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Our patient has several signs suggesting sepsis-induced tissue hypoperfusion (high lactate level, hypotension, tachycardia). Early and aggressive hemodynamic optimization is indicated to decrease the progression of organ failure and improve overall outcome. The hemodynamic profile of severe sepsis and septic shock is characterized by components of hypovolemic, cardiogenic, and distributive shock.21 Early in sepsis, increased capillary leak and increased venous capacitance will result in effective hypovolemia with decreased venous return to the heart and a depressed cardiac output. Administration of intravascular fluids can alter this early phase of sepsis. The importance of early intervention in patients with sepsis-induced tissue hypoperfusion has been highlighted by the results of an early goal-directed therapy (EGDT) clinical trial by Rivers et al.22 In this study patients with sepsis-induced hypoperfusion (lactate > 4 mmol/L and/or hypotension after fluids) were randomized to receive either standard resuscitation or an EGDT protocol during the first 6 hours of admission to the emergency department. In both groups end points of resuscitation included central venous pressure (CVP) greater than or equal to 8 to 12 mm Hg, mean arterial pressure (MAP) greater than or equal to 65 mm Hg, and urine output greater than or equal to 0.5 mL/kg per hour. In order to achieve these goals patients were treated with intravenous crystalloids and vasopressors. The EGDT group had as an additional end point an ScvO2 greater than or equal to 70%, which was continuously measured from a subclavian or jugular central venous catheter. ScvO2 was used as an index for oxygen delivery. If ScvO2 was less than 70% after reaching targets for CVP and MAP, patients received packed red blood cells for a hematocrit ≥ 30, or dobutamine infusion for a hematocrit was ≥ 30. Patients in the EGDT group received more fluids, dobutamine, and transfusions in the first 24 hours. In-hospital mortality rate was significantly lower in the EGDT group when compared to the standard therapy group (30.5% versus 46.5%, respectively; P = .009). Although the specific merits of each treatment within the EGDT protocol can be discussed, the results of this study strongly support early intervention with predefined hemodynamic settings and protocolized care. A recent study showed that within the context of early goal-directed resuscitation for severe sepsis/septic shock, an end point of lactate clearance (decrease in lactate ≥ 10% over first 6 hours) was noninferior to management targeting ScvO2.23 The Surviving Sepsis Campaign's recommendations for the Sepsis Resuscitation Bundle are based on the Rivers study and others that have shown the benefits of early intervention with predefined goals.22, 24, 25, 26
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The initial step in optimizing hemodynamics in our patient should be aggressive fluid resuscitation. Although experts agree on the value of early and aggressive volume replacement, controversy persists over the optimal type of fluid. This debate revolves around the use of crystalloids (saline, Ringer lactate) versus colloids (albumin, hydroxyethyl starches). Meta-analyses of clinical studies performed in general critical care populations have demonstrated no difference in outcomes between patients treated with crystalloids and those treated with colloids.27, 28, 29 The Saline versus Albumin Fluid Evaluation (SAFE) study prospectively randomized 7000 critically ill patients to receive 4% albumin or 0.9% saline for fluid resuscitation.30 There were no significant differences between groups in mortality and other secondary outcomes. A subgroup analysis conducted in patients with sepsis revealed a trend toward improved outcomes in patients treated with albumin, although this difference did not achieve statistical significance. We believe that achieving end points of resuscitation is more important than the type of fluid utilized. In North America consideration for cost differences has made crystalloids the fluid of choice for resuscitating patients with severe sepsis. How much fluid should be given? Patients with severe sepsis may present with significant intravascular volume depletion. Aggressive fluid boluses are usually required to restore tissue perfusion. An initial bolus of at least 20 mL/kg of crystalloid (or colloid equivalent) is currently recommended.8 This may be supplemented with more fluids in repeated boluses of 300 to 500 mL based on markers of perfusion.8, 31 Current guidelines recommend a target CVP greater than or equal to 8 to 12 mm Hg as an initial end point for volume resuscitation during the first 6 hours of treatment.8, 31 After the initial hours of treatment, determining the need for further fluid administration may be challenging. Although CVP has been used for many years, static parameters (such as CVP) have been shown to be poor surrogates for volume responsiveness. Ideally, dynamic measures such as those measured by arterial pulse pressure variation, changes in stroke volume/cardiac output, or echocardiography should be utilized in addition to initial CVP measurements.
