areas toward better ventilated regions. Accordingly, HPV decreases blood flow to the collapsed lung regions during OLV, controlled by alveolar PO₂ (Fig. 7.1).

• Fig. 7.1 Overview of the hypoxic vasoconstriction, its effects on the lung, and how it can be influenced to end in physiologic or pathophysiologic settings. *FiO₂*, Fraction of inspired oxygen; *PEEP,* positive end-expiratory pressure; *V_A/Q,* ventilation/perfusion relation; PVP, pulmonary vascular pressure; PvO₂, venous partial pressure of oxygen; PaCO₂, arterial partial pressure of carbon dioxide; PGI2, Prostaglandi I2; PGE1, Prostaglandin E1; Qt, intrapulmonary shunt. (Courtesy of Edmond Cohen M.D.)

However, many anesthetics, such as volatiles in concentrations above 1 MAC, and different procedures can impair beneficial effects of HPV during OLV with subsequently impaired arterial oxygenation and hypoxemia.¹⁴^,¹⁵ Therefore the anesthesiologist makes an effort to increase HPV response with various drugs and techniques to reduce the intrapulmonary shunt.

A number of clinical studies have evaluated the possibility to increase perfusion distribution to the ventilated regions by administration of a vasodilator, that is, inhalation of nitric oxide (NO) or aerosolized prostacyclin (PGI2, Iloprost) to the dependent lung with a combination of vasoconstriction agents, such as almitrine or phenylephrine, to diminish the perfusion in the nonventilated regions.¹³

As an example, dexmedetomidine as a highly selective a₂-adrenergic receptor agonist with sedative, analgesic, antiinflammatory, and organ protection side effects was accordingly evaluated during OLV.¹⁶ The drug diminishes high sympathetic activation and results in lower heart rates, decreased blood pressure, and myocardial oxygen consumption.

Applied Physiology of Pulmonary Circulation

General Considerations

The primary mission of the coordinated interplay of respiration and circulation is to deliver oxygen to peripheral organs and tissues with relation to their metabolic requirements, and to eliminate the carbon dioxide that is generated during metabolism. For the purpose of gas exchange, the pulmonary circulation transports the blood to and from the alveoli.

The normal pulmonary circulation uses a low-resistance, highly compliant vascular bed, which is interposed between the two ventricles of the heart that function in synchrony. As a consequence, another important function of pulmonary circulation is to serve as a major reservoir for blood volume.

The pulmonary circulation operates in close relation with the alveolar ventilation to ensure optimal gas exchange. For this interchange, the lungs receive the entire cardiac output, and the pulmonary blood flow is about the match of the alveolar ventilation. Although the respiratory and circulatory cycles are phasic, their rates are entirely different (i.e., about 15 breaths and 80 heartbeats per minute at rest). Therefore the matching of respiration and perfusion for optimal arterialization of mixed venous blood requires subtle tuning of operations that are not in phase, at rest, during exercise, or during general anesthesia.

The outputs of the two cardiac ventricles are approximately the same when calculated over many respiratory cycles, although the left ventricle delivers slightly more blood than the right one, because of venous admixture of bronchial to pulmonary venous blood. This anatomic shunt comprises less than 2% of the total left cardiac output. However, even a doubling of total cardiac output can be accommodated in the capacious pulmonary vessels with virtually no increase in the mean pulmonary arterial pressure (MPAP).

Thus the lungs have a remarkable ability to maintain their PVR even as their vascular pressures, raised through the mechanisms of recruitment and distension. These mechanisms allow the lungs to increase their blood volume capacity with relatively small increases in pulmonary arterial and venous pressure. This may also be observed when a subject lies down after standing or when a patient is placed from supine to lateral position, for example, for thoracic surgery. The blood is then diverted from both lungs into the more dependent parts.

The pulmonary circulation has a relatively poor autoregulation. Consequently, it is important to monitor and control vascular pressures. A change in mechanical ventilation pattern or in cardiac performance as it may occur during the shift from two-lung ventilation (TLV) to OLV can passively affect the partition between the stored and pass-through components of the stroke volume, as well as modify the peripheral transmission of the pressure and flow pulses.

Intraoperative Monitoring of Pulmonary Circulation

The key to intraoperative management of thoracic surgery patients is to limit dangerous increases in PVR or myocardial oxygen demand to preserve myocardial perfusion and oxygen delivery. The induction of anesthesia, mechanical ventilation, lateral positioning, OLV, pulmonary artery clamping, blood loss, and emergence from general anesthesia are the most critical periods. It is necessary to avoid hypoxemia, hypercarbia, acidosis, hypervolemia, hypothermia, and unnecessary sympathetic stimulation because each of them can induce maldistribution of pulmonary perfusion.

The standard monitoring in patients undergoing thoracic surgery usually comprises an electrocardiogram (ECG) with automated ST-segment analysis, temperature monitoring, pulse oximetry (SpO₂), and continuous end-tidal carbon dioxide (EtCO₂) measurement (Table 7.1).

