Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

13. Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

Robert Maclaren and Joseph F. Dasta


KEY CONCEPTS

 Images Continuous hemodynamic monitoring with an arterial catheter or a central venous catheter capable of measuring mixed venous oxygen saturation (SVO2) or central venous oxygen saturation (SCVO2) should be used early and throughout the course of septic shock to assess intravascular fluid status and ventricular filling pressures, determine cardiac output (CO), and monitor arterial and venous oxygenation. They can be used for monitoring the response to drug therapy and guiding dosage titration.

 Images Early goal-directed therapy with aggressive fluid resuscitation in the emergency department within the first 6 hours of presentation improves survival of patients with sepsis and septic shock.

 Images Lactate production is increased under anaerobic conditions. Elevated serum lactate concentrations represent global perfusion abnormalities. Lactate clearance may be used to assess repayment of oxygen to the tissues. GI tonometry and sublingual capnometry represent methods of assessing regional perfusion but are used infrequently.

 Images Derangements in adrenergic receptor sensitivity or activity frequently result in resistance to catecholamine vasopressor and inotropic therapy in critically ill patients. These changes may be a function of endogenous catecholamine concentrations, dosage/duration of exposure to and type of exogenously administered vasopressors, stage of septic shock, preexisting illness, and other factors.

 Images In refractory septic shock, rational use of vasopressor or inotropic agents should be guided by receptor activity, pharmacologic and pharmacokinetic characteristics, and regional and systemic hemodynamic effects of the drug and should be tailored to the patient’s physiologic needs. Pharmacologically sound combinations of vasopressor and/or inotrope agents should be initiated early to optimize and facilitate rapid response.

 Images Goals of therapy with vasopressors and inotropes should be predetermined and should optimize global and regional perfusion parameters (e.g., cardiac, renal, mesenteric, and periphery) to normalize cellular metabolism. This can be accomplished by continuous or intermittent measurements. Targeted goals should be central venous pressure (CVP) of 8 to 12 mm Hg (up to 15 mm Hg in mechanically ventilated patients, patients with preexisting left ventricular dysfunction, or patients with abdominal distension), mean arterial pressure (MAP) ≥65 mm Hg, SVO2 ≥65% or SCVO2 ≥70%, and lactate clearance of ≥20%.

 Images Dose titration and monitoring of vasopressor and inotropic therapy should be guided by the “best clinical response” while observing for and minimizing evidence of myocardial ischemia (e.g., tachydysrhythmias, electrocardiographic changes, troponin elevation), renal (decreased glomerular filtration rate and/or urine production), splanchnic/gastric (low intramucosal pH, bowel ischemia), or peripheral (cold extremities) hypoperfusion, and worsening of partial pressure of arterial oxygen (PaO2), pulmonary artery occlusive pressure (PAOP), and other hemodynamic variables.

 Images Much higher dosages of all vasopressors and inotropes than traditionally recommended are required to improve hemodynamic and oxygen-transport variables in patients with septic shock. Arbitrarily targeting vasopressor and inotrope therapy to supranormal values of global oxygen-transport variables cannot be recommended because of the lack of clear benefit and possible increased morbidity.

 Images First-line therapy of septic shock is aggressive volume resuscitation with crystalloid or colloid types of fluids. Norepinephrine is the preferred initial vasopressor agent for hemodynamic support. Norepinephrine achieves greater hemodynamic response than dopamine and is less likely to cause tachydysrhythmias and a decrease in splanchnic oxygen utilization. Dopamine is also limited by its inability to adequately increase CO and complications of increased PAOP and decreased splanchnic oxygen use. Low-dose dopamine should not be used to prevent renal failure.

 Images Phenylephrine may be a particularly useful alternative in patients who cannot tolerate tachycardia or tachydysrhythmia associated with the use of other agents. Its effects on cardiac performance and splanchnic oxygen utilization are variable.

 Images Epinephrine is an effective initial agent and as an add-on agent. It is particularly useful in the young, in patients with otherwise healthy myocardium, and potentially in patients when used early in the course of treatment. However, because epinephrine causes a significant increase in lactate and worsening of splanchnic oxygen utilization, it is not the agent of first choice in patients with septic shock and is reserved as adjunctive therapy when other vasopressors do not adequately increase MAP. It should be used cautiously in patients with a history of coronary artery disease or underlying cardiac disturbances.

 Images Dobutamine may be used as adjunctive therapy for its inotropic effect. It enhances CO and may increase SVO2/SCVO2. Concurrent vasopressor therapy is needed because dobutamine causes vasodilation. Dobutamine therapy may be limited by tachycardia and dysrhythmias.

 Images Therapy with vasopressors and inotropes is continued until the myocardial depression and vascular hyporesponsiveness of septic shock improve, usually measured in hours to days. Discontinuation of vasopressor or inotropic therapy should be executed slowly; therapy should be “weaned” to avoid a precipitous worsening in regional and systemic hemodynamics.

 Images Vasopressin produces vasoconstriction independent of adrenergic receptors and reduces the dosages of catecholamine vasopressors. Replacement dosages of vasopressin (0.01 to 0.04 units/min) can be considered in patients with septic shock refractory to catecholamine vasopressors despite adequate fluid resuscitation. Dosage rates should not be titrated upward. Vasopressin may enhance urine production but it may worsen splanchnic and peripheral perfusion. Given the current data, corticosteroids can be administered to patients with septic shock refractory to vasopressors or when adrenal insufficiency is suspected. Side effects of short-term corticosteroids are minimal.


Shock is an acute, generalized state of inadequate perfusion of critical organs that can produce serious pathophysiologic consequences, including death, when therapy is not optimal. Shock is defined as systolic blood pressure <90 mm Hg or reduction of at least 40 mm Hg from baseline with perfusion abnormalities despite adequate fluid resuscitation.1 Previously, mortality from septic or cardiogenic shock exceeded 70% but now ranges between 20% and 40%.25 This chapter reviews the theory and current status of hemodynamic monitoring and presents an update on the optimal use of inotropes and vasopressor drugs in shock states, specifically septic shock.615

The general goal of therapy during resuscitation from shock is to achieve and maintain mean arterial pressure (MAP) above 65 mm Hg while ensuring adequate perfusion to the critical organs.615Hemodynamic and perfusion monitoring can be categorized into two broad areas: global versus regional monitoring. Global parameters, such as systemic blood pressure, oxygen tension, and lactate, assess perfusion and oxygen utilization of the entire body. Regional monitoring techniques, such as tonometry or cardiac function, focus on oxygen delivery and subsequent changes in metabolism of individual organs and tissues. Patients in shock generally have several modes of monitoring so therapies are based on all gathered information and correlating with the patient’s clinical response. Normal values for commonly monitored parameters are listed in Table 13-1. Evidence-based goals of therapy are listed in Table 13-2.621 The adequacy of regional perfusion can be assessed by indices of specific organ perfusion.6,1521 These measurements include coagulation abnormalities (disseminated intravascular coagulation), altered renal function with reduced urine production or increased serum concentrations of blood urea nitrogen and creatinine, altered hepatic parenchymal function with increased serum concentrations of transaminases and bilirubin, altered GI perfusion manifested by ileus and diminished bowel sounds, cool extremities, cardiac ischemia with elevated troponin concentrations and electrocardiographic changes, and altered sensorium. Although none of these indices alone is a reliable indicator of adequate resuscitation, they offer immediate detection and may be prognostic of recovery when combined and defined at the level of organ function. As a result, these indices are frequently used as surrogate endpoints for the goals of resuscitation.22 While it is assumed that normalization of these parameters infers benefit, the clinician must first treat the patient clinically rather than relying solely on data from continuous monitoring to guide therapy.22

TABLE 13-1 Hemodynamic and Oxygen-Transport Monitoring Parameters

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TABLE 13-2 Evidence-Based Treatment Recommendations for Management of Severe Sepsis or Septic Shock

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GLOBAL PERFUSION MONITORING

Arterial Blood Pressure Measurement

MAP is the product of cardiac output (CO) and systemic vascular resistance (SVR). Conditions that may lower blood pressure through diminished CO in critically ill patients include cardiac failure (etiology may be myocardial infarction, arrhythmia, acute heart failure, or valvular disease) and hypovolemia (etiology may be hemorrhage, intractable diarrhea, or heat stroke). Vasodilatory conditions such as sepsis, anaphylaxis, pancreatitis, acute hepatic failure, or neurotrauma, lower blood pressure by reducing SVR. Arterial blood pressure is the commonly used end point of therapy; however, restoration of adequate perfusion pressure is the primary criterion of effectiveness.621Profound hypotension (MAP <60 mm Hg) is associated with pressure-dependent decreases in coronary, cerebral, and renal blood flow and may rapidly produce myocardial, cerebral, and renal ischemia. Therefore, a goal MAP of 65 mm Hg is often targeted for shock to maintain perfusion.

Arterial blood pressure can be determined by noninvasive and invasive methods. All noninvasive blood pressure monitoring techniques depend on the use of an occluding cuff. Systolic and diastolic blood pressures are further determined by oscillometry, auscultation, palpation (systolic pressure only), or Doppler technique (systolic pressures are most reliable). Oscillometry is the only noninvasive method used in the intensive care unit (ICU) to measure MAP because the data are valid during low-flow states and the method provides automatic cycling and serial measurements (every 1 to 3 minutes) that do not require operator intervention, a key component in ICU monitoring. The oscillometry method operates by sensing arterial blood pressure changes, or oscillations, against an inflated cuff. Rapid changes in oscillation amplitude correspond to systolic and diastolic pressure. The use of narrow cuffs or cuffs applied too loosely can result in falsely high readings, whereas wide cuffs may produce falsely low readings. Fingertip devices offer another avenue for continuous indirect blood pressure measurement, but their accuracy in ICU patients may be significantly diminished by concurrent administration of vasoactive drugs.

Images The use of invasive arterial catheters makes possible the continuous measurement of MAP as well as procurement of blood samples for laboratory testing. The radial artery is the most commonly used vessel, but the dorsalis pedis, femoral, brachial, and axillary arteries and the umbilical artery in the newborn also can be accessed. This method of blood pressure monitoring is the standard technique used in the ICU against which all other methods are compared. Major complications of peripheral artery catheterization include infection and distal ischemia. Acute distal ischemia and catheter-related bacteremia occur in <1% of catheter insertions. This translates to 2.9% of bloodstream infections per 1,000 catheter-days.23 Ischemia is most common in patients with multiple or prolonged arterial cannulations, hypertension, or vasopressor therapy.8 Invasive techniques are labor intensive, require aseptic techniques, and offer potential sources of equipment errors, such as length and quality of tubing, air bubbles, stopcocks, thrombus formation, tube kinking, and transducer placement. Hypertension, advanced age, and atherosclerosis also may affect the accuracy of invasive blood pressure readings.

Central Venous Catheter

Images The central venous catheter is used to measure the central venous pressure (CVP), to obtain venous samples for laboratory testing, and to administer drugs or fluids directly to the central circulation. A triple-lumen catheter frequently is used, whereby drugs with known incompatibility can be administered. Blood volume, venous wall compliance, right-sided cardiac function, intraabdominal and intrathoracic pressures, and vasopressor therapy affect CVP. The CVP is not a reliable estimate of blood volume but can be used to qualitatively assess blood volume changes in patients during the early phases of fluid resuscitation.24,25 The goal of fluid administration is to maintain the CVP at 8 to 12 mm Hg, but values of 15 mm Hg may be targeted in mechanically ventilated patients or patients with abdominal distension or preexisting ventricular dysfunction.24,25 Sustained elevated pressures may be indicative of fluid overloading. Few data support the use of continuous CVP monitoring in the ICU. However, CVP monitoring of fluid therapy during resuscitation of septic shock is associated with reduced mortality.68,24,25

Pulmonary Artery Catheter

Images Pulmonary artery catheterization provides multiple cardiovascular parameters, including CVP, pulmonary artery pressure, pulmonary artery occlusive pressures (PAOP, commonly called the “wedge pressure”), CO, SVR, and the mixed-venous oxygen saturation (SVO2).26 Ideally, the pulmonary artery catheter should be positioned fluoroscopically; however, satisfactory placement also may be obtained by observing pulmonary artery pressure readings and electrocardiographic waveforms during catheter advancement. Proper positioning, or wedging, in the lower lung (zone 3) is essential to measure PAOP and to prevent distal pulmonary artery collapse. Inflation of the balloon at the catheter tip occludes the pulmonary artery, isolates the distal catheter tip from the right side of the heart, and allows the user to measure the PAOP, an approximate measure of the left ventricular end-diastolic volume and a major determinant of left ventricular preload. Poor wedging may be caused by catheter migration, patient movement, mechanical ventilation, or eccentric balloon inflation. Pulmonary artery catheters equipped with a distal thermistor also allow measurement of CO by thermodilution. Rapid injection of cold saline or dextrose solutions via the right atrial port allows complete mixing of blood with the injectate, and the resulting change in blood temperature is measured in the pulmonary artery. From the temperature change, the patient’s CO can be calculated. Newer pulmonary artery catheters contain a temperature coil or filament that intermittently warms the blood in the right ventricle for near-continuous CO measurement. Significant tricuspid regurgitation, an intracardiac shunt, the respiratory phase, and significant positive end-expiratory pressure decrease the validity of CO measurements. The most common complications of pulmonary artery catheterization include mural thrombus formation (14% to 91%), transient ventricular tachydysrhythmias (11% to 63%), pulmonary infarction (1% to 7%), pulmonary artery rupture (0.06% to 2.0%), and sepsis (0.3% to 0.5%).27,28 Most pulmonary artery catheters are heparin bonded which requires consideration in patients with unexplained thrombocytopenia. The relative risk (RR) of infection is 2.6 per 1,000 patient-days, similar to the risk with central venous catheters of 2.3 per 1,000 patient-days.27,28 Controversy surrounds the utility and safety of the pulmonary artery catheter, including issues surrounding correct placement and impact of the device on patient outcome. Recent studies failed to demonstrate beneficial outcomes with the use of the pulmonary artery catheter.29 The most recent guidelines suggest careful evaluation of the indications and the risk of placing a pulmonary artery catheter for resuscitation of critically ill patients.30

Images The optimal PAOP needs to be individualized for each patient. Administering a fluid bolus followed by simultaneous PAOP and CO measurements with the goal of increasing the PAOP until CO does not change can be accomplished and is based on Starling’s law of the heart. However, clinical experience suggests that most patients have an optimal response to PAOP values in the range from 12 to 15 mm Hg. Limited data are available comparing the use of CVP and PAOP for guiding therapy in patients with shock. The results of recent studies of critically ill patients suggest CVP and PAOP are equivalent in terms of clinical outcomes, including mortality.31 Therefore, a pulmonary artery catheter should be inserted when hemodynamic data are needed that cannot be obtained from a central venous catheter or when the validity of measurements from the central venous catheter is questionable.

