Neurogenic and Humoral Vasoconstriction in Acute Pulmonary Thromboembolism

Pulmonary thromboembolism (PE) contributes to 50,000 to 200,000 deaths annually (1). A massive PE that results in circulatory shock can rapidly cause death (2). Patients who survive long enough to be diagnosed with a PE have a 6-mo mortality rate of 17%(3). Development of right ventricular failure after sudden pulmonary hypertension is a major determinant of death after PE (4). This sudden pulmonary hypertension is the result of a reduced cross-sectional pulmonary vascular area caused by mechanical obstruction of the pulmonary artery (PA) (4) and PA vasoconstriction (Fig. 1).Figure 1: Simplified overview of pathophysiologic events during acute pulmonary thromboembolism (PE). Cardiovascular events culminate in a downward spiral originating from, and culminating in, an unfavorable ratio of right ventricular (RV) oxygen supply and demand. This is augmented by respiratory consequences of the embolism. FRC-CC = functional residual capacity minus closing capacity; LV = left ventricular; RV = right ventricular; PAP = pulmonary artery pressure.Anesthesiologists and intensivists often care for patients who have suffered massive PE. When encountered in the operating room, PE may present as sudden, refractory systemic hypotension or pulseless electrical activity. Classic symptoms and signs of PE (tachypnea, hypocarbia, and a normal or high arterial pH value) may be absent in the anesthetized, mechanically ventilated patient. Instead, severe hypoxia, hypercarbia, and a mixed acidosis may be present (5). Supporting the unstable circulation and rapidly initiating anticoagulation and judicious thrombolysis are logical and established treatment principles but fail to prevent fatal right ventricular failure (RFV) in up to 40% of patients (2). However, reversal of RFV occurred in some patients in extremis when therapy targeting pulmonary vasoconstriction was instituted (6–9). A better understanding of events leading to increased pulmonary artery pressure (PAP) and RVF is required to develop additional treatments and to further reduce mortality in this challenging patient population. This review focuses on neurogenic and humorally mediated pulmonary vasoconstriction and its contributions to the pathophysiology of PE. The section on therapeutic options focuses on drugs that might be useful adjuncts in the treatment of PE but are difficult to evaluate systematically for this indication, owing to logistic and ethical constraints of conducting prospective investigations in very sick patients. Unless otherwise specified, cited data were derived from animal experiments, and therefore, their application to the human condition must be done with caution. Mechanical Obstruction When a thrombus embolizes to the pulmonary vessels, part of the vasculature is obliterated. If cardiac output is preserved, pressure proximal to the obstruction increases. PAP does not increase unless 60%–70% of the pulmonary vasculature is obliterated by a nonhematogenous obstruction (10–14). However, only 25%–30% of the pulmonary vasculature must be obstructed to increase PAP when a thromboembolus causes the obstruction (1,15). Increased PAP increases right ventricular afterload and may lead to RVF (Fig. 1). Whereas embolus size is important in determining outcome of PE, mechanical obstruction alone cannot explain the events occurring with an acute PE (1). Neural and humoral stimuli are important co-determinants of severity of hemodynamic disturbance in acute PE. Large and medium sized PAs, as well as pulmonary arterioles and pulmonary veins, are constricted to varying degrees by theses stimuli (14). Constriction of PAs of >1000 μm (e.g., by serotonin) and pulmonary arterioles of 700 μm (29). The response to sympathetic stimulation when the intravascular pressures are normal is different from that observed when the intravascular pressures are high. In animals, increased pressure is generally induced by ventilation with 10% O2 or by IV administration of thromboxane analogs (23). The effect of various sympathomimetics at normal and increased PAP is summarized in Table 1(30–34). The effect of an 8-Hz electrical stimulation of the stellate ganglia when PAPs are increased is brief vasoconstriction followed by vasodilation (23). Pulmonary venous tone also increases and may contribute to the increase in PVR (28). However, acetylcholine decreases PVR indirectly through release of nitrous oxide (NO) from endothelial cells (35) and by inhibiting norepinephrine release from sympathetic nerve terminals (23) (Table 1).Table 1: Effects of Some Sympathomimetics and of Acetylcholine on Pulmonary Artery Pressure (PAP) as a Function of Resting PAPOther neurotransmitters are released from nerves innervating pulmonary vessels, but little is known of their role in regulating the tone of these vessels. The neurogenic increase in vasomotor tone with acute PE may be a prerequisite for subsequent augmentation of PVR by humoral factors (27). Cellular and Humoral Factors In 1953, Comroe et al. (22) were the first to provide convincing evidence that vasoconstriction of the pulmonary vasculature is responsible for part of the symptoms and signs of acute PE. Some investigators now consider this the pivotal event in PE (36). Once a thrombus lodges in a PA, there is rapid and complex interaction of cellular and molecular events that cause release of procoagulants and vasoconstrictors plus anticoagulants and vasodilators. It seems likely that the body’s ability to balance these