Table 7.1

Representative Hemodynamic Values for Normal Adults at Rest
Cardiac output (L/min)	4–6
Heart rate (beats/min)	80
Right atrial pressure (mm Hg)	4–6
Pulmonary artery pressures (mm Hg)
Systolic	20–25
Diastolic	10–12
Mean	14–18
Pulmonary wedge pressure (mm Hg)	6–9
Systemic arterial pressure (mm Hg)	120/80
Mean	90–100
Pulmonary vascular resistance (units)	0.70–0.95

The majority of patients scheduled for thoracic surgery with OLV in lateral position requires an intraarterial catheter for blood pressure monitoring and blood sampling for blood-gas-analysis. However, the insertion of a central venous, as well as a pulmonary artery catheter (PAC) is disputed and is for the most part not routinely inserted for thoracic procedures. In patients with significant cardiac debased or with known pulmonary hypertension, the PAC can provide simultaneous measurement of central venous pressure (CVP), pulmonary artery pressure (PAP), cardiac output, and mixed venous oxygen saturation (SvO₂); all of them represent very useful variables in assessing pulmonary circulation and possible effects of short-acting pulmonary vasodilators on HPV.

However, it should be noted that PAC usage did not result in decrease in patients mortality, hospital length of stay, or cost in intensive care unit.¹⁷ On the contrary, a retrospective data analysis has demonstrated an association of PAC with increased mortality in patients submitted to cardiac surgery.¹⁸ Nevertheless, PAC usage can be very helpful and should be limited for the management of hemodynamic therapy in selected high-risk patients undergoing thoracic surgery.

A modern approach to pressure load of the right ventricle, PAP, and volume status assessment is the use of transesophageal echocardiography (TEE), which is especially indicated in lung transplantation and other high-risk thoracic interventions.¹⁹^,²⁰ The echocardiographic evaluation of these physiologic factors appears important because right heart hypertrophy or dilation and decreased left ventricular filling of the coronary arteries may result in dangerously restricted perfusion and ischemia. As a consequence, intraoperative ischemia can lead to right heart failure.

Pulmonary Vascular Resistance

In daily anesthetic practice, the rationale about the regulation of the pulmonary circulation follows the concept of PVR that can be described as a normal vascular muscle tone, as vasoconstriction or vasodilation. The small precapillary pulmonary muscular arteries and arterioles act as resistance vessels and are considered as the principal sites of pulmonary vasomotor activity. Several factors interact with pulmonary circulation and subsequently with right heart function by increasing PVR, especially during OLV. Mechanical ventilation, in particular, the effects of high tidal volume (V_T), driving pressures and PEEP, hypoventilation, hypoxia, hypercapnia, nitrous oxide (N₂O), isoflurane, and desflurane. In contrast, high FiO₂, hypocapnia, and intravenous anesthetics may act as pulmonary vasodilators.

The PVR can be calculated by R = (P_PA – P_LA)/Q_T, where R represents PVR and P_PA – P_LA gives the drop in mean pressure between the pulmonary artery and left atrium (mm Hg). Commonly, pulmonary wedge pressure (P_PW) is substituted for P_LA, Q_T is the mean pulmonary blood flow (mL/s). The formula expresses PVR in R (resistance) units. For normal pulmonary circulation, the value for R is about 0.1 mm Hg/L/min. PVR can also be displayed in dynes.s.cm^–5. For this, the numerator of the equation is multiplied by 1332. The normal value is around 100.

Ventilation-Induced Changes in Pulmonary Hemodynamics

In comparison with systemic blood pressures, pulmonary vascular pressures are rather low. The thin-walled pulmonary vessels are in close contact with the air-containing alveoli of the lungs; therefore marginal changes in external forces can exert rather large hemodynamic effects. This can be observed during mechanical positive pressure ventilation, and the effect is more pronounced during OLV, with application of much higher driving pressures.

From a hemodynamic point of view, the best-analyzed features of mechanical ventilation are positive-pressure ventilation (PPV) and PEEP. During PPV, airway pressures increase with inflation and return promptly to PEEP (or atmospheric pressure) during expiration.

In healthy humans, the imposition of high PEEP has several hemodynamic consequences: stroke volume, cardiac output, and central blood volume decrease, while heart rate remains unaffected. Pulmonary arterial pressures increase, and the increase in alveolar pressure may cause the P_PWs to exceed the left atrial pressures. The stiffening of the lungs by higher transpulmonary pressures or during pulmonary edema requires higher levels of PEEP to achieve a beneficial effect. At higher levels, however, the risk of barotrauma to the lungs markedly increased.

The cardiac output decreases when normal lungs are subjected to PEEP because of a reduction in venous return (preload) to the right ventricle, a decrease in left ventricular preload, or from impairment of both right and left ventricular performance. In addition, cardiovascular inhibitory mechanisms in the brain and the local release of prostaglandins may contribute to this.

Regulation of Pulmonary Vascular Resistance

PVR is physiologically regulated by substances released by vascular endothelium: pulmonary vasodilators such as NO (Fig. 7.2) and endogenous prostacyclin, and by pulmonary vasoconstrictors such as endothelin-1 and thromboxane. Because of the balance in favor of vasodilation, vascular tone is predominantly low in normal pulmonary circulation. The vasodilators are released promptly in response to shear stresses, whereas endothelin-1 is released slowly and controls the vascular tone in a prolonged manner. It is believed that the pulmonary circulation is in a constant state of contraction and dilatation, which is controlled by the secretion of endogenous NO.