Images Other methods used to assess CO include carbon dioxide (CO2) partial rebreathing, esophageal Doppler, and transpulmonary (ultrasound) indicator dilution.1522 The CO2 partial rebreathing technique compares end-tidal CO2 partial pressure obtained during a nonrebreathing period with that obtained during a subsequent rebreathing period. The ratio of change in end-tidal CO2 and CO2 elimination estimates CO but must be corrected for blood shunting. Poor to acceptable agreement exists between this method and the thermodilution method of assessing CO in critically ill patients. In addition, low minute ventilation, a high shunt fraction, or a high CO produce inaccurate results. The esophageal Doppler technique measures flow velocity in the descending aorta by means of a Doppler transducer. CO is calculated based on the diameter of the aorta, the distribution of CO to the aorta, and the flow velocity of blood in the aorta. The CO reported by this method correlates with therapeutic interventions and demonstrates excellent agreement with the pulmonary artery catheter. Unfortunately, this method is technologically difficult and may not produce reliable measurements over time. The transpulmonary (ultrasound) indicator dilution method is functionally similar to the pulmonary artery catheter in that it employs thermodilution to calculate CO but it uses a central venous catheter rather than introducing a catheter into the pulmonary artery. This method of measuring CO correlates well with the values obtained from the pulmonary artery catheter and may display less respiratory phase variations. It also may estimate global end diastolic volume but other hemodynamic variables are not readily obtained.

Oxygen Tension and Saturation Monitoring

Partial pressure of arterial oxygen (PaO2) and arterial oxygen saturation (SaO2) can be assessed subjectively by assessing capillary refill or invasively by obtaining an arterial blood sample. Arterial blood gases measured by conventional arterial sampling are considered standard, but their accuracy and usefulness are affected by poor sampling techniques, transportation and analysis delays, analyzer accuracy, sample cellular metabolism, and inability to trend results. Indwelling fiberoptic and electrochemical systems that allow continuous monitoring and trend analyses of blood pH, PaO2, and partial pressure of arterial carbon dioxide (PaCO2) while decreasing patient blood loss from less frequent sampling are in development. Mixed-venous oxygen saturation (SVO2) and central-venous oxygen saturation (SCVO2) reflect oxygen delivery (DO2, or DO2I, indexed to body surface area) with low values indicative of inadequate tissue perfusion that may occur during the early stages of septic shock, cardiogenic shock, or hypovolemic shock. Both measurements depend on CO, oxygen demand, hemoglobin, and SaO2.

Images SVO2 is measured in patients using a pulmonary artery catheter. Initially, critically ill septic patients may present with a low SVO2 value (<65%), indicating high extraction of oxygen by tissues or lack of adequate DO2 to tissues. In patients with sepsis and other conditions who present with a low SVO2 value, rapid intervention should be undertaken to increase DO2 to tissues, with the goal of obtaining SVO2≥65%.24,32 The length of time SVO2 is <65% is associated with mortality.24 As sepsis worsens, however, SVO2 may be ≥65%. This occurs because extraction of oxygen in the arteriolar beds is hampered and is indicative of poor outcome.

Images SCVO2 is a less invasive measure of venous oxygen saturation because the catheter is placed at the junction of the inferior and superior venae cavae rather than at the pulmonary artery.1821 It is as accurate as SVO2 but provides slightly higher normal values. Concentrations of SCVO2 <70% reliably indicate inadequate oxygenation in shock states and detect subclinical (“cryptic”) shock much earlier than hypotension. Targeting fluid and hemodynamic resuscitation to achieve SCVO2 ≥70% is a sensitive indicator and measure of the extent of global tissue hypoxia, a determinant of the adequacy of hemodynamic resuscitation, and is associated with improved survival in patients with sepsis and septic shock.1521,24,32

Oxygen Delivery and Consumption

Tissue oxygen debt is indicative of organ damage in critical illness. In normal individuals, oxygen consumption (VO2 or VO2I [oxygen consumption index], indexed to body surface area) depends on DO2 (or DO2I) up to a certain critical level (VO2 flow dependency). At this point, tissue oxygen requirements apparently are satisfied and further increases in DO2 will not alter VO2 (VO2 flow independency). The point that VO2 becomes dependent on DO2represents a pathologic transition from aerobic to anaerobic cellular metabolism and lactate production.21,24,33,34 Although animal models of sepsis substantiate this relationship, studies in critically ill humans show a continuous, pathologic dependence relationship of VO2 with DO2.21,24,33,34 The VO2/DO2 ratio, or oxygen extraction ratio (O2ER), can be used to assess adequacy of perfusion and metabolic response.21,24,33,34 Maintaining the O2ER at <25% without a changing VO2 may be helpful in maintaining or improving the body’s reserve in meeting the oxygen demands. However, low VO2 and O2ER values are indicative of poor oxygen utilization and lead to greater mortality. Patients who are able to increase VO2 when DO2 is increased show improved survival. This finding became the basis for targeting supranormal DO2 and VO2 values in the treatment of ICU patients in the 1970s and 1980s. However, a meta-analysis of randomized clinical trials involving 1,016 adult ICU patients failed to show that achievement of this goal improved mortality.35 This may have been due in part to the heterogeneous nature of the ICU patients studied and therapies provided, lack of study blinding, crossover patients (control patients who achieve supranormal DO2 and VO2 values by themselves), or lack of adequate control of cointerventions. The debate continues in more homogeneous patient populations. For example, in high-risk surgical patients, supranormal DO2 values decrease mortality except in the subgroup of patients exceeding 75 years of age in whom achieving DO2I >600 mL/m2/min shows mixed mortality results.35 Of note, the systematic assessment of DO2 and VO2 dependence is rarely done in practice but the concepts are frequently applied indirectly.

A review of alternative potential mechanisms of beneficial effect of supranormal DO2 suggests that catecholamines exert antiinflammatory actions by modulating cytokine response.615 In general, catecholamines inhibit the production of inflammatory cytokines (e.g., interleukin [IL]-6, tumor necrosis factor [TNF]-α) and may enhance synthesis of antiinflammatory cytokines (e.g., IL-4 and IL-10). The actions of epinephrine on these cytokines are blocked by propranolol and thus are mediated by adrenergic β-receptors.

Another issue with therapy directed to achieve supranormal oxygen transport values is that the apparent linear relationship between DO2 and VO2 has been questioned because both share variables, and this mathematical couplingcan produce artifactual relationships between variables.21,24,33,34 The DO2 and VO2 indexed parameters are calculated as follows:

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where CI is the cardiac index, CaO2 is the arterial oxygen content determined by hemoglobin concentration and SaO2, and CVO2 is the mixed venous oxygen content determined by hemoglobin concentration and SVO2.

However, variable relationships between DO2 and VO2 are observed when VO2 is measured independently by indirect calorimetry. Therefore, a linear relationship between DO2 and VO2 may be the result of mathematical coupling or flow-dependent VO2. Currently available data do not support the concept that patient outcome or survival is improved by treatment measures directed toward achieving supranormal DO2 and VO2 values.35 In fact, a consensus conference concluded that although pulmonary artery catheterization is useful for guiding therapy, routinely increasing cardiac index to predetermined supranormal values does not improve outcome.7 Furthermore, achievement of a supranormal DO2 does not ensure parallel improvements in regional organ blood flow and oxygenation. One approach that may decrease the effect of mathematical coupling and provide individualized therapy may lie in titrated therapy, with sequential measurements of DO2 and VO2 to achieve VO2 flow independency along with normalization of blood lactate and hemodynamic parameters.

Images The most recent data regarding goal-directed therapy in the hemodynamic support of sepsis relates to the importance of achieving predetermined parameters early in the management of sepsis.36 In a meta-analysis of early (defined as 8 to 12 hours postoperatively or before the development of organ failure) versus late (defined as after the onset of organ failure) resuscitative efforts targeting supranormal oxygen-transport variables, early goal-directed therapy reduced mortality and the development of organ failure in patients who were more severely ill when therapeutic interventions produced differences in DO2.36 Survival outcome was not improved significantly in less severely ill patients (control group mortality <15% and normal DO2 values as goals) or when therapy did not improve DO2.

Images Images The rapid initiation of therapy to optimize the components of DO2 (CO, hemoglobin, and SaO2) improves survival. In a prospective, randomized controlled trial, Rivers et al. demonstrated a significant reduction in mortality (30.5% vs. 46.5%; P < 0.001) in patients with severe sepsis and septic shock randomized to receive therapy based on goal-directed hemodynamic end points that were achieved within 6 hours of hospital presentation.32They used a strategy of serial administering (a) fluids rapidly to achieve CVP 8 to 12 mm Hg, (b) vasopressor agents to achieve MAP at least 65 mm Hg, (c) red blood cell transfusion to maintain hematocrit ≥30%, and (d) dobutamine to achieve SCVO2 ≥70%. During the 6-hour window, the goal-directed therapy group received substantially more fluid, blood transfusions, and dobutamine administration but required less vasopressor and ventilator support later. This approach demonstrates the benefits of initiating therapy early in the course of sepsis and directs therapy toward clearly defined goals of optimizing DO2 in a consistent manner. The results of several evaluations of protocols or order sets designed to achieve the hemodynamic end points of early goal-directed therapy show that implementation is easily accomplished, cost is reduced, and patient outcomes, including survival, are improved.3743 A meta-analysis of nine studies showed reduced mortality when quantitative resuscitation goals are used to guide therapy (odds ratio [OR] 0.64; 95% confidence interval [CI]: 0.43 to 0.96; P = 0.03).43 Therefore, healthcare facilities should implement strategies to achieve early goal-directed therapy using the predefined hemodynamic variables of the study by Rivers et al.32


Clinical Controversy…

GOALS OF EARLY GOAL-DIRECTED THERAPY

The results of studies cannot delineate which end point or combination of end points was most beneficial with respect to early goal-directed therapy. These studies also offer limited information about specific interventions to achieve the predefined goals. In addition, whether these goals must be maintained after resuscitation is unknown. Several studies are ongoing to address some of these issues. Current practice should rapidly target all the parameters of early goal-directed therapy by employing a protocol.

Blood Lactate

Images Lactate is a metabolic product of pyruvate. Its production is increased under anaerobic conditions when VO2 exceeds DO2, such as may occur during shock.21,24,33,34 Blood lactate concentrations are used as a diagnostic and prognostic tool in sepsis; they also are used to measure the repayment of oxygen debt to tissues.1521 Several studies have demonstrated risk stratification of mortality rates based on initial lactate concentrations.44,45 Serial lactate concentrations may show better correlation with outcome than oxygen transport parameters and may be superior to hemodynamic markers in determining adequacy of restoration of systemic oxygenation. Continuously elevated concentrations are predictive of morbidity and mortality. Maintaining lactate elimination (commonly termed “clearance”) of 10% for 6 hours during initial resuscitation produces similar survival outcomes as achieving SCVO2≥70%.46 The utility of blood lactate measurements in guiding therapy was recently demonstrated in a study of 348 septic patients that showed targeting a 20% lactate reduction during the first 2 hours of resuscitation reduced hospital mortality compared to conventional assessment methods (hazard ratio [HR], 0.61; 95% CI: 0.43 to 0.87; P = 0.006).47

Several caveats guide the use of lactate concentrations in septic patients. First, lactate may accumulate in patients with other conditions, such as significant hepatic dysfunction or acute respiratory distress syndrome, who are not in shock. Second, both well-perfused and poorly perfused tissues contribute to arterial and mixed venous lactate concentrations and therefore are not reflective of regional perfusion. Third, elevated lactate concentrations may result from cellular metabolic failure rather than global hypoperfusion in shock.