opposing responses determines outcome. Table 2(23,37,38) lists some of the humoral mediators involved in the response to acute PE. This table illustrates that the overall contribution of a mediator to the outcome of acute PE involves more than effects on the smooth muscles of pulmonary vessels. Table 3 shows an example of how certain cell types contribute to the coagulant and vasomotor balance after PE by releasing a variety of mediators. The following section summarizes current (limited) knowledge about the most important of the cellular and molecular elements involved in the coagulant and vasomotor balance after acute PE.Table 2: Examples of Mediators Affecting the Aggregatory-Pulmonary Vasomotor Balance After Pulmonary EmbolismTable 3: Factors Produced by Endothelial Cells Affecting the Aggregatory and Vasomotor BalancePlatelets Platelet activation and aggregation are key events of both thrombus formation and vasoconstriction after acute PE. Platelet activity on the surface of an embolus remains increased despite the embolus having been formed at a site remote from the lungs (39). 5-hydroxytryptamine (HT), a powerful constrictor of the pulmonary vasculature (11), is released from the dense granules of activated platelets. 5-HT is removed and metabolized by the lung (40). An acute PE may reduce the functional size of the vascular bed, decrease uptake and metabolism of 5-HT (41), and increase the systemic concentrations of 5-HT (42). The reduced extraction and metabolism of 5-HT makes it difficult to predict how long after a PE that the PAP will be increased in humans. Both mechanical obstruction and pulmonary vasoconstriction are thought to reduce the metabolic capacity of the lung (11,41), which is probably an underappreciated entity in the pathophysiology of PE. 5-HT promotes platelet aggregation and adherence to activated endothelium, thereby increasing the local concentration of 5-HT and platelets (42). Platelets inhibit clot lysis in the lung (43). Because 5-HT also inhibits prostacyclin (PG-I2) release from pulmonary endothelium, it may initiate and propagate a vicious cycle of increased platelet aggregation, decreased clot lysis, and vasoconstriction in the PA (41). Thromboxane A2 (Tx-A2), another platelet product, causes pulmonary vasoconstriction (11), which contributes to mismatching of ventilation-perfusion. With increasing, PAP shunt vessels are opened (19). This causes hypoxia and further pulmonary vasoconstriction (44). Tx-A2 also has proaggregatory effects on platelets that contribute to further release of 5-HT from platelets. Adenosine diphosphate (ADP) is another compound that causes pulmonary vasoconstriction, recruitment of additional platelets, and activation of platelet G-protein, a class of second messengers. G-proteins activate membrane phospholipase, which causes mainly from is the of and which vasoconstrictive and has It the release of and vascular It also inhibits further platelet activation and aggregation through or more of which involves the stimulation of by formation in a systemic often a PE Although the clot seems when it activity the clot remains increased smooth and indirectly (11), which is to contribute to increased A2 and in endothelial cells and platelets, which that cause pulmonary vasoconstriction and activation also and platelet aggregation clot from the PA after experimental PE was with platelets The receptor for interaction is known and is likely involved in both and This that receptor may have therapeutic However, events can lead to pulmonary from human endothelial cells and from The the increase in PVR after acute experimental PE are of and are by platelets, and endothelial cells in response to a of clot The pathway Tx-A2 and the pathway The pathway for metabolism on the cell Endothelial cells the and cannot from However, of the are from to endothelial can be further metabolized to vasoconstrictors such as and Both and cause further aggregation, and of platelets which seems and is another example of the of the interaction of elements involved in PE and understanding There is an platelets, and endothelial cells that that the pathophysiology of pulmonary vasoconstriction after PE. and platelet are important of is by both platelets and and both platelets and In causes release of a pulmonary from endothelial cells also inhibits by these cells which contributes to the increase in that have or pulmonary vasoconstrictive effects and and oxygen are thought to be the cellular mediators of after Although both and and have been to prevent pulmonary after PA during pulmonary (e.g., or are and contribute to after A IV lung in The and balance after PE on endothelial cell When the has and vasodilating When the vasoconstrictive and effects (Table for this endothelial are decreased release of most and decreased interaction of with In endothelium, this interaction to activation of and its both of which are on the endothelial This interaction inhibits factors pathway of and of on the to is not endothelial cells release at a Endothelial decreases the concentration of this compound occurring during PE that have a effect on the increased PAP high of hypoxia and activation release of and the effects of and its of endothelial are in Table endothelial lead to vasoconstriction and activation of the with further endothelial Effects of Endothelial platelets have been to pulmonary endothelial cell through effects on or the adherence of platelets to endothelial It is this in the of PE. mediators to the balance of vasoconstriction and vasodilation have been