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The cornerstones of the initial treatment and stabilization of severe sepsis are early recognition, early reversal of hemodynamic compromise, and early infection control.40 Base the resuscitation on administering fluids, frequently assessing response, and adding adjunct therapies including vasopressors based on the conditions. The specific method of titrating resuscitation is less important than treating early and aggressively.
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The goals of resuscitation are to improve preload, tissue perfusion, and oxygen delivery. There is no "set amount of fluid," although most patients will require a total (bolus plus infusion) of 2 to 5 L of crystalloid in the first 6 hours to achieve optimal outcomes. Similarly, do not delay vasopressors when blood pressure does not respond to volume or if volume overload seems likely. Administer appropriate antibiotics, and remove any nidus of infection. Each of these interventions will be discussed in detail below. Once the patient is stabilized, other interventions such as appropriate management of oxygenation and ventilation, fever control to reduce metabolic demand, and control of hyperglycemia may be needed to improve patient outcomes.
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EARLY QUANTITATIVE RESUSCITATION
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The primary deficit leading to poor outcomes in shock states (typically studied in hemorrhagic shock) is a mismatch between oxygen supply and demand,44 and after a certain time point, processes initiated by this mismatch are irreversible. In 2001, Rivers et al45 described the use of an early, structured hemodynamic resuscitation protocol driven by a central venous catheter with continuous oximetric capability to titrate fluids to central venous pressure, vasopressors to mean arterial pressure, and transfusion of blood or inotropes to central venous oxygen saturation (SCVO2). This protocol, termed "early goal-directed therapy," decreased mortality when compared with standard care, although all patients had central venous catheters placed early. Follow-up uncontrolled observational studies confirmed that even partial use of this approach lowered mortality in settings compared with previous times without aggressive early sepsis detection or care.46-50
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In a second large trial, Jones et al4 randomized patients to the Rivers early goal-directed therapy protocol or to a protocol that measured lactate clearance of ≥10% rather than SCVO2. The lactate clearance protocol was noninferior to continuous SCVO2 monitoring in the setting of ED-based resuscitation of septic shock. Lactate clearance–guided therapy (titrating fluids and vasopressors) became an alternative to invasive SCVO2 monitoring and early goal-directed therapy. Although the ideal lactate clearance target remains unclear, a minimum of 10% relative lactate clearance27,28 and normalization of lactate to <2 mmol/L emerged as goals.40,51 Still, about one third of patients with severe sepsis have a normal lactate,51 and up to one half or more have a normal SCVO2,52 limiting either tool in guiding therapy.
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The newly released ProCESS trial53 compared three ED treatment groups after early identification and antibiotics: protocol-based resuscitation using invasive central venous monitoring (the Rivers early goal-directed therapy protocol), protocol-based care using clinical parameters such as blood pressure and shock index (but no catheter-driven care), and nonprotocol usual care chosen by the bedside physician(s). These resuscitative approaches all delivered different care, but all groups received aggressive fluids and pressors in addition to early recognition and antibiotic use; however, no one approach was superior in terms