Clinical Controversy…

SVO2 or Scvo2 versus lactate

The goal of resuscitation is to reverse tissue hypoxia by facilitating DO2. Both SVO2 OR SCVO2 and lactate clearance measure global tissue perfusion. Limited data are available comparing the use of SVO2 or SCVO2 and lactate clearance for guiding therapy in patients with shock. The results of a recent study of critically ill septic patients suggest that they are equivalent in terms of clinical outcomes, including mortality.47 The decision to use one parameter over the other will depend on clinician preference and patient characteristics.

REGIONAL PERFUSION MONITORING

GI Tonometry

Blood pressures, CO, blood lactate, and global oxygen homeostasis parameters do not offer information about the function of individual organs. Organ-specific hypoxia may be evident by coagulopathy as indicated by thrombocytopenia (platelet count <100,000/L and/or prolonged clotting times [international normalized ratio >1.5 or activated partial thromboplastin time at least 1.5-fold the upper limit of normal]), impaired renal function with urine production <0.5 mL/kg/h and/or increased serum concentrations of blood urea nitrogen and creatinine, altered hepatic function with substantially increased serum concentrations of transaminases and bilirubin, altered GI perfusion manifested by ileus and diminished bowel sounds, cardiac ischemia with elevated troponin levels and electrocardiogram changes, and altered sensorium.6,22 Objective measurement of regional perfusion to detect inadequate tissue oxygenation has focused on the mesenteric/splanchnic circulation, which is sensitive to changes in blood flow and oxygenation for several reasons.1520,34,48 Normally, most blood flow to the gut mucosa is redistributed toward the serosa and muscularis. Second, the gut may have a higher critical DO2 threshold than other organs. Third, the tip of the villus has a countercurrent oxygen-exchange mechanism, rendering it highly sensitive to alterations in regional blood flow and oxygenation.

Images Gastric tonometry measures gut luminal partial pressure of carbon dioxide (PCO2) at equilibrium by placing a saline- or air-filled gas-permeable balloon in the gastric lumen. Assuming that carbon dioxide (CO2) permeates freely among tissues and that the arterial bicarbonate Images concentration is equal to that of the gut mucosa, the intramucosal pH (pHi) may be calculated using the Henderson–Hasselbalch equation:

Images

Increases in mucosal PCO2 and calculated decreases in pHi are associated with mucosal hypoperfusion and perhaps increased mortality.1520,34,48 Calculation of pHi can be confounded by increases in luminal PCO2, such as may occur when buffering antacids are used. Histamine2-receptor antagonists or proton pump inhibitors can be used instead. The presence of respiratory acid–base disorders; systemic bicarbonate administration; arterial blood gas measurement errors; or enteral feeding products, blood, or stool in the gut may confound pHi determinations. As a result, the change in gastric mucosal PCO2 may be more accurate than pHi. Furthermore, because mucosal PCO2 is influenced by arterial PCO2, the mucosal–arterial PCO2 difference (PCO2 gap) likely is the optimal measurement.1520,34,48 Gastric tonometry can be performed using either a saline- or air-filled balloon. The time delay (30 minutes) associated with equilibration of saline inside the balloon makes this method impractical for monitoring of resuscitation and inconvenient for routine bedside monitoring. An air-filled balloon requires a shorter equilibrium time, is simpler to use, and is equally accurate. However, the clinical utility of gastric tonometry remains uncertain. Clinical trials of pHi-directed therapy do not show that it aids resuscitation when other goals are concomitantly targeted. Gastric tonometry, in general, inconsistently predicts mortality.

Images Evidence suggests that the most proximal part of the GI tract, the sublingual mucosa, may be an acceptable location for monitoring regional perfusion and PCO2.1520,34,48 Unlike GI circulation, limited intra- and interpatient variability exists in the microvasculature and only few arterioles are available for assessment. Sublingual capnometry is noninvasive, is not technically complex, and provides results within minutes. The device consists of a disposable sublingual carbon dioxide pressure (PslCO2) sensor, a fiberoptic cable that connects the disposable sensor to a blood gas analyzer, and a blood gas monitoring instrument. Small studies of critically ill patients with and without sepsis and septic shock show that the PslCO2 and the sublingual-to-arterial PCO2 gap correlate better with the enhancement of DO2with dobutamine than the mucosal PCO2 and the mucosal-to-arterial PCO2 gap.1520,34,48 The initial sublingual-to-arterial PCO2 gap is a better predictor of mortality. These pilot studies must be expanded before this technology becomes part of routine practice, but it offers the possibility of noninvasive measurement of regional perfusion. Of note, some institutions have incorporated the PslCO2 into their algorithms of early goal-directed therapy in an effort to provide additional information about the effectiveness of therapies during resuscitation.

Myocardial Dysfunction

Images Although loss of vascular tone is the hallmark of septic shock, myocardial dysfunction characterized by transient impairment of contractility is a recognized complication.5,49 The range of left ventricular ejection fraction (LVEF) upon presentation is wide, but approximately 35% of patients with septic shock have left ventricular hypokinesis (mean ejection fraction 38% ± 17%) and low CO.5,49 Because LVEF also is affected by preload and afterload, the low SVR of septic shock may mask depressed myocardial contractility that may be revealed upon restoration of MAP by administration of fluid and vasopressors. Therefore, CO may not reflect the extent of myocardial dysfunction. While it requires technical and interpretive training, echocardiography is a relatively simple method of assessing cardiac function and ventricular response to therapies.50 It can assess chamber size, ventricular contractility, valve function, blood flow, and CO. Patients with tissue hypoxia or a hypercontractile left ventricle may benefit from fluid administration or vasopressor therapy; whereas, patients with poor left ventricular function may require inotropic intervention. Like sublingual capnometry, some institutions use echocardiography to direct resuscitation therapies.

Cardiac troponin release in septic patients occurs in the absence of flow-limiting disease, likely due to a loss in membrane integrity with subsequent leakage or microvascular thrombosis. Elevation of cardiac troponin concentrations in patients with sepsis indicates left ventricular dysfunction and portends a poor prognosis.4951 Troponin concentrations also correlate with the duration of hypotension and the intensity of vasopressor therapy. Early recognition of myocardial dysfunction is crucial for administration of appropriate therapy. In the absence of other mechanisms for assessing cardiac function, echocardiographic findings and troponin concentrations may help guide and monitor therapy. Whereas cardiac troponins may be integrated into the monitoring of myocardial dysfunction to identify patients requiring aggressive therapy, natriuretic peptides show variable correlation with LVEF and should not be routinely monitored.4951

VASOPRESSORS AND INOTROPES

Images Vasopressors and inotropes in patients with septic shock are required when volume resuscitation fails to maintain adequate blood pressure (MAP ≥65 mm Hg) and organs and tissues remain hypoperfused despite optimizing CVP to 8 to 12 mm Hg or PAOP to 12 to 15 mm Hg.6 However, vasopressors may be needed temporarily to treat life-threatening hypotension when filling pressures are inadequate despite aggressive fluid resuscitation. Inotropes are frequently used to optimize cardiac function in cases of cardiogenic shock. The clinician must decide on the choice of agent, therapeutic end points, and safe and effective doses of vasopressors and inotropes to be used. This section reviews adrenergic receptor pharmacology, exogenous catecholamine use, and alterations in receptor function in critically ill patients. It also provides guidelines for the clinical use of adrenergic agents, optimization of pharmacotherapeutic outcomes, and minimization of adverse effects in critically ill patients with septic shock. Therapies of hypovolemic shock and cardiogenic shock are discussed in other chapters.

Of note, agents other than catecholamines have been used as inotropes and vasopressors in shock states. They include phosphodiesterase III inhibitors, naloxone, nitric oxide (NO) synthase (NOS) inhibitors, and calcium sensitizers. This chapter focuses on catecholamines. Vasopressin and corticosteroids, as they relate to septic shock, also are emphasized because they have pharmacologic interactions with catecholamines, possess hemodynamic effects, and are frequently used.

Catecholamine Receptor Pharmacology

Images Comparative receptor activities of endogenous and exogenously administered catecholamines are summarized in Table 13-3.615,5254 Endogenous catecholamines are responsible for regulation of vascular and bronchiolar smooth muscle tone and myocardial contractility. These effects are mediated by sympathetic adrenergic receptors of the autonomic nervous system located in the vasculature, myocardium, and bronchioles. Postsynaptic adrenoceptors are located at or near the synaptic junction. These receptors can be activated by naturally circulating or exogenous catecholamines (e.g., norepinephrine, epinephrine, and phenylephrine), whereas presynaptic adrenoceptors are stimulated by locally released neurotransmitters (e.g., norepinephrine) and are controlled by a negative feedback mechanism.

TABLE 13-3 Adrenergic, Dopaminergic, and Vasopressin Receptor Pharmacology, and Organ Distribution

Images

The signal transduction pathways associated with catecholamine and vasopressin-induced effects in the heart and blood vessels are illustrated in Figure 13-1.615,5254 Agonists of β-adrenoceptors and dopamine (D1) receptors stimulate adenylate cyclase by a G-protein (Gs)-dependent mechanism (Fig. 13-1, top). Adenylate cyclase generates cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). cAMP-dependent protein kinase A, which is activated by elevations in intracellular cAMP, phosphorylates target proteins to modify cellular function. Through these mechanisms, β1-adrenoceptor activation exerts positive inotropic and chronotropic effects in the heart, and β2-adrenoceptor and D1-receptor activation induces vascular smooth muscle relaxation. Agonists of α1-adrenoceptors stimulate phospholipase C-β (PLC-β) through a G-protein (Gq)-dependent process (Fig. 13-1, bottom). PLC-βproduces inositol trisphosphate and diacylglycerol from cell membrane phosphatidylinositol bisphosphate. Diacylglycerol activates protein kinase C, an enzyme that phosphorylates several key proteins (e.g., extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and-mitogen-activated protein kinases) that modify cellular function (e.g., hypertrophy). Inositol trisphosphate elicits the release of calcium from intracellular stores, such as the sarcoplasmic reticulum. Calcium forms a complex with calmodulin, which then activates calcium–calmodulin-dependent protein kinases (CaMK). CaMKs phosphorylate target proteins to alter cellular function. Myosin light-chain kinase is an example of a CaMK. Its action of phosphorylating myosin light chain leads to vascular smooth muscle contraction.

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FIGURE 13-1 Signal transduction pathways in heart and blood vessels. Top: Catecholamine (CCA)-induced effects mediated in heart (β1) or vascular smooth muscle (β2, D1). (AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, cAMP-dependent protein kinase; +, stimulation.) Bottom: CCA (α1) and vasopressin (VP)-induced actions in vascular smooth muscle. (Ca++, calcium ion; CaMK, calcium/calmodulin-dependent protein kinase; DAG, diacylglycerol; IP3, inositol trisphosphate; NO, nitric oxide; PIP2, phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC-β, phospholipase C-β; SR, sarcoplasmic reticulum.) These pathways have been extensively simplified, and denoted cellular effects represent one of many produced. (Figure based on data from references 6–15, 52–54.)

The normal heart contains primarily postsynaptic β1-receptors, which when stimulated cause increased rate and force of contraction. This effect is mediated by activation of adenylate cyclase and subsequent generation and accumulation of cAMP. Stimulation of postsynaptic cardiac α1-receptors causes a significant increase in contractility without an increase in rate, an effect mediated by PLC rather than adenylate cyclase. The increased contractility is more pronounced at lower heart rates and has a slower onset and longer duration in comparison with β1-mediated inotropic response. Presynaptic α2-adrenoceptors also are found in the heart and appear to be activated by norepinephrine released by the sympathetic nerve itself. Their activation inhibits further norepinephrine release from the nerve terminal.

Both presynaptic and postsynaptic adrenoceptors are present in the vasculature. Postsynaptic α1- and α2-receptors mediate vasoconstriction, whereas postsynaptic β2-receptors induce vasodilation. Presynaptic α2-receptors inhibit norepinephrine release in the vasculature, also promoting vasodilation. Presynaptic β1-adrenoceptors promote neurotransmitter release. Stimulation of peripheral D1-receptors produces renal, coronary, and mesenteric vasodilation and a natriuretic response. Stimulation of D2-receptors inhibits norepinephrine release from sympathetic nerve endings, sequesters prolactin and aldosterone, and may induce nausea and vomiting. D1- and D2-receptor stimulation also suppresses peristalsis and may precipitate ileus.

Images Vasopressin-induced vasoconstriction occurs through a variety of direct and indirect mechanisms.52,53 Stimulation of vascular vasopressin (V)1 receptors causes vasoconstriction by receptor-coupled activation of PLC and calcium release from intracellular stores via secondary messengers similar to α1-adrenergic stimulation (Fig. 13-1, bottom). Vasopressin also directly inhibits vascular potassium-sensitive ATP channels to produce vasoconstriction (Fig. 13-1, bottom). V1-receptor stimulation inhibits the actions of IL-1β and thereby facilitates vasoconstriction. Vasopressin also increases the activity of adrenergic receptors. The greatest vasoconstriction occurs in the skin and soft tissue, skeletal muscle, fat tissue, pancreas, and thyroid gland. In contrast, vasopressin causes vasodilation in the cerebral, pulmonary, coronary, and selected renal vascular beds by enhancing endothelial NO release through V1-receptor stimulation in these tissues.5254 Vasopressin has minimal to no inotropic or chronotropic effects.