in animal of PE to and The pulmonary a role in the vasoconstriction after an acute PE. is released by a variety of or stimuli present during PE, hypoxia, and (41). The systemic effects of are by extraction of this compound during through the lung and by release of the and (41). Table an overview of the effects of stimulation and of of A and are present on pulmonary endothelial cells and are responsible for pulmonary of in In metabolism increases concentrations of this after PE There is a and Tx-A2 the which Tx-A2 formation decreases PVR after or receptor stimulation vasoconstrictive effects that are of its effects on Tx-A2 formation The of is released from the lungs after PE and causes arterial vasoconstriction which the with acute PE. also a and an through increase of decrease of and of the release of Effects of and of the vasodilating and mediators released by endothelium, and are the most important well as the PA, inhibits platelet and Both activation of the in the platelet and vascular smooth which increases concentrations When these concentrations the concentration This causes and inhibits to the receptor on the surface of the platelet which is required for platelet aggregation vasoconstrictors released in the of a PE release by the pulmonary endothelium, and hypoxia and (11), inhibit Although the exact role of in acute PE remains it is likely a key compound in the balance vasodilation and vasoconstriction, as by a of treatment of cardiac from acute PE by administration of is a pulmonary and an of platelet aggregation and activation its effects by increasing the The of in blood is A that treatment with increased of patients with pulmonary hypertension and this the and to IV for the treatment of of have been to long A variety of released in response to PE cause the to release (11), and decreases systemic 5-HT concentrations and may also be a has with and This compound is by both endothelial cells and vascular smooth cells The of seems to be pulmonary vasodilation is by the lungs than it is (41). concentrations of with PAP and PVR which may a role for this also has an effect on endothelial cells The exact role of the above in acute PE is Whereas by a circulation normal pulmonary endothelial cells may as a of the hemodynamic and respiratory with PE. When from the pulmonary endothelial cells rapidly to the of by instantaneous of of endothelial is and are at the surface of the cell membrane after the of the concentrations increase of release of from and by This the to After of increased is This has been as an by endothelial cells to blood to the area However, vasodilation may not When are are by to a by (Fig. The most important by which are thought to contribute to pulmonary vasoconstriction are of release and endothelial the results of animal on the effect of on pulmonary vascular tone are and Both pulmonary vasodilation and vasoconstriction have been in pigs of after a PE the increase in PVR of Tx-A2 effects a the increase in vascular with of the PA in in patients after lung 2: oxygen are both during and the seems to be the more important of the pathophysiologic events after PE have their in hypoxia or culminate in The by which hypoxia after PE formation of very low and very high as a result of vascular obstruction and vasoconstriction, through a to of respiratory failure caused by increased of that is to and to a decrease in lung compliance lung and of and decrease in cardiac output that results in decreased mixed venous oxygen (16). There are the molecular pathophysiology and after hypoxia, is released are and 5-HT is released from pulmonary cells all of which can contribute to pulmonary hypoxia causes both of and endothelial which cause pulmonary and and are This that hypoxia can cause both pulmonary vasoconstriction and a and In well experiments, of a PE clot in after 3 and after If these data are to which may or may not be the it is difficult to clot for brief of does not the pulmonary vasculature to reduce the increased PVR present after a PE. for this might be that the clot causes an (e.g., RV that is not by of the may be that that cause a PE in humans might not be in the animal of their increases the required for of the clot in humans clot after the PE occurred might be that as pulmonary vasoconstriction occurs, a of clot have to for despite clot formation on the clot surface at Unless anticoagulation is of the PA may therapy for acute PE the ratio of RV O2 supply and to normal or illustrates the pivotal of supply and that events during acute PE reduce the RV pressure increases both RV size and which increases RV and O2 It also decreases right If RV output culminating in RV failure and death (Fig. 1). the to increase right artery pressure is In a and the of in unstable patients for which decreases PVR and increases cardiac systemic blood pressure and The result is a outcome (23). The to seems for when PAP are all norepinephrine decrease PVR (Table norepinephrine circulation after PE despite its effects on PVR and in of RV failure with RV the RV failure by increasing right artery pressure of therapy hypoxia, RV and and left ventricular LV and systemic all of which increase mixed venous oxygen This the pathophysiologic downward spiral but can be challenging to It seems to increase the of oxygen and to to the of ventilation and and to increase cardiac output the shunt is PVR systemic The be an but is very difficult to unless pulmonary or pulmonary vasodilation can be major pathophysiologic of increased and humoral are to Mechanical obstruction is by thrombolysis