Inotropic therapy

High-risk surgical patients

The concept of attempting to achieve supranormal hemodynamic endpoints emerged from studies in high-risk surgical patients. In a prospective study in high-risk patients undergoing surgery, Shoemaker and colleagues showed that the use of supranormal hemodynamic values as therapeutic endpoints was associated with a reduction in mortality rate from 33% to 4%. In the protocol group, dobutamine and dopamine were given as inotropic drugs, even in the absence of evidence of reduced cardiac contractility, when volume resuscitation (and packed red blood cells, if necessary) failed to achieve supranormal values of oxygen delivery (>600 mL/min/m ² ). Thereafter, some debate concerning the perioperative fluid management strategy has emerged, especially during abdominal surgery. On the one hand, restricted perioperative fluid management could decrease the rate of postoperative complications and promote faster recovery. On the other hand, randomized trials did not confirm the supposed benefits of fluid restriction on recovery after elective surgery. ^, Excessive fluid restriction could lead to higher rates of acute kidney injury and renal replacement therapy and more postoperative complications such as anastomotic leaks and surgical site infection.

In fact, the most important point was not the use of the perioperative fluid strategy itself, but rather the use of a goal-directed strategy based on stroke volume, oxygen delivery index, ^, or cardiac index. In these randomized studies, the volume of intraoperative fluids was decreased, ^, unchanged, or increased. Nevertheless, in all these studies, postoperative complications or hospital length of stay was decreased. The potential beneficial effects of intraoperative goal-directed fluid therapy in elective major abdominal surgery in terms of morbidity and hospital and ICU length of stay were confirmed in a meta-analysis. Two reviews confirmed that a deliberate perioperative increase in oxygen delivery above supranormal values using fluid infusion and various inotropic drugs (dobutamine, dopamine, epinephrine, dopexamine) in high-risk patients undergoing surgery was associated with a decreased mortality rate and postoperative complications. ^, It is important to emphasize that (1) benefits are most pronounced in patients receiving fluid and inotropic therapy as opposed to fluids alone to achieve supranormal values of cardiac index or oxygen delivery with the use of minimally invasive cardiac output monitors, (2) benefits related to the use of an intraoperative goal-directed therapy could also concern low- and moderate-risk patients, and (3) such an early goal-directed therapy (EGDT) is not considered after complications have already developed. However, more recently, the interest of perioperative goal-directed therapy has been questioned. ^, In a pragmatic, multicenter randomized trial in high-risk patients undergoing major gastrointestinal surgery, Pearse and colleagues assessed the clinical effectiveness of a deliberate perioperative strategy including fluid administration and dopexamine to achieve and maintain a maximal stroke volume. When compared with usual care, goal-directed therapy was not associated with a significant reduction in moderate or major postoperative complications. Nevertheless, after incorporating these results into an updated systematic review and meta-analysis, the deliberate perioperative strategy was associated with a significant reduction in the percentage of patients who developed postoperative complications. It is important to note that in the group of usual care, fluid administration was based on central venous pressures and could be considered, in part, as goal-directed therapy. It remains unclear, however, whether potential benefits could be related to the increased oxygen delivery per se or other antiinflammatory effects of catecholamines. In this regard, it has been demonstrated that the increased oxygen delivery per se improved microvascular flow and tissue oxygenation. Nevertheless, an experimental study of murine septic shock has shown that dopexamine infusion per se reduces the systemic inflammatory response, attenuates leukocyte infiltration, and prevents hepatic and renal injury at doses that have no effects on global or regional hemodynamics. The issue of drug dosage is also essential. A recent meta-analysis has suggested that in the setting of major surgery, dopexamine at low doses, but not at high doses, could improve outcome. From all these findings, it is still reasonable to consider the increase in cardiac output and oxygen delivery toward supranormal values during the perioperative period in high-risk patients undergoing elective major surgery and to guide the perioperative management of these high-risk patients by hemodynamic monitoring.