V2 receptors located in the kidneys are responsible for the antidiuretic properties of vasopressin.5254 Stimulation of V2 receptors facilitates integration of aquaporins into the luminal cell membrane of distal tubules and collecting duct capillaries to increase permeability and thus retain intravascular volume. However, vasopressin stimulation of V1 receptors causes vasoconstriction of efferent arterioles and relative vasodilation of afferent arterioles to increase glomerular perfusion pressure and filtration rate to enhance urine production.

Vasopressin rapidly increases serum cortisol concentration by stimulating V3 receptors in the pituitary gland to enhance the release of adrenocorticotropic hormone (ACTH).5254 Cortisol helps regulate the proinflammatory state associated with sepsis and increases blood pressure through several mechanisms, including inhibition of inducible nitric oxide synthase (iNOS) to reduce NO production, reversal of adrenergic receptor desensitization, and increased intravascular volume through retention of sodium and water.

Altered Adrenoceptor Function: Implications for Critically Ill Patients

Images Most of the work describing receptor function and associated clinical pharmacology has been performed in either animal models or human volunteers. In critically ill septic patients, derangements in adrenergic receptor activity may result in resistance to exogenously administered catecholamine.615,52,53 This “desensitization” frequently is characterized by myocardial and vascular hyporesponsiveness to high dosages of inotropes and vasopressor agents. Prolonged exposure of vascular endothelial tissue to vasopressor drugs (α-adrenergic agonists) or endogenous catecholamines may promote additional receptor downregulation. Increased endogenous catecholamine concentrations have been reported in endotoxemic and other critically ill patients, suggesting an acquired adrenergic receptor defect and desensitization of adrenergic receptors and alteration in voltage-sensitive calcium channels. The problem in critically ill patients may be related to decreased receptor activity or density. However, in patients with septic shock, catecholamine concentrations are even higher, so abnormalities in adrenergic receptor function are greater, with associated reductions in the concentrations of intracellular signal transduction mediators. The worsened receptor abnormality may be explained by defects distal to the receptor site, such as uncoupling of adrenergic receptors from adenylate cyclase or PLC, or dysfunction in the regulatory G-protein unit of signal transduction pathways.

In addition to catecholamines, circulating inflammatory cytokines may be partly responsible for distal alterations.52,53 Macrophage-derived IL-1 and TNF-α produce impaired coupling of β-adrenoceptors to adenylate cyclase. Patients with septic shock exhibit impaired β-adrenergic receptor stimulation of cAMP associated with myocardial hyporesponsiveness to various vasopressors and inotropes. However, increased chronotropic sensitivity to β-adrenergic stimulation with hypersensitivity of the adenylate cyclase system to isoproterenol stimulation also has been reported in animal models of bacteremia and endotoxemia. In the presence of intrinsic myocardial dysfunction and increased metabolic demands, this dysfunctional adrenergic system is incapable of mobilizing functional cardiac reserve to maintain adequate myocardial performance.49,52,53

IL-1 and TNF-α suppress gene expression of α1-adrenoceptors, resulting in fewer receptor proteins. Overproduction of NO by iNOS directly contributes to vasodilation by cyclic guanosine monophosphate-mediated smooth muscle relaxation. NO indirectly produces vasodilation by combining with superoxide to form peroxynitrite, a highly toxic reactive species that causes endothelial dysfunction, uncoupling of α1-adrenoceptors to PLC, and deactivation of catecholamines. The result of sepsis-induced inflammation is a system that promotes adrenergic receptor dysfunction to accentuate vasodilation and shock.615,49,52,53

Images Functional α1-adrenergic receptor changes occur at various stages of sepsis; thus, adrenoceptor sensitivity may be time dependent during progression of sepsis to septic shock. The findings are not always consistent in various animal models of sepsis and in critically ill septic patients. Time-dependent alterations in the production of NO, a potent vasodilator, may explain the apparent differences in vascular reactivity to phenylephrine during the phases of endotoxemia. This finding suggests that the clinical response to vasopressors and possibly inotropic agents is variable during the stages of hemodynamic, myocardial, and peripheral vascular derangements of septic shock. β-adrenergic receptor changes are present within 24 to 48 hours of septic shock. In summary, α- and β-adrenergic receptor derangements may vary among patients and during each bacteremic insult; therefore, doses of catecholamines vary among patients and during the insult.615,52,53 For these reasons, these drugs should be dosed to clinical end points and not to arbitrary maximal doses. High dosages are frequently required.

Relative Deficiencies of Vasopressin and Cortisol

Images Endogenous arginine vasopressin, a peptide hormone also known as antidiuretic hormone, is important for osmoregulation under normal physiologic conditions. Vasopressin is produced in the hypothalamus, stored in the posterior pituitary, and released from magnocellular neurons of the hypothalamus.54 Increased serum osmolality and hypovolemia are the major stimuli for vasopressin release.54Other stimuli commonly associated with shock are dopamine, histamine, angiotensin II, prostaglandins, pain, hypoxia, acidosis, hypotension, hypercarbia, and α1-adrenergic receptor stimulation. Vasopressin release is inhibited by NO, natriuretic peptides, γ-aminobutyric acid, β-adrenergic receptor stimulation, and α2-adrenergic receptor stimulation.54

Normal serum vasopressin concentrations are <4 pg/mL.54 Serum vasopressin concentrations are elevated with hypotension. Vasopressin response in septic shock is biphasic. During the first 8 hours of septic shock requiring catecholamine adrenergic therapy, serum concentrations of vasopressin are appropriately high to help maintain blood pressure and organ perfusion. Thereafter, serum vasopressin concentrations decline dramatically over the next 96 hours to physiologically normal but inappropriately low values, resulting in a state of “relative deficiency.” In contrast, serum vasopressin concentrations remain elevated in patients with cardiogenic shock. Administration of vasopressin at 0.01 to 0.06 units/min produces concentrations similar to those observed in early septic shock and other hypotensive states; however, vasopressin concentrations do not correlate with blood pressure.54 Administration of vasopressin improves arterial pressure while minimizing the dose of catecholamine vasopressors.54

The mechanism of vasopressin insufficiency in septic shock is not well understood. Neurohypophyseal stores in the posterior lobe of the pituitary gland are depleted during septic shock, likely as a result of excessive and continuous baroreceptor stimulation that eventually exhausts the limited vasopressin secretory stores. In addition, secretion of vasopressin is inhibited by enhanced endothelial production of NO, high circulating concentrations of adrenergic agonists (both endogenous and exogenous), and tonic inhibition by stretch receptors in response to volume replacement and mechanical ventilation.54

Images As with vasopressin, during sepsis a state of “relative adrenal insufficiency” is produced by continuous activation of the hypothalamic–pituitary–adrenal axis by IL-1, IL-6, and TNF-α that causes depletion of cortisol in the adrenal glands.55 Administration of corticosteroids improves arterial pressure while minimizing the dose of catecholamine vasopressors.56,57 Current proposed mechanisms of the vasoconstrictor effect of corticosteroids include increasing the number and stimulating the function of α1- and β-adrenergic receptors and attenuating the production of inflammatory mediators responsible for vasodilation.

The use of corticosteroids for treatment of septic shock has been a topic of controversy for many years. Meta-analyses of early studies of steroids in patients with sepsis demonstrated a lack of benefit and potential harm in sepsis and septic shock.56,57 Interest in corticosteroid use is renewed because of the increased awareness of adrenocortical insufficiency in critically ill patients with septic shock.55 Relative adrenal insufficiency has been defined as a random cortisol concentration <10 mcg/dL (278 nmol/L) or an increase of <9 mcg/dL (250 nmol/L) following a dose of synthetic ACTH irrespective of the initial serum cortisol concentration.58 Although absolute insufficiency is rare, relative adrenocortical insufficiency is present in 50% to 70% of patients with septic shock and is associated with a poor outcome.5962

An elevated random cortisol concentration (>34 mcg/dL) is an independent predictor of mortality.58 Mortality is further increased if ACTH response is <9 mcg/dL, suggesting that the risk of mortality is greatest in situations of adrenal gland “fatigue” (i.e., degree of stress is not matched by sufficient cortisol production by the adrenal glands despite operating at maximal functional capacity).

Clinical Pharmacology of Vasopressors and Inotropes

Images Images The receptor selectivity of clinically used, catecholamine-based vasopressors and inotropes and hemodynamic effects are listed in Table 13-4.615,5254,63,64 In general, these drugs are fast acting, with short durations of action. As such, these drugs are given as continuous infusions and titrated rapidly to predetermined effects.6 Vasopressin is administered as a replacement dosage of 0.01 to 0.04 units/min and should not be titrated.54 Careful monitoring and calculation of infusion rates are advised for all vasopressors because dosing adjustments are made frequently, and varying admixtures and concentrations are used in volume-restricted patients.

TABLE 13-4 Receptor Pharmacology and Adverse Events of Selected Inotropic and Vasopressor Agents Used in Septic Shocka

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Images Norepinephrine is a combined α- and β-agonist that produces vasoconstriction primarily via its more prominent α-effects on all vascular beds, thus increasing SVR.615,52,53,63,64 Norepinephrine administration generally produces either no change or some increase in CO. Norepinephrine is considered the first-line option for initial vasopressor therapy of septic shock.6

Images Phenylephrine is a pure α1-agonist and increases blood pressure through vasoconstriction.615,52,53,63,64 Given the presence of cardiac α1-receptors, phenylephrine also may increase contractility and CO although no change or a slight reduction in CO is often observed. It is a therapeutic option in hypotensive patients experiencing a tachyarrhythmia when a vasopressor with minimal to no β1-agonist activity is indicated.6

Images Epinephrine exerts combined α- and β-agonist effects.615,52,53,63,64 At the high epinephrine infusion rates used for patients with septic shock, predominantly α-adrenergic effects are observed, and SVR and MAP are increased. While epinephrine traditionally has been reserved as the vasopressor of last resort due to peripheral vasoconstriction, particularly in the splanchnic and renal beds, it is considered second-line therapy according to the current guidelines.6 It is widely used in other countries where other agents may not be readily available or are relatively expensive.

Images Dopamine has been described as having dose-related receptor activity at D1-, D2-, β1-, and α1-receptors (Table 13-4).615,52,53,63,64 This dose–response relationship has not been confirmed in critically ill patients. In patients with septic shock, great overlap of hemodynamic effects occur, even at dosages as low as 3 mcg/kg/min. Tachydysrhythmias are common due to the release of endogenous norepinephrine by dopamine entering the sympathetic nerve terminal. For this reason, it is no longer considered first-line therapy for septic shock.6 Dopamine may increase PAOP through pulmonary vasoconstriction. This drug also may depress ventilation and worsen hypoxemia in patients dependent on the hypoxic ventilatory drive.

Images Dobutamine, a synthetic catecholamine, is primarily a selective β1-agonist with mild β2- and vascular α1-activity, resulting in strong positive inotropic activity without concomitant vasoconstriction.615,52,53,63,64 In comparison with dopamine, dobutamine produces a larger increase in CO and is less arrhythmogenic. α1-Adrenoceptors in the heart are directly stimulated by the (–) isomer of dobutamine, but β1 and β2 activity resides in the (+) isomer. The strong inotropic action of dobutamine is a function of its structure, the additive effect of cardiac α1- and β1-agonist activity, and a relatively weak chronotropic effect limited to the (+) isomer action on the β-receptors. Clinically, β2-induced vasodilation and the increased myocardial contractility with subsequent reflex reduction in sympathetic tone lead to a decrease in SVR. Dobutamine is used optimally for patients in low CO states with high filling pressures (e.g., CI <3 L/min/m2, left ventricular dysfunction demonstrated with echocardiography, or SCVO2 <70%) or in those in cardiogenic shock; however, vasopressors may be needed to counteract arterial vasodilation.6,32

Images Unlike adrenergic receptor agonists, the vasoconstrictive effects of vasopressin are preserved during hypoxia and severe acidosis. Initiating vasopressin at ≤0.04 units/min in patients with septic shock increases SVR and arterial blood pressure to reduce the dose requirements of catecholamine adrenergic agents.54,6366 These effects are rapid and sustained. Organ-specific vasodilation reduces pulmonary artery pressure and may preserve cardiac and renal function. It may enhance urine production, likely due to increased glomerular filtration rate.54,67 At dosages exceeding 0.04 units/min, however, vasopressin is associated with ischemia of the mesenteric mucosa, skin, and myocardium. Limiting the dosage to a maximum of 0.04 units/min may minimize the development of these adverse effects. At present, vasopressin is not recommended as a replacement for norepinephrine in patients with septic shock but may be considered as adjunctive therapy in patients who are refractory to catecholamine vasopressors despite adequate fluid resuscitation.6 If used, vasopressin should be administered at dosages not exceeding 0.04 units/min.6,54,65

Desired Outcomes and Clinical Application

Resuscitation Goals of Septic Shock

Images Images Images Initial hemodynamic therapy for septic shock is the administration of IV fluid (30 mL/kg of crystalloid fluid), with the goal of attaining CVP of 8 to 12 mm Hg or 15 mm Hg in mechanically ventilated patients or patients with abdominal distension or preexisting ventricular dysfunction.615 Crystalloid fluids (e.g., normal saline, Ringer lactate) and colloid fluids (e.g., albumin, hydroxyethyl starch, dextran products, blood products) are considered equivalent for shock resuscitation.6,6870 Crystalloid fluids are generally preferred unless patients are at risk for adverse events from redistribution of IV fluids to extravascular tissues and/or are fluid restricted (e.g., patients with renal dysfunction, decompensated heart failure, ascites compromising diaphragmatic function).6 Recent data suggest hydroxyethyl starch may increase the risk of acute renal dysfunction in a dose-dependent manner and possibly enhance mortality.71,72 Its use warrants extreme caution and consideration of a dose threshold.