and anticoagulation in or (2). and circulatory was a of the patients are not for are in Because circulatory shock and cardiac increase mortality it is not that mortality with pulmonary is However, to a or functional does not to increase the of is an and a to all the ratio by and be to and therapy of RV and of is an to that to at of the However, the mortality is to that with to is thrombolysis by infusion of and of the clot with a or of the of an be to prevent further PE and the mortality are as mechanical obstruction alone does not for all the effects of a PE, the mechanical obstruction alone may not a outcome of the of PA vasoconstriction as a of PE is and are the therapeutic in which of the therapeutic may be is a patient with acute PE who is either not to or has a to of the established treatment systemic pressure and increasing PAP or cardiac despite has to consider the of not established to to reduce PA have been or for the treatment of acute and stellate ganglion Platelets are a key in the of pulmonary platelet activity the acute increase in PVR and the of hypoxia with acute PE for are some of the involved in platelet and is a of platelet aggregation but a very of platelet aggregation induced by such as and does not prevent release in response to a platelet does inhibit platelet aggregation The PE was a prospective that to deaths from PE. The results were but of such as size and of It was also that additional benefit administration Consequently, the of in patients cannot be at the present a a more activity than in different animal of effect on platelets, of Tx-A2 release and of activity to to but a vasodilating is observed in after administration of the and the effect for beneficial effects of to of of factors reduced of and of activation has not been in the of PE. drugs the low receptor and and the receptor of platelets and the and and may also inhibit drugs also have not been for the treatment of acute PE. a from to a of In both the release of 5-HT and the formation of Tx-A2 from platelets in the were by reduced the of platelets to the of the in this has not been or in acute PE. and low molecular inhibit and This decreases platelet activation by which in the release of mediators. release of plus of clot may be important is well established in the treatment of PE an will by only arterioles that are to ventilated The when therapy is the for systemic pressure and RV The be for the pulmonary drugs this and have in the treatment of acute PE. The first such is probably beneficial in the treatment of acute PE. It by better ventilation and and by its effects reports the beneficial effects of for the treatment of acute PE have been but there has been of outcome data at Consequently, the of in acute PE must be with the same that but experimental therapy and effects of this therapy have been in The second such PAP and PVR but of hemodynamic to after the is Although it seems that the role for for the treatment of acute PE might be to that of with this in the of acute PE is (5). The role of in thromboembolism and the of the up for the and treatment of PE. A of a receptor that of both of on human platelets from and from PE of the receptor not to their is not with in these In administration of a receptor arterial and The role of these in the and treatment of PE is to be Tx-A2 receptor is to decrease the increase in PAP that in response to PA stimulation with but there is effect on the increase in PAP with administration of and pulmonary vasoconstrictors Tx-A2 receptor was than inhibiting Tx-A2 and both the of Tx-A2 and its receptor and has some for the treatment of acute there is role for Tx-A2 receptor in acute PE. 5-HT receptor be another logical 5-HT different (27). inhibits the which hypoxia and pulmonary hypertension in and after PE. In the receptor is to pulmonary vasoconstriction, in the the receptor this (27). In the of vascular the receptor pulmonary vasoconstriction in humans. When in humans is the receptor is thought to vasoconstriction (27). The administration of to patients with symptoms from PE caused only a of hemodynamic and this response was caused by of the for the receptor or patient is increased mixed venous oxygen cardiac all the that contribute to hypoxia after PE, mixed venous is to be of the most important factors by some (1). This explain the in in that The understanding of 5-HT and their role in acute PE is and more 5-HT receptor can be to but there are It has been that an acute PE a mediated pulmonary vascular reflex (29). PAs at have a very low humoral mediators to cause pulmonary vasoconstriction, an increase in tone is required (27). The sympathetic may be responsible for this increase in tone in small, muscular sympathectomy has been in humans and in for the treatment of PE cannot be by the above that it a sympathectomy to PE, is the treatment of severe PE often involves thrombolysis or the of a thoracic epidural to a sympathectomy be of the for an epidural Instead, a stellate ganglion block is probably more This block has been in patients in extremis after a massive PE and has rapid, of symptoms of decrease of the respiratory rate from to of and reversal of and of circulatory shock occurred This therapeutic further during acute PE are and difficult to from A understanding of PE in humans remains which is in part of the to events in humans. In and animal of experimental PE have to in understanding the pathophysiology of this therapeutic are on the but are difficult to systematically in these patients. PE remains the of a for which is better than