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Septic shock is defined by hypotension refractory to fluid resuscitation. If after administration of fluids a patient with severe sepsis remains hypotensive, vasopressors targeted at raising the MAP should be initiated. Catecholamines such as dopamine, epinephrine, norepinephrine, and phenylephrine have traditionally been used to raise blood pressure in patients with septic shock (Table 47-4). The vasopressor of choice for septic shock is still an unresolved discussion, mostly because of the lack of convincing clinical data showing improved mortality rate with a specific agent. Additional considerations include agent-specific effects, individual patient characteristics, and effects on regional vascular beds (eg, splanchnic and renal circulations).32 Dopamine and epinephrine are more likely to cause or exacerbate tachycardia than norepinephrine and phenylephrine. Dopamine, epinephrine, and norepinephrine will increase cardiac output via stimulation of β-adrenergic receptors. Phenylephrine is a pure α-receptor antagonist, and its vasoconstricting effects can be associated with a drop in cardiac index. With regards to effects of individual vasopressors on regional vascular beds, it is important to emphasize that there is no renal protection provided by "low-dose" dopamine. Studies have shown that low-dose dopamine targeting stimulation of dopaminergic receptors in the renal vasculature is not associated with any beneficial effects on renal function.33, 34 Ultimately, the most important factor determining our choice of vasopressors in septic shock should be clinical effect on patient outcomes. Human and animal studies suggest a potential benefit of norepinephrine and dopamine over epinephrine (epinephrine is associated with more tachycardia, increased lactate, and worse effects on the splanchnic circulation). There is, however, no clear evidence that epinephrine is harmful to patients with septic shock. Furthermore, a recent prospective randomized trial comparing norepinephrine plus dobutamine to epinephrine in patients with septic shock found no significant difference in the primary outcome of 28-day mortality rate.35 The largest study to date (> 1600 patients) enrolled patients with shock (the majority with septic shock) and randomized them to dopamine or norepinephrine.36 There was no significant difference in the primary outcome of 28-day mortality rate (dopamine 52.5% versus norepinephrine 48.5%; P = 0.10). However, there were more arrhythmic events among patients treated with dopamine than among those treated with norepinephrine (dopamine 24.1% versus norepinephrine 12.4%; P < .001).36 In recent years there has been increased interest in the use of vasopressin to raise blood pressure in septic shock. Studies have found that patients with septic shock have lower vasopressin levels than patients with other types of shock.37 This phenomenon has been labeled "relative vasopressin deficiency." Studies have shown that low-dose vasopressin may be effective in raising blood pressures in patients refractory to other vasopressors.38, 39 The VASST trial, a randomized controlled trial, compared norepinephrine alone to norepinephrine plus vasopressin (0.03 units/h). There was no significant difference in mortality rate at 28 days between groups.40 The trial had two predefined subgroups for analysis: a group with less-severe shock (patients receiving < 15 μg/min of norepinephrine) and a high-severity group (patients receiving < 15 μg/min of norepinephrine). The pretrial hypothesis was that vasopressin would improve mortality rate in the sickest group of patients. However, what the results showed was an improvement in mortality rate with vasopressin in patients with low-severity shock (norepinephrine 35.7% versus vasopressin 26.5%; P = .05).40 The clinical significance of this finding is unclear. Current guidelines recommend that (1) norepinephrine or dopamine should be used as first-line vasopressors in septic shock, (2) epinephrine should be added in patients who remain hypotensive on the first-line agents, and (3) low-dose vasopressin can be utilized in cases refractory to catecholamines.8 Titration of vasopressors should target MAP and patients ideally should have an arterial line for monitoring. Titration of vasopressors to a MAP of 65 mm Hg has been shown to preserve tissue perfusion.41, 42 In addition, preexisting conditions should be considered when defining the most appropriate target MAP for an individual patient. In patients who are chronically hypertensive, a higher MAP may be indicated; conversely, in a young normotensive patient a lower MAP may be appropriate. Current guidelines recommend a target MAP greater than or equal to 65 mm Hg.8 It is important to supplement this end point with other markers of global and regional perfusion as well as clinical considerations that may apply to individual patients.
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The final components in the hemodynamic optimization of patients with severe sepsis and septic shock are the evaluation and treatment of myocardial depression. Most patients will have adequate cardiac output (CO) after adequate fluid resuscitation. However, in early unresuscitated sepsis and in a subgroup of patients later in the disease process, there is evidence of low or inadequate CO. The CO can be measured using various techniques, most commonly in the ICU via a pulmonary artery catheter or from echocardiographically derived measurements. In addition, the measurement of venous oxygen saturation (SvO2) or the ScvO2 can be utilized as surrogates for adequate global oxygen delivery (and by proxy, adequate CO). In patients with low CO after achieving volume and perfusion targets, inotropes such as dobutamine can be utilized. Ideally, the cardiac index (CO/body surface area) should be greater than or equal to 2.5 L/min per m2, the SvO2 greater than or equal to 65%, or the ScvO2 greater than or equal to 70%.
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In summary, the hemodynamic support of patients with severe sepsis and septic shock should be implemented early and should be guided by predefined hemodynamic end points. The Sepsis Resuscitation Bundle includes the following end points: CVP 8 to 12 mm Hg (may be higher in mechanically ventilated patients); MAP greater than or equal to 65 mm Hg; and ScvO2 greater than or equal to 70%. These end points should be achieved as a group within the first 6 hours of treatment. At our institution we have adopted a protocol that is implemented in all patients with evidence of sepsis-induced hypoperfusion as soon as they are identified in the emergency department or medical ward; this protocol is then used as a guide for resuscitation once the patient is transferred to the intensive care unit (Figure 47-3).43
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After aggressive fluid resuscitation, norepinephrine (10 μg/min) and dobutamine (5 μg/min) are initiated. At this point the patient has the following hemodynamic parameters: CVP 10 mm Hg, MAP 68 mm Hg, and ScvO2 75%. The patient remains on the same ventilator settings and is now on a midazolam continuous infusion for sedation. Blood cultures that were sent last night are reported as growing gram-positive cocci.