Images Norepinephrine is the preferred initial vasopressor agent in septic shock not responding to fluid administration.6 Other agents include phenylephrine, epinephrine, dopamine, and dobutamine. Optimizing MAP to 65 mm Hg as the goal of vasopressor therapy does not uniformly correlate with decreased mortality in patients with septic shock but global perfusion may be improved.1521 Historically, significant concerns about the adverse effects of vasopressors limited their use. The past focus of achieving supranormal oxygen-transport variables also yielded poor results in patients with septic shock.35 In fact, normalization of systemic DO2 and VO2, whether spontaneously or with intervention, is associated with improved outcome and is not dependent on administration of vasopressor agents.35 Part of the inability to detect an improvement with vasopressor or inotropic therapies may result from the limited ability to quantify regional tissue perfusion. However, use of early goal-directed therapy to MAP ≥65 mm Hg and SCVO2 ≥70% reduces mortality in patients with sepsis and septic shock.32

Images Images Images Images Images Images ImagesImages Dosage titration and monitoring of vasopressor and inotropic therapy should be guided by the “best clinical response,” the goals of early goal-directed therapy, and lactate clearance.621,32Norepinephrine is considered the agent of choice as initial vasopressor therapy.6 Epinephrine may be added in cases where suboptimal hemodynamic response is obtained from to norepinephrine.6 Phenylephrine may be tried as the initial vasopressor in cases of severe tachydysrhythmias.6 Dobutamine is used in states of low CO states despite adequate fluid resuscitation pressures (e.g., CI <3 L/min/m2, left ventricular dysfunction demonstrated with echocardiography, or SCVO2 <70%). Low dosage rates are initiated and titrated rapidly (usually every 5 to 15 minutes) to clinical response. Clinically effective dosing of vasopressors and inotropes in septic shock often requires doses much higher than recommended by most references.621 These large infusion rates must be tempered with the development of adverse effects. The goal is to use the lowest effective infusion rate while minimizing evidence of myocardial ischemia (e.g., tachydysrhythmias, electrocardiographic changes, troponin elevations), renal (decreased glomerular filtration rate and/or urine output), splanchnic/gastric (low pHi, bowel ischemia), or peripheral (cold extremities) hypoperfusion, and worsening PaO2, PAOP, and other hemodynamic variables.

Images Vasopressin may be considered as adjunctive therapy in patients who are refractory to catecholamine vasopressors despite adequate fluid resuscitation.6 Dosages of ≤0.04 units/min increase SVR and arterial blood pressure to reduce the dose requirements of catecholamine adrenergic agents.54,6366

Images Therapy with catecholamine vasopressors and inotropes is continued until myocardial depression and vascular hyporesponsiveness (i.e., blood pressure) of septic shock improve, usually measured in hours to days.6Discontinuation of vasopressor or inotropic therapy should be executed slowly; therapy should be “weaned” to avoid a precipitous worsening in regional and systemic hemodynamics. Careful monitoring of global and regional end points also should be geared toward discontinuation of vasopressors and inotropes as soon as the patient is hemodynamically stable. This requires constant observation. Because vasopressors and inotropes often are started while the patient is not yet optimally volume resuscitated, clinicians should reevaluate intravascular volume status continuously so that the patient can be weaned from the vasopressor as soon as possible. Dosage rates should be titrated carefully downward approximately every 10 minutes to determine if the patient can tolerate gradual withdrawal and eventual discontinuation of the vasopressor and/or inotrope. Discontinuation of agents may occur only minutes to hours after their initiation, or it may take days to weeks. Septic shock requiring vasopressor and/or inotropic support usually resolves within several days to 1 week.

Comparative Studies of Catecholamine Vasopressors

Images Images The results of several observational and randomized studies support norepinephrine as the first-line vasopressor for septic shock.6 A recent meta-analysis of 11 trials (N = 2768) showed dopamine was associated with increased risk of death (RR, 1.23; 95% CI: 1.05 to 1.43; P < 0.01) compared to norepinephrine.63 Tachydysrhythmias were more common with dopamine (RR, 2.34; 95% CI: 1.46 to 3.77; P = 0.001). The results of two recent studies contribute to the majority of data. The first randomized 1,679 patients with shock unresponsive to volume resuscitation to norepinephrine or dopamine and found similar 28-day mortality rates (48.5% vs. 52.5% of patients; P = 0.10) although death from refractory shock tended to occur less frequently with norepinephrine (41% vs. 46%; P = 0.05).73 The mortality rate was significantly lower in the subgroup of 280 patients with cardiogenic shock that received norepinephrine (P = 0.03). Overall, patients receiving norepinephrine had fewer arrhythmic events (12.4% vs. 24.2%; P < 0.001) despite using dobutamine more frequently, had more vasopressor-free days, and were less likely to require open-label vasopressor support (20% vs. 26%; P < 0.001). Limitations of this landmark study include combining heterogeneous shock etiologies (cardiogenic, septic, hypovolemic, and other), the use of a relatively conservative definition of “shock unresponsive to fluid administration” (only 1 L of crystalloid or 0.5 L of colloid), the use of open-label norepinephrine in patients with inadequate hemodynamic response to study drug regimens, and the lack of standardization of other shock therapies that affect hemodynamic variables (e.g., corticosteroids, vasopressin, dobutamine, additional fluid administration). Another recent study randomized 252 septic shock patients found statistically similar 28-day mortality rates between norepinephrine and dopamine (43% vs. 50%; P = 0.282).74 Similar to the aforementioned study, arrhythmic events were less likely to occur with norepinephrine (5.3% vs. 23.3%; P< 0.0001).

Images Images Images Two randomized, double-blind studies compared epinephrine with norepinephrine in 330 and 280 patients with septic shock, respectively.75,76 Both studies found similar 28-day mortality rates with epinephrine and norepinephrine (40% vs. 31%; P = 0.31; and 22.5% vs. 26.1%; P = 0.48). Time to hemodynamic recovery and vasopressor withdrawal were also similar between agents in both studies. One study found more events of tachydysrhythmias with epinephrine leading to study discontinuation.75 Both studies also showed that epinephrine was associated with lower arterial pH values and higher serum lactate concentrations over the first days of therapy, possibly demonstrating deleterious circulation, exaggerated glycolysis, or mobilization of lactate with epinephrine. These findings support the use of epinephrine in septic shock but it is considered second-line therapy due to its association with impaired lactate clearance.6

Vasopressin

Images Small studies of septic shock patients demonstrate that initial therapy with vasopressin achieves blood pressure control as effectively as traditional catecholamine vasopressors but the response is delayed.54 Therefore, vasopressin therapy should not be initiated as first-line therapy. Several small studies showed that adjunctive vasopressin therapy reduces the dose requirements of catecholamine vasopressors and maintains blood pressure to expedite the discontinuation of catecholamine vasopressors.54 A recent meta-analysis of 10 trials (N = 1,134) confirmed a negative correlation between vasopressin and norepinephrine dosages.66 Some studies document enhancement of urine production.54,67 The results of a randomized, double-blind study of 776 patients with septic shock requiring catecholamine vasopressors showed that 28-day mortality rates were similar when vasopressin 0.01 to 0.03 units/min or norepinephrine 5 to 15 mcg/min was added to traditional catecholamine therapy (35.4% vs. 39.3%; P = 0.26).65 A trend toward reduced 28-day mortality favored vasopressin in the subset of patients categorized as having less severe septic shock defined by a baseline norepinephrine requirement of <15 mcg/min (26.5% vs. 35.7%; P = 0.05). This trend was evident when sepsis severity was defined by lactate quartiles or number of organ failures, suggesting that adjunctive vasopressin may be most beneficial when it is started prior to escalation of therapy with catecholamine vasopressors. Post hoc analyses demonstrated greatest benefit with early vasopressin treatment relative to the onset of shock. The adverse event profiles were similar between groups. Of note, vasopressin therapy expedited the discontinuation of catecholamine vasopressors in all patients and helped preserve renal function in patients with acutely declining urine production as defined by the injury (doubling of serum creatinine concentration, glomerular filtration rate reduced by half, or urine production less than 0.5 mL/kg/h) category of Risk, Injury, Failure, loss, End-stage renal disease (RIFLE).67 Whereas V2 stimulation promotes water retention from the distal tubules and collecting ducts, V1 receptors cause vasoconstriction of efferent arterioles and relative vasodilation of afferent arterioles to increase glomerular perfusion pressure and filtration rate, enhancing urine production. In the studies reporting benefit on renal function, the maximum dosage used was 0.08 units/min.54 Use of vasopressin for preventing dose escalation of adrenergic agents should be considered, but the risks must be weighed prior to initiating therapy. At present, vasopressin should not be used for the sole purpose of improving or maintaining renal function.6


Clinical Controversy…

Epinephrine or vasopressin

Current guidelines suggest epinephrine or vasopressin may be added to norepinephrine but do not delineate which agent is preferred or when this should occur with respect to resuscitation goals.6 Adding epinephrine may worsen lactate clearance while adding vasopressin may enhance the occurrence of ischemic events to digits. Both agents may worsen splanchnic circulation.

Corticosteroids

Images Since two meta-analyses reported in 1995 increased mortality with corticosteroids,56,57 several randomized controlled trials of low-dose corticosteroids in vasopressor-dependent septic shock patients have been published.5862These studies use moderate physiologic dosages (200 to 300 mg/day) of hydrocortisone. A meta-analysis of five studies (N = 465) showed that steroid therapy was associated with an overall improvement in the survival rate (RR, 1.23; 95% CI: 1.01 to 1.50; P = 0.036) and shock reversal (RR, 1.71; 95% CI: 1.29 to 2.26; P < 0.001).59 These effects were beneficial in both responders and nonresponders to ACTH stimulation testing. These studies also showed that low-dose corticosteroid administration improves hemodynamics and reduces the duration of vasopressor support. All of these studies differ from earlier studies in that steroids were administered at lower total doses (hydrocortisone equivalents: 1,209 mg vs. 23,975 mg; P = 0.01) starting later in septic shock (23 hours vs. <2 hours; P= 0.02) for longer courses (6 days vs. 1 day; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; P = 0.06) who were more likely to be vasopressor dependent (100% vs. 65%; P= 0.03). The relationship between corticosteroid dose and survival was linear, with survival benefit at low doses (P = 0.02). Another meta-analysis of 17 trials (N = 2,138) found similar results with long-term administration of corticosteroids associated with lower mortality in hospital (RR, 0.83; 95% CI: 0.68 to 1; P = 0.05) and at 28 days (RR, 0.84; 95% CI: 0.71 to 1; P = 0.05), reduced ICU stay by 4.49 days (95% CI: –7.04 to –1.95; P < 0.001), and greater shock reversal at 28 days (RR, 1.12; 95% CI, 1.02 to 1.23; P = 0.02).60 The rates of GI bleeding, super infections, and neuromuscular weakness were similar.

Images The results of these meta-analyses are heavily driven by data supplied by two, somewhat discordant, studies.61,62 The first randomized 300 patients with septic shock within 8 hours of hypotension to placebo or a daily combination of hydrocortisone 50 mg IV every 6 hours and fludrocortisone 0.05 mg enterally for 7 days.61 Similar to the meta-analyses, use of hydrocortisone reduced 28-day mortality (OR, 0.65; 95% CI: 0.39 to 1.07; P = 0.09), but all the benefit was seen in patients with adrenal insufficiency (OR, 0.54; 95% CI: 0.31 to 0.97; P = 0.04). The placebo group was more likely to continually require vasopressor therapy (HR, 1.54; 95% CI: 1.10 to 12.16; P = 0.01), but differences between groups were exhibited only in patients with adrenal insufficiency (HR, 1.91; 95% CI: 1.29 to 2.84; P = 0.001). Approximately 77% of patients were deemed adrenally insufficient. The second study randomized 499 of 800 intended subjects with severe sepsis or shock within 72 hours of presentation to placebo or hydrocortisone 50 mg IV every 6 hours for 5 days followed by a 6-day taper.62 Mortality rates were similar between groups (32% vs. 34%), irrespective of adrenal function. Median time to shock reversal was shorter in patients receiving corticosteroid therapy (3.3 vs. 5.8 days; P < 0.001), again irrespective of adrenal function. Reversal of organ dysfunction was also expedited with corticosteroid therapy. Unlike the previous study, however, only 47% of patients demonstrated adrenal insufficiency likely reflective of the entry criteria and lower overall mortality rate of the study population.


Clinical Controversy…

Corticosteroid therapy

Current guidelines do not suggest assessing adrenal function to determine the need for corticosteroid therapy.6 Instead, they recommend initiating corticosteroids when hemodynamic goals are not achieved with fluid resuscitation or vasopressor therapy. This is controversial given the limitations and differences between studies and the difficulty of determining the adequate achievement of hemodynamic goals in patients requiring vasopressor therapy.

Images A post hoc analysis of the large vasopressin study revealed a significant interaction between vasopressin and corticosteroids.77 In patients receiving vasopressin therapy, concurrent corticosteroid administration increased vasopressin concentrations by 33% to 67% over the initial 24 hours compared with patients only receiving vasopressin. The addition of corticosteroids to vasopressin was associated with reduced mortality compared with concurrent administration of corticosteroids and norepinephrine (35.9% vs. 44.7%; P = 0.03). In the absence of corticosteroid therapy, however, mortality was greater with vasopressin therapy compared with norepinephrine (33.7% vs. 21.3%; P= 0.06). Similar results were reported in a retrospective, matched assessment that found lower 7-day mortality was associated with combination therapy compared with vasopressin alone (19.1% vs. 52.4%; P = 0.02).78 This interaction warrants further investigation in studies.

Hemodynamic Considerations and Adverse Effects

Images Images Images Images Images Catecholamine vasopressors may result in adverse peripheral vasoconstrictive, metabolic, and dysrhythmogenic effects that limit or outweigh their positive effects on the central circulation.615,52,53 Table 13-4lists potential adverse effects of commonly used vasopressors and inotropes.615,52,53 Excessive peripheral vasoconstriction may cause ischemia or necrosis of already poorly perfused tissues such as the skin and the mesenteric and splanchnic circulations. Some of these profound vasoconstrictive effects have been compounded by the concurrent use of other vasopressor agents in patients with septic shock who are significantly hypovolemic. These agents may be used in the context of late septic shock, where hypotension is refractory to less selective vasoconstrictors (e.g., dopamine) such that very large doses of norepinephrine or epinephrine or phenylephrine are required but provide little or no benefit. Myocardial ischemia and dysrhythmias may occur in patients with coronary artery disease, atherosclerosis, cardiomyopathies, left ventricular hypertrophy, congestive heart failure, or underlying dysrhythmias because of their inability to tolerate β1 cardiac stimulation that mediates increases in CO. However, the effect usually is opposite in healthy myocardium and in young patients. β1 cardiac stimulation is well tolerated, ventricular filling pressures decrease, and CO and DO2 increase, with a resulting increase in peripheral perfusion. The dysrhythmogenic potential of the catecholamine vasopressors includes a variety of resulting atrial and ventricular arrhythmias. Norepinephrine, phenylephrine, and especially epinephrine can produce lactic acidosis secondary to excessive constriction in peripheral arterioles or enhanced glycogenolysis, or as a result of mobilization of lactate from peripheral tissues as a result of improved oxygenation. Sympathomimetic vasopressors also have been found to possess immunomodulatory actions, primarily mediated by β2-adrenergic actions (e.g., epinephrine) because almost all immune cells express this receptor. The actions include down regulating the expression of proinflammatory cytokines such as TNF-α by neutrophils, suppression of oxygen free radical production from neutrophils, and direct proapoptotic effects. Dopamine suppresses prolactin secretion from the anterior pituitary gland, which may lead to reduced T-cell responsiveness. These effects may be either beneficial or deleterious by dampening harmful effects of oxygen free radical-mediated tissue injury or by reducing neutrophilic defense against bacteria.

Vasopressor catecholamines have the potential to cause extravasation-associated tissue damage if infusions infiltrate during peripheral administration. In the event of infiltration, an α-receptor antagonist such as phentolamine (10 mg in 10 mL saline) should be injected intradermally to reverse local vasoconstriction, with administration of vasopressor drugs into a large central vein.

Norepinephrine

ImagesImages Images Images Norepinephrine is the first-line therapy for septic shock as it effectively increases MAP.615,52,53,7376 It has combined strong α1-activity and less potent β1-agonist effects while maintaining weak vasodilatory effects of β2-receptor stimulation.619,49,50,6876 Several studies have demonstrated improved MAP and mortality in ICU patients with severe hypotension treated with norepinephrine either as first-line therapy or after therapeutic failure with fluid resuscitation treatment.63,7376

Norepinephrine infusions are initiated at 0.05 to 0.1 mcg/kg/min and rapidly titrated to preset goals of MAP (usually at least 65 mm Hg), improvement in peripheral perfusion (to restore urine production or decrease blood lactate), and/or achievement of desired oxygen-transport variables while not compromising the cardiac index. Norepinephrine 0.01 to 2 mcg/kg/min reliably and predictably improves hemodynamic parameters to “normal” values in most patients with septic shock. As with other vasopressors, norepinephrine dosages exceeding those recommended by most references frequently are needed in critically ill patients with septic shock to achieve predetermined goals. A significant increase in MAP generally is caused by an increase in SVR. Heart rate generally does not increase significantly with norepinephrine because of diminished stimulation of cardiac β1-receptors in septic shock and reflex bradycardia from increased SVR.615,52,53,7376 Increasing norepinephrine doses to maintain higher MAPs may increase heart rates, cardiac index, DO2, and cutaneous blood flow but these results are inconsistent. Older patients may benefit from the combined α- and β-adrenergic effects of norepinephrine given the higher incidence of coronary disease and compromised ventricles in this patient population. By virtue of restored MAP and hence coronary perfusion, cardiac index is increased in older patients, whereas in younger patients with less coronary artery disease and a higher cardiac index at baseline, norepinephrine acts primarily as a vasopressor. Norepinephrine does not influence PAOP.

The effect of norepinephrine on oxygen transport parameters is variable and depends on baseline values and concurrently administered vasoactive agents. In most studies of norepinephrine alone, either an increase or no change in DO2 is seen with no change in O2ER, particularly when DO2 values were “supranormal” prior to therapy. Norepinephrine demonstrates either no effect or improvement in PCO2 gap, pHi, or serum lactate concentrations. Splanchnic blood flow and fractional blood flow are higher with norepinephrine than either dopamine or epinephrine despite higher CO with the two latter agents.

Taken together, these data suggest that norepinephrine should be the primary vasopressor of choice in patients in septic shock because of its multiple benefits: (a) norepinephrine may decrease mortality in septic shock; (b) it reverses inappropriate vasodilation and low global oxygen extraction; (c) it attenuates myocardial depression at unchanged or increased CO and increased coronary blood flow; (d) it improves renal perfusion pressure and renal filtration; (e) it enhances splanchnic perfusion; and (f) it is less likely than other vasopressors to cause tachycardias and tachydysrhythmias.615,52,53,7376 The primary limitation to use is that norepinephrine is not available as premixed ready-to-use solutions so use requires preparation time.

Phenylephrine

Images Images Images Images Despite its purported use in refractory septic shock, little information is available regarding the clinical efficacy of phenylephrine. Nevertheless, it is an attractive agent for use in sepsis because of its selective α-agonism with primarily vascular effects.615,52,53 As with other vasopressors, phenylephrine dosages required to achieve goals of therapy are significantly higher than dosages traditionally recommended for use.

Phenylephrine 0.5 to 9 mcg/kg/min, used alone or in combination with dobutamine or low doses of dopamine, improves blood pressure and myocardial performance in fluid-resuscitated septic patients. Incremental doses of phenylephrine result in linear dose-related increases in MAP, SVR, heart rate, and stroke index when administered alone as a single agent in stable, nonhypotensive but hyperdynamic, volume-resuscitated surgical ICU patients. In septic shock, phenylephrine does not impair the cardiac index, PAOP, or peripheral perfusion. In sepsis, phenylephrine improves MAP by increasing the cardiac index through enhanced venous return to the heart (increase in CVP and stroke index) and by acting as a positive inotrope. It improves myocardial performance in hyperdynamic, normotensive septic patients but worsens myocardial performance in cardiac controls. In cardiac patients, myocardial performance worsens as a result of a decrease in the cardiac index and an increase in SVR. Therefore, phenylephrine use warrants caution in septic shock patients with impaired myocardial performance.

In septic shock, phenylephrine appears to increase global tissue oxygen use, although data regarding the relationship of the oxygen-transport variables with increases in MAP and cardiac index are conflicting. Increases in VO2appear to be dissociated from DO2, representing an increase in O2ER as the cardiac index remains unchanged. Increases in VO2 may result from redistribution of blood flow to previously underperfused areas, improving oxygen use as a result of changes in MAP and SVR. Evidence of globally improved peripheral tissue perfusion is observed as lactic acid concentration declines or remains unchanged and urine production increases significantly at increased or maximal VO2. An increased O2ER may contribute to improved tissue response.

Few data regarding the effect of phenylephrine on regional hemodynamics and oxygen-transport variables are available. When phenylephrine replaced norepinephrine in patients with septic shock, phenylephrine selectively reduced splanchnic blood flow and thus splanchnic DO2 and splanchnic lactate uptake rate without changing the overall splanchnic VO2. Concomitantly, pHi decreased and arterial lactate concentrations increased. Because all of these parameters normalized when norepinephrine was reinstated, these data suggest that exogenous β-adrenergic stimulation (norepinephrine) may determine hepatosplanchnic perfusion and oxygen availability but not utilization in septic shock. Phenylephrine and norepinephrine demonstrate similar hemodynamic profiles and indices of global and regional perfusion.615

The available data on hemodynamics, oxygen-transport variables, and mortality with phenylephrine in septic shock patients may not be generalizable because of the small numbers of patients evaluated. Adverse effects, such as tachydysrhythmias, are notably infrequent with phenylephrine, particularly when it is used as a single agent or at higher doses, because phenylephrine does not exert any activity on β1-adrenergic receptors. Whether the beneficial effects can be sustained with longer administrations of phenylephrine is unclear. Phenylephrine may be a particularly useful alternative in patients who cannot tolerate tachycardia or tachydysrhythmias with use of dopamine or norepinephrine and in patients who are refractory to dopamine or norepinephrine (because of β-adrenergic receptor desensitization).6 Its use in patients with myocardial dysfunction warrants further investigation. Like norepinephrine, it is not available as premixed ready-to-use solutions.

Epinephrine

Images Images Images Images Epinephrine is an acceptable choice for hemodynamic support of septic shock because of its combined vasoconstrictor and inotropic effects but it is associated with tachydysrhythmias and lactate elevation.75,76 As a result, it is considered an alternative agent.6 It is as effective as norepinephrine for blood pressure control. Epinephrine infusion rates of 0.04 to 1 mcg/kg/min alone increase hemodynamic and oxygen-transport variables to “supranormal” values without adverse effects in septic patients without coronary artery disease. Large dosages (0.5 to 3 mcg/kg/min) often are required. Smaller dosages (0.10 to 0.50 mcg/kg/min) are effective when epinephrine is added to other vasopressors and inotropes. In addition, younger patients appear to respond better to epinephrine, possibly due to greater β-adrenergic reactivity.

Despite a linear dose–response curve with rapid improvement of hemodynamic variables and DO2, epinephrine has deleterious effects on regional hemodynamics and oxygen utilization. Although DO2increases mainly as a function of increases in the cardiac index and a more variable increase in SVR, VO2 may not increase, and O2ER may fall. A fall in pHi may be seen during epinephrine administration but the impairment in gastric mucosal perfusion can be counteracted in part by dobutamine. This may be explained by the vasodilatory effect of dobutamine on gastric mucosal microcirculation resulting in a redistribution of blood flow toward the mucosa. In contrast to other vasopressors, lactate concentrations frequently rise during epinephrine therapy resulting in variable arterial pH values. When compared with a combination of norepinephrine and dobutamine, epinephrine preferentially decreases splanchnic DO2, worsens pHi, and increases systemic lactate concentration without increasing VO2. The effects of epinephrine on absolute and fractional splanchnic blood flow are more pronounced during severe shock. The increase in lactate may be a result of worsened DO2 to the liver (and subsequent anaerobic metabolism) or to the hepatosplanchnic circulation, a direct increase in calorigenesis and breakdown of glycogen, or lactate mobilization. However, evidence suggests that epinephrine, in contrast to dopamine, increases the proportion of total CO delivered to the splanchnic circulation, although VO2 is not increased sufficiently. As a result, O2ER values are usually lower with epinephrine than with other vasopressors but the concomitant administration of dobutamine helps maintain O2ER. Of all the vasopressors, epinephrine exhibits the most pronounced capacity to induce hyperglycemia by increased gluconeogenesis and glycogenolysis with α-mediated suppression of insulin secretion.52,53

Despite the administration of high doses, epinephrine-associated clinically important dysrhythmias or cardiac ischemia occur at variable rates irrespective of age or underlying cardiac status.615,52,53,75,76Nevertheless, caution must be exercised before considering epinephrine for managing hypoperfusion in hypodynamic patients with coronary artery disease, in whom ischemia, chest pain, or myocardial infarction may result. Based on the current evidence, epinephrine should not be used as initial therapy in patients with septic shock refractory to fluid administration.6 Although it effectively increases CO and DO2, it has deleterious effects on the splanchnic circulation. If it is used as a second-line agent in septic shock, factors that may influence successful therapy with epinephrine include the time from onset of septic shock to effective therapy, the age of the population, and the selection of concurrent vasopressors and inotropes. Like norepinephrine and phenylephrine, it is not available as premixed ready-to-use solutions.

Dopamine

Images Images Images Images Dopamine is a natural precursor to norepinephrine and epinephrine and generally not as effective as these two agents for achieving goal MAP in patients with septic shock.615,52,53,73,74Most studies of patients with septic shock have shown that dopamine at dosages of 5 to 10 mcg/kg/min increase the cardiac index by improving contractility and heart rate, primarily from its β1 effects. It increases MAP and SVR as a result of both increased CO and, at higher doses (>10 mcg/kg/min), its α1 effects.

The clinical utility of dopamine as a vasopressor in the setting of septic shock is limited because large dosages are frequently necessary to maintain CO and MAP. At dosages exceeding 20 mcg/kg/min, further improvement in cardiac performance and regional hemodynamics is limited. Its clinical use frequently is hampered by tachycardia and tachydysrhythmias, which may lead to myocardial ischemia. Although tachydysrhythmias theoretically should not be expected to occur until administration of dopamine 5 to 10 mcg/kg/min, these β1 effects are observed with dosages as low as 3 mcg/kg/min. They seem to be more prevalent in patients who are inadequately resuscitated (hypovolemic), in the elderly, in those with preexisting or concurrent cardiac ischemia or dysrhythmias, and in patients currently receiving other dysrhythmogenic agents, including vasopressors and inotropes.

Dopamine increases PAOP and pulmonary shunting to decrease PaO2. The increase in PAOP may be due to changes in diastolic volumes from decreased cardiac compliance or increased venous return to the heart by α-adrenergic receptor-mediated venoconstriction. This may affect gas exchange and decrease PaO2. The increase in pulmonary shunting also may result from acute enhancement of pulmonary blood flow to nonhomogeneous lung regions. Thus, dopamine should be used with caution in patients with elevated preload because the drug may worsen pulmonary edema. In the instance of high filling pressures, tachycardia, or tachydysrhythmias, dopamine should be replaced by another vasopressor and/or inotrope such as norepinephrine, dobutamine, phenylephrine, or epinephrine, depending on the desired effect.

The effect of dopamine on global oxygen-transport variables parallels the hemodynamic effects. Although dopamine improves global DO2 in septic patients, it may compromise O2ER in the splanchnic and mesenteric circulations by α1-mediated vasoconstriction. Splanchnic blood flow and DO2 increase with dopamine, but with no preferential increase in splanchnic perfusion as a fraction of CO and systemic increases in DO2. Large doses of dopamine worsen pHi and the PCO2 gap. This is reflected by a decrease or lack of change in regional VO2 and a decrease in tissue O2ER. Dopamine at low or vasopressor dosages directly impedes gastric motility in critical illness and may aggravate gut ischemia in septic shock. Similar to high-dose administration, low-dose dopamine increases splanchnic blood flow but lowers splanchnic VO2 in sepsis. Therefore, dopamine at all dosages impairs hepatosplanchnic metabolism despite an increase in regional perfusion. Low dosages increase renal blood flow and glomerular filtration rate in studies of animals and healthy volunteers but did not demonstrate improved renal function in a randomized, placebo-controlled study of 328 critically ill patients with early renal dysfunction.79 A meta-analysis of 61 trials (N = 3359) confirmed that low-dose dopamine fails to enhance renal function or survival in critically ill patients.80

While dopamine may improve hemodynamic function, the use of dopamine for septic shock is questionable because regional hemodynamics, oxygen-transport variables, and functional parameters of improved organ perfusion are not consistently enhanced in a sustained manner and may be negatively impaired.6 The negative findings of low-dose dopamine use and the deleterious effects of inotropic and vasopressor dosages of dopamine on regional hemodynamics, oxygen transport, and functional performance of organ perfusion raise concern over whether dopamine should be considered in patients with severe sepsis or septic shock.6,79 Unlike other vasopressor agents, however, dopamine is available as premixed ready-to-use solutions of various concentrations that can be stored in automated dispensing systems for rapid initiation.

Dobutamine

Images Images Images Images Dobutamine is an inotrope with vasodilatory properties (an “inodilator”).615,52,53 It is used for treatment of septic and cardiogenic shock to increase the cardiac index, typically by 25% to 50%.6 In septic shock, LVEF and right ventricular function are depressed despite a high cardiac index, whereas ventricular volumes and compliance are increased. Stroke index is maintained by an increased heart rate and ventricular dilation. In survivors, myocardial depression is reversible and normalizes 5 to 10 days after the onset of sepsis. Dobutamine increases stroke index, left ventricular stroke work index, and thus cardiac index and DO2 without increasing PAOP.615 The ability of dobutamine to enhance cardiac index and DO2 during septic shock appears to be related to its chronotropic effect. However, dosage increments of dobutamine beyond 20 mcg/kg/min are limited by complications of tachycardia, ischemic changes on electrocardiogram, hypertension, and tachydysrhythmias despite the absence of preexisting cardiac abnormalities. The combination of dobutamine and norepinephrine results in a lower increase in heart rate compared with use of other vasopressors alone.

Increased cardiac performance measures in response to adjunctive dobutamine therapy are predictive of survival during sepsis. However, the achievement of supranormal oxygen transport values with dobutamine is of little value compared with treatment to normal values. In addition, administration of dobutamine to achieve these high values may increase the mortality rate and/or the incidence of adverse effects. Dobutamine increases DO2 without affecting VO2, resulting in decreased O2ER. Arterial lactate concentrations decrease significantly with norepinephrine and dobutamine compared with dopamine and epinephrine infusions.

Studies have focused on the effects of dobutamine on gastric mucosal flow and the splanchnic circulation. The addition of dobutamine to other vasopressors improves gastric mucosal perfusion without increasing the cardiac index. This is consistent with findings that dobutamine may improve pHi and mucosal perfusion in septic patients. The addition of dobutamine to norepinephrine or epinephrine treatment improves gastric mucosal perfusion as measured by improvements in pHi and PCO2 gap. This effect may relate to blood flow redistribution toward gastric mucosa, due to either an increase in the fraction of CO distributed to the global hepatosplanchnic blood flow and/or a redistribution of blood flow within gastric wall layers toward the mucosa by “stealing” blood away from the muscularis potentially as a result of greater β2-mediated vasodilation. Sublingual microcirculation improves after dobutamine is added to vasopressor-dependent septic shock patients in a manner unrelated to arterial pressure or cardiac index, suggesting that enhanced perfusion is the result of the “steal” phenomenon. Of note, gastric mucosal perfusion and tissue oxygen utilization are most improved with concurrent norepinephrine and dobutamine therapies compared with other vasopressor combinations at the same level of MAP.

Dobutamine should be started at dosages ranging from 2.5 to 5 mcg/kg/min. In the study of early goal-directed therapy, dobutamine was administered to 13.7% of patients within 6 hours of resuscitation to achieve SCVO2 ≥70%.32Although a dose response may be seen, evidence now suggests that dosages >5 mcg/kg/min may provide limited beneficial effects on oxygen transport values and hemodynamics and may increase adverse cardiac effects. If given to patients who are intravascularly depleted, dobutamine will result in hypotension and a reflexive tachycardia. Pathophysiologic factors influence dosing requirements and pharmacokinetic parameters over the time course of the illness and the duration of the infusion. Decreases in PaO2, as well as myocardial adverse effects such as tachycardia, ischemic changes on electrocardiogram, tachydysrhythmias, and hypotension are seen. Thus, infusion rates should be guided by clinical end points and SVO2/SCVO2 or lactate clearance. Dobutamine, like other inotropes, usually is given until improvement in myocardial function with resolution of the septic episode or dose-limiting side effects are observed. Dobutamine is available as premixed ready-to-use solutions.

Vasopressin

Images Studies involving vasopressin infusion for management of septic shock show rapid and sustained improvement in hemodynamic parameters.54,65,66 These effects are evident with administration of dosages not exceeding 0.04 units/min. Administration of dosages >0.04 units/min are associated with negative changes in CO and mesenteric mucosal perfusion. The reduction in CO likely is the result of lowered stroke volume.54 The studies that reported cardiac function indicate patients had adequate CO prior to initiating vasopressin therapy. Therefore, vasopressin use in septic shock patients with cardiac dysfunction warrants extreme caution. Cardiac ischemia appears to be a rare occurrence and may be related to administration of dosages ≥0.05 units/min.

Mesenteric ischemia associated with vasopressin may be clinically relevant. Increased hepatic transaminases and total bilirubin concentrations may occur with vasopressin therapy, suggesting impaired hepatic blood flow or a direct effect on excretory hepatic function.54 Most studies have found that vasopressin at dosages of 0.04 to 1.8 units/min worsen pHi or PCO2 gap when it is added to low or high doses of catecholamine vasopressors.54 Mesenteric mucosal hypoperfusion may be expected with vasopressin because mesenteric vasoconstriction occurs at vasopressin serum concentrations as low as 10 pg/dL, and the effect is dose dependent. Of concern is the additive effective with norepinephrine despite substantially reduced dosages of norepinephrine when vasopressin is initiated. Although controversial, the degree of hypoperfusion with vasopressin may be greater than with norepinephrine alone unless the dose of norepinephrine is markedly increased to maintain adequate arterial blood pressure.

Vasopressin’s strongest vasoconstrictive action occurs in the skin and soft tissues, skeletal muscles, and fat tissues.54 As a result, ischemic skin lesions have been observed in several studies, with an occurrence rate as high as 30% after vasopressin was added to norepinephrine-resistant shock.54,60 Although vasopressin may have deleterious effects on mesenteric and skin perfusion, studies report vasodilation of cerebral, pulmonary, coronary, and some renal vasculature beds. The clinical outcomes associated with selective vasodilation are not yet determined except for the possibility of enhanced urine production in patients not anuric at baseline.67

In order to minimize the potential for adverse events and maximize the beneficial effects, vasopressin should be used as add-on therapy to one or two catecholamine adrenergic agents rather than as first-line therapy or salvage therapy and dosages should be limited to 0.04 units/min.6,54 The results of studies showed that vasopressin markedly reduced the requirements for adrenergic agents, but few studies demonstrated complete discontinuation of these therapies.54,65,66 Therefore, vasopressin should be used only if response to one or two adrenergic agents is inadequate or as a method for reducing the dosage of these therapies.6 Increased arterial pressure should be evident within the first hour of vasopressin therapy, at which time the dose(s) of adrenergic agent(s) should be reduced while maintaining goal MAP. This method should help limit the degree of ischemia.

Most studies evaluated vasopressin use for <48 hours, and several studies reported difficulty discontinuing vasopressin therapy. Whether additional benefits, deleterious effects, or tolerance is observed with longer infusions remains unclear. Long-term administration of vasopressin is associated with hyponatremia and thrombocytopenia. Because vasopressin is being used to replace a physiologic deficiency, it stands to reason that the requirement for vasopressin will subside with reversal of the septic process. Attempts to discontinue vasopressin should occur when the dosage(s) of adrenergic agent(s) has been minimized (e.g., dopamine ≤5 mcg/kg/min, norepinephrine ≤0.1 mcg/kg/min, phenylephrine ≤1 mcg/kg/min, and epinephrine ≤0.15 mcg/kg/min). At present, vasopressin should not be initiated as first-line therapy or added to existing therapy solely because a patient is septic. Vasopressin is not available as premixed ready-to-use solutions.

Corticosteroids

Images Corticosteroids can be initiated in cases of septic shock when adrenal insufficiency is suspected (e.g., patients receiving long-term corticosteroid therapy for other indications prior to the onset of shock), when vasopressor dosages are escalating, or when weaning of vasopressor therapy proves futile.5562 Assessment of adrenal function to guide therapy is no longer recommended.6 Adverse events are few because corticosteroids are administered for a finite period of time, usually 7 days. Acutely, elevated serum concentrations of blood urea nitrogen, white blood cell count, and glucose occur. Although long-term administration of corticosteroids is associated with several chronic disease states, meta-analyses do not show an increase in adverse events, including GI hemorrhage (RR, 1.12; 95% CI: 0.81 to 1.53; P = 0.5), superinfections (RR, 1.01; 95% CI: 0.82 to 1.25; P = 0.92), and neuromuscular weakness (RR, 0.63; 95% CI: 0.12 to 3.35; P = 0.58).59,60 Hyperglycemia (RR, 1.16; 95% CI: 1.07 to 1.25; P < 0.001) and hypernatremia (RR, 1.61; 95% CI: 1.26 to 2.06; P < 0.001) are associated with corticosteroid therapy.59,60 Therefore, therapy of septic shock with corticosteroids improves hemodynamic variables and lowers catecholamine vasopressor dosages with minimal to no effect on patient safety.6

EXPERIMENTAL THERAPIES

Nitric Oxide Inhibitors

NO is a short-acting, potent vasodilator derived from enzymatic oxidation of arginine. Its production is under control of NOS. This enzyme is present (expressed) in two forms: a constitutive form (constitutive nitric oxide synthase [ecNOS]) and an inducible form (iNOS). Small amounts of NO normally are produced by the vascular endothelium under the control of ecNOS for physiologic control of vascular tone and blood flow distribution. Under pathophysiologic conditions such as stimulation by lipopolysaccharide or cytokines, iNOS becomes diffusely expressed, producing large amounts of NO. The latter has been implicated in the cardiovascular failure of septic shock.