Critically ill patients

It was debated whether a supranormal hemodynamic target approach can be applied to patients admitted to the ICU for acute illnesses. On the one hand, a pathologic oxygen consumption/supply dependency, presumably the result of impaired oxygen extraction capacities, has been reported in various categories of acute illnesses such as sepsis and acute respiratory distress syndrome. Such a phenomenon was reported to correlate with the presence of increased blood lactate, to be a marker of global tissue hypoxia, and to be associated with a poor outcome. This so-called pathologic oxygen consumption/supply dependency would incite the clinician to increase oxygen delivery toward supranormal values to overpass its critical level. However, such an aggressive therapeutic approach has been seriously questioned since the publication of randomized clinical trials performed in patients with acute illnesses and who did not demonstrate any benefit from the deliberate manipulation of hemodynamic variables toward values higher than physiologic values. ^, In one of these studies, the mortality rate was higher in the group of patients assigned to receive an aggressive treatment aimed at achieving supranormal values of oxygen delivery. It was postulated that the deleterious consequences of the use of high doses of dobutamine in patients in the protocol group were responsible for the increased mortality rate. It should be noted that (1) the patients in the protocol group received high doses of the inotropic agent despite no evidence of any deficit of inotropic function and that (2) in most of these patients the aggressive inotropic support failed to achieve the target value of oxygen consumption (170 mL/min/m ² ). The later analysis of the subgroup of septic patients in a study showed that survivors were characterized by their ability to increase both oxygen delivery and oxygen consumption, regardless of their group of randomization. Nonsurviving patients were characterized by their inability to increase oxygen consumption despite the increase in oxygen delivery, suggesting a more marked impairment of peripheral oxygen extraction in nonsurvivors than in survivors. In addition, the ability to increase cardiac output and oxygen delivery was also significantly reduced in nonsurvivors than in survivors, suggesting a decrease in cardiac reserve in patients who will die. This is not a surprising finding because the degree of myocardial dysfunction in septic shock correlates with an increased risk of death. In this regard, it has been suggested that the response to a dobutamine challenge has a prognostic value in septic patients because in two prospective studies survivors were able to increase both oxygen consumption and oxygen delivery in response to dobutamine, whereas nonsurvivors were unable to increase either oxygen delivery or oxygen consumption or both. ^,

Data from all the results of randomized controlled studies indicate that a deliberative attempt to achieve supranormal hemodynamic targets in the general population of critically ill patients is no longer recommended. ^, Nevertheless, in the early phase of septic shock with low blood flow and oxygen delivery, an aggressive hemodynamic therapy, including inotropes, aimed at rapidly normalizing the central venous oxygen saturation (ScvO ₂ ) as a surrogate of oxygen delivery, was demonstrated to result in a better outcome in a monocenter, randomized controlled trial. This result has led to the popularity of the concept of EGDT with (ScvO ₂ ) as the main hemodynamic target. Nevertheless, three recent multicenter, randomized studies have shown that EGDT using (ScvO ₂ ) did not reduce all-cause mortality, duration of organ support, or hospital length of stay. ^, In addition, compared with usual care, EGDT resulted in higher hospitalization costs and was associated with increased utilization of ICU resources. However, compared with the study by Rivers and colleagues, patients included in the three multicenter, randomized controlled trials were fluid resuscitated before randomization, such that the average baseline (ScvO ₂ ) was already higher than 70% (the target of the EGDT arm). Such a fact certainly accounted for the absence of superiority of EGDT over the control arms in these studies. This clearly cannot rule out the strategy of increasing oxygen delivery and targeting (ScvO ₂ ) higher than 70% when (ScvO ₂ ) is lower than 70%, as this was the case in the majority of the patients in the study by Rivers et al. Thus in the early phase of septic shock and maybe in other acute illnesses, it could be essential to rapidly restore normal global blood flow conditions to avoid further deleterious consequences of systemic hypoperfusion. In later stages of the disease, with inflammatory processes and organ dysfunction already developed, no evidence of benefit from a further increase in oxygen delivery has been shown in the literature. Nevertheless, it seems likely that cardiac output should be kept in the normal range by using fluids and/or inotropes to prevent worsening of the insult. It should be stressed that even in the EGDT approach, their use should not only be based on ScvO ₂ but also on the presence of established cardiac dysfunction, which is at best diagnosed on echocardiography, ^, and after checking that hypovolemia and hypotension have been already corrected.

Beta-1 adrenergic receptors

Beta-adrenergic receptors are transmembrane proteins located in the sarcolemma. The beta-1 receptor subtype is mainly represented in the human heart. Its stimulation induces inotropic, lusitropic, chronotropic, and dromotropic effects that result from the enhancement in Ca ^{2 +} cytosolic concentration. Binding of a beta-1 agonist agent to its receptor stimulates the Gs protein. Guanosine diphosphate, normally fixed to the stimulatory αs subunit of the Gs protein, is replaced by guanosine triphosphate, and the αs–guanosine triphosphate complex binds to adenyl cyclase, which then becomes activated. Cyclic adenosine monophosphate (cAMP) is formed from ATP and activates protein kinase A. Protein kinase A phosphorylates and activates several cellular structures as follows:

• The ryanodine receptors of the sarcoplasmic reticulum, leading to the enhanced extrusion of Ca ^{2 +} out of the sarcoplasmic reticulum. Indeed, the main part of the Ca ^{2 +} cytosolic content needed for contraction is provided by the sarcoplasmic Ca ^{2 +} store. The entry of Ca ^{2 +} through the membrane L-type channels modifies the molecular conformation of the ryanodine receptor of the sarcoplasmic reticulum. Parts of these ryanodine receptors are Ca ^{2 +} channels that enable the massive release of Ca ^{2 +} out of the sarcoplasmic reticulum (see Fig. 81.1 ).