Pharmacologic inhibition of NO production has been investigated as an adjunct to standard therapies of septic shock.81 L-Arginine analogs such as monomethyl-L-arginine (L-NMMA) and L-arginine-methylester (L-NAME) are competitive inhibitors of NOS and have been shown to increase blood pressure, partially restore vascular reactivity, and reduce vasopressor use.11 However, because these arginine analogs nonselectively block ecNOS and iNOS, their use has been associated with extensive vasoconstriction, decreased CO, and regional hypoperfusion, thus promoting organ failure and mortality.82 Some S-substituted thiourea derivatives have demonstrated, both in vitro and in vivo (rodent), dose-dependent selectivity for iNOS inhibition, but the clinical application must be evaluated. Several phase I/IIa clinical trials of septic shock patients are underway.

Pyridoxalated hemoglobin polyoxyethylene is a scavenger of NO. A phase II study of 62 patients with vasodilatory shock requiring vasopressors showed that an infusion of 20 mg/kg/h for up to 100 hours rapidly increases blood pressure and shortens the duration of vasopressor therapy.83 Additional studies are needed.

Methylene Blue

Methylene blue counteracts ecNOS, iNOS, and soluble guanylate cyclase to reduce serum concentrations of NO and cyclic guanosine monophosphate.84 Despite these effects, methylene blue does not alter the expression of inflammatory cytokines. Clinically, methylene blue at dosages of 0.25 to 3 mg/kg/h increases SVR, MAP, myocardial contractility, and DO2 in septic shock patients refractory to vasopressors while improving PCO2 gap.84 Dosages exceeding 3 mg/kg/h worsen splanchnic perfusion. It may increase pulmonary vascular resistance, potentially worsening oxygenation. Additional studies are needed before methylene blue can be recommended; at present, it has been used only for salvage therapy.

Terlipressin

Terlipressin, a prodrug that is converted into lysine vasopressin, has been used in septic shock patients and is available in other countries.66,85 This drug has a half-life of 6 hours and acts via vascular V1receptors and renal tubular V2receptors. Terlipressin increases MAP to a greater extent than norepinephrine when it is used as the initial vasopressor in septic shock. Despite a decrease in CO, heart rate, and DO2I, terlipressin increases gastric mesenteric perfusion, urine production, and creatinine clearance while reducing lactate concentration. Both terlipressin and vasopressin increase blood pressure and decrease heart rate to the same extent but terlipressin is associated with less supplemental norepinephrine usage and improved mesenteric perfusion.66,85 These preliminary findings suggest that a clinical trial evaluating mortality as well as hemodynamic effects should be conducted.

Levosimendan

Levosimendan is a novel inotropic and vasodilator calcium-sensitizing drug.86 In acute decompensated heart failure, it improves cardiac contractility by sensitizing troponin C to calcium. In septic shock patients with and without left ventricular dysfunction, levosimendan 0.1 to 0.2 mcg/kg/min decreases PAOP, increases LVEF and cardiac index, improves mesenteric and sublingual perfusion, and enhances urine production.86 Levosimendan improves SCVO2 to the same extent as dobutamine when it is used in early goal-directed therapy. Levosimendan is associated with declining serum lactate concentrations. While additional clinical trials of levosimendan in septic shock are needed, increased mortality was demonstrated in studies of acute decompensated heart failure.

Dopexamine and Isoproterenol

Dopexamine is a structural and synthetic analog of dopamine that exerts systemic vasodilation through stimulation of β2-adrenoceptors and peripheral D1 and D2 receptors and weak inotropic properties through stimulation of β1-adrenoceptors.812,52,53 It has been used in patients with acute heart failure and septic shock. Similar to dobutamine, dopexamine is administered in combination with a vasopressor in septic shock. In small studies of septic shock, dopexamine produced a dose-related (range, 2 to 6 mcg/kg/min) increase in cardiac index, stroke volume, and heart rate, as well as a decrease in SVR over the course of 0.5 to 1 hour while the dosages of other vasopressors were kept constant. The increase in myocardial oxygen demand is less than with dopamine, but tachycardia and tachydysrhythmia may lead to myocardial ischemia, especially when ischemic heart disease is present. Global oxygen-transport variables are similar to those of dopamine: DO2 increases but VO2 increases insufficiently, resulting in impaired O2ER. The combined β2-adrenoceptors and peripheral D1 agonistic effects of dopexamine should improve distribution of blood flow. However, the results of studies of dopexamine use in septic shock failed to show preferential increase in splanchnic blood flow. In fact, gastric pHi was lowered. When administered over 7 days, dopexamine had no impact on renal function. Therefore, initial data do not support a role for dopexamine in improving regional hemodynamics and blood flow, but studies continue to investigate dopexamine as an alternative therapy for septic shock.

Isoproterenol is a synthetic catecholamine that stimulates only β1- and β2-adrenoceptors to produce vasodilatory and inotropic effects.87 Although not thought of as a traditional agent for managing septic shock, isoproterenol has received attention because of the concepts of early goal-directed therapy.32 The strong β-adrenergic effects of isoproterenol make it a potential alternative to dobutamine for optimizing DO2 in patients with low SVO2 despite use of other therapies (e.g., fluid resuscitation, vasopressors, red blood cell transfusion). In patients with septic shock and SVO2 <70% despite volume administration, norepinephrine, and red blood cell transfusion, adding isoproterenol increases SVO2, cardiac index, and stroke index while decreasing lactate concentration without increasing heart rate or causing myocardial ischemia. Although these results are intriguing, additional studies are needed to define the role of isoproterenol, especially considering that dobutamine has become standard therapy for early goal-directed therapy. At present, isoproterenol is an agent of last resort.

Other Therapies

As with vasopressin and cortisol, critical illness impairs hypothalamic–pituitary function, producing relative deficiencies of triiodothyronine (T3) and thyroxine (T4). This condition, referred to as euthyroid sick syndrome, may contribute to hypotension and mortality.88,89 Concentrations of thyrotropin-releasing hormone and thyroid-stimulating hormone are inappropriately low. Measured concentrations of free T3and T4 may be low or normal, but synthesis is consistently impaired. Only scant data regarding the replacement of these hormones in critically ill patients are available, and the results are variable, depending on the extent of additional hormone replacement (growth hormone, gonadotropin-releasing hormone, leptin, insulin, thyrotropin-releasing hormone, and thyroid-stimulating hormone). Given the data for replacing vasopressin and cortisol in septic shock, it is reasonable to assume that one day a “thyroid replacement” regimen will be offered as an adjunctive treatment to vasopressors.

GENERAL CONCLUSIONS AND RECOMMENDATIONS

Norepinephrine is the recommended first-line vasopressor for septic shock.6 The choice of additional vasopressor or inotropic agents should be made according to the clinical needs of the patient and the data obtained from hemodynamic and perfusion monitoring.615 Figure 13-2 presents an algorithm for the management of septic shock.615 This algorithm suggests a stepwise approach of early goal-directed therapy to optimize DO2, first with fluid resuscitation and using norepinephrine. Dobutamine is added for low CO states or to optimize SVO2/SCVO2 or lactate clearance. Occasionally, epinephrine and phenylephrine are used when necessary. Although this approach is empirical, it is used broadly in clinical practice and has been justified by the desire to avoid the adverse events associated with strong vasoconstriction. Developing a strategy to titrate therapy early in the course of illness to predetermined values reduces mortality. Goals of initial resuscitation should include fluids to achieve CVP 8 to 12 mm Hg, vasopressor agents to achieve MAP at least 65 mm Hg, red blood cell transfusion to maintain hematocrit ≥30%, and inotropic therapy to achieve SCVO2 ≥70% or lactate clearance ≥20%.6,32 For all catecholamine vasopressors, doses higher than recommended traditionally are required for goal-directed therapy to MAP and for normalization of oxygen-transport variables. Patients who develop supranormal DO2 and VO2 values have lower mortality, but whether this effect is achieved intrinsically or with exogenous administration of vasopressors/inotropes appears inconsequential. Therefore, goal-directed therapy to supranormal oxygen-transport variables cannot be recommended because little or no benefit has been demonstrated. Further work is required to better elucidate the differential effects of vasopressors on regional hemodynamic and oxygen-transport values as measures of local tissue perfusion.

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FIGURE 13-2 Algorithmic approach to resuscitative management of septic shock. The algorithmic approach is intended to be used in conjunction with clinical judgment, hemodynamic monitoring parameters, and therapy end points, as discussed in the text. (CI, cardiac index; CVP, central venous pressure; echo, echocardiography; Hct, hematocrit; MAP, mean arterial pressure; PAOP, pulmonary artery occlusive pressure; SCVO2, central venous oxygen saturation; SVO2, mixed venous oxygen saturation.) (Figure based on data from references 6–15.)

This algorithmic approach (Fig. 13-2) is consistent with the recommendations made in the Surviving Sepsis Campaign6 and the American College of Critical Care Medicine’s guidelines to the hemodynamic support of adult patients with sepsis (Table 13-2).7 Personalized pharmacotherapy (Table 13-5) for hemodynamic support of shock may be rationale in certain situations but it is difficult to achieve because patient response is variable and the acute nature of emergent resuscitation often necessitates treatment before pharmacotherapy can be personalized. Although difficult to demonstrate, true differences in clinical outcomes as a result of differences in the pharmacologic activity of vasopressors and inotropes may exist. For example, evidence suggests that norepinephrine, when used appropriately with fluid replenishment, is safe and effective in treating septic shock; it decreases mortality, particularly when started early in the course of septic shock. It is effective in optimizing hemodynamic variables and improving systemic and regional (e.g., renal, gastric mucosal, and splanchnic) perfusion. Epinephrine causes a greater increase in the cardiac index and DO2 and increases gastric mucosal flow but may not preserve splanchnic circulation adequately. It may cause increases in lactic acid. Epinephrine may be particularly useful when used earlier in the course of septic shock in young patients. Unlike epinephrine, dopamine does not increase the proportion of CO that preferentially goes to the splanchnic circulation. The ability of dopamine to increase CO by not more than 35% accompanied by a tachycardia or tachydysrhythmias limits its utility. Dopamine, as opposed to norepinephrine, has been shown to worsen splanchnic VO2 and O2ER and is of limited value in improving urine production. The only benefit of dopamine is that it is readily available as a premixed solution. Low-dose dopamine has not been shown consistently to increase the glomerular filtration rate, does not prevent renal failure, and actually worsens splanchnic tissue oxygen utilization. Low-dose dopamine should not be used. Phenylephrine should be used when a pure vasoconstrictor is desired in patients who may not require or cannot tolerate the β-effects of other vasopressors or inotropes. In patients with a high filling pressure and hypotension, the combination of phenylephrine and dobutamine may be useful.

TABLE 13-5 Personalized Pharmacotherapy for Shock

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Shortcomings of study methodology prevent the establishment of definitive conclusions. As a consequence, published guidelines for the management of severe sepsis and septic shock have many inconclusive recommendations (Table 13-2). Short infusions during studies may show differences that are not clinically significant after 24 hours, as demonstrated for epinephrine and dobutamine. Most studies comparatively evaluated vasopressors once patients were hemodynamically stable as the process of obtaining consent and randomization precluded the initiation of study drug during early resuscitation. Clinically, vasopressors and inotropes are used for hours to days. Possible confounding factors are the variable times at which studies are initiated with respect to the stage of sepsis or septic shock, the inherent differences in circulating catecholamine concentrations, changes in receptor activity, as well as differences in prestudy duration and type of exogenous catecholamine administration.

Initial studies with vasopressin suggest a potential role in the management of vasopressor-dependent septic shock patients. Vasopressin reduces the requirements of adrenergic agents while maintaining hemodynamic function. While it may enhance urine production, it is associated with mesenteric and peripheral ischemia. Therefore, vasopressin should be used only if response to one or two adrenergic agents is inadequate or as a method for reducing the dosage of these therapies. Close monitoring of ischemic events is needed. Data indicate that moderate doses of hydrocortisone (200 to 300 mg/day) administered over several days may reverse septic shock and dependency on vasopressor agents. Given the discrepancy of the current data, corticosteroids may be administered to patients with septic shock refractory to vasopressors or when adrenal insufficiency is suspected. Data on optimal dosage regimens and definitive outcomes still are needed.

Further pharmacotherapeutic and outcome studies are required to elucidate the place in therapy of individual vasopressors and inotropes or their combinations in the supportive care of patients with bacteremia or septic shock. As supportive therapy, it is imperative that primary therapy aimed at the source of (antimicrobials) and consequences of (anticytokines) infection be initiated quickly to afford the patient the best chance of survival. Once this goal is accomplished, we will need to direct our efforts to pharmacoeconomics and the cost-effectiveness of these therapies.

ABBREVIATIONS

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