• The sarcolemmal L-type Ca ^{2 +} channels, increasing their opening time. This leads to an increased amount of cytosolic Ca ^{2 +} available for sarcoplasmic reticulum Ca ^{2 +} release and for contraction. The increase in intracytosolic Ca ^{2 +} concentration also leads to the activation of calmodulin. This ubiquitous protein enables the phosphorylation of other proteins once it has fixed Ca ^{2 +} .

• The myosin light chain through the myosin light chain ATPase. This phosphorylation enhances the responsiveness of the cardiac contractile protein to Ca ^{2 +} and helps increase the affinity of myosin for actin, thus participating in the inotropic effect.

• The phospholamban and the sarcolemmal Na ⁺ /Ca ^{2 +} exchanger, leading to a faster decrease in Ca ^{2 +} cytosolic concentration after contraction and accounting for the lusitropic effect. Indeed, relaxation is dependent on Ca ^{2 +} reuptake by the sarcoplasmic reticulum through the sarcoendoplasmic reticulum Ca ^{2 +} ATPase pump. The activity of sarcoendoplasmic reticulum Ca ^{2 +} ATPase is normally inhibited by phospholamban located in the sarcoplasmic reticulum membrane near the Ca ^{2 +} pump. The phosphorylation of phospholamban relieves this inhibition, and Ca ^{2 +} uptake by the sarcoplasmic reticulum is thus stimulated.

Beta-2 adrenergic receptors

The beta-2 receptor subtype is mainly represented in noncardiac structures. Beta-2 adrenergic stimulation induces arterial and venous relaxation. The effects of beta-2 stimulation in vascular smooth muscle result from a different activation pathway: once the Ca ^{2 +} intracytosolic concentration increases, it fixes the calmodulin regulatory protein, and the Ca ^{2 +} –calmodulin complex activates the myosin light chain kinase, leading to the inhibition of phosphorylation of the myosin light chain and finally smooth muscle relaxation.

Alpha-adrenergic receptors

When an agonist fixes the alpha-1 receptor, Gh, which is one of the G-protein family, it stimulates phospholipase C, which splits phosphatidyl inositol into inositol triphosphate and 1,2-diacylglycerol. Inositol triphosphate stimulates the release of Ca ^{2 +} from the sarcoplasmic reticulum. Alpha-2 adrenoreceptor stimulation inhibits adenylate cyclase and reduces cAMP intracellular concentration. Alpha adrenoreceptors are not prominent in the cardiac tissue but are in the vascular wall. Cardiac alpha-1 stimulation induces a positive inotropic effect; alpha-1 and alpha-2 stimulations induce potent arterial and venous constriction.

Epinephrine

Epinephrine is the main physiologic adrenergic hormone of the adrenal medullar gland. It is a potent stimulator of alpha, beta-1, and beta-2 receptors. The alpha-adrenergic effect is responsible for a marked arterial and venous vasoconstriction. Epinephrine increases systolic arterial pressure, but its effect on vasculature is partly counteracted by beta-2–mediated vasodilation. Diastolic blood pressure is thus only slightly affected by epinephrine, and the increase in mean arterial pressure (MAP) is less than that with norepinephrine.

Through cardiac beta-1 stimulation, epinephrine increases heart rate and inotropism. The effects of the combination of the latter, along with the alpha-mediated venous constriction promoting venous return and cardiac preload, results in an increase in cardiac output. Epinephrine also facilitates ventricular relaxation and enhanced coronary blood flow through the increase in myocardial oxygen consumption.

Norepinephrine

Norepinephrine is the physiologic mediator released by the postganglionic adrenergic nerves. It is a potent alpha and beta-1 adrenergic agonist, but it has little activity on beta-2 receptors. Through its alpha-adrenergic effect, norepinephrine induces potent arterial and venous constriction. It increases systolic and diastolic blood pressure, left ventricular afterload, and cardiac filling pressures. Its alpha-adrenergic effect also induces the reduction of peripheral venous capacitance and thus results in decreased unstressed venous blood volume and increased stressed venous blood volume. This is responsible for increased mean systemic filling pressure, venous return pressure gradient, and venous return. ^, Beta-1 stimulation results in a positive inotropic effect and an increase in stroke volume. However, the chronotropic effect is counteracted by baroreflex stimulation after vasoconstriction. Consequently, the heart rate is unchanged or reduced, and the cardiac output can be unchanged. The coronary blood flow is enhanced by norepinephrine because of coronary vasodilation secondary to enhanced cardiac metabolism and the normalization of diastolic blood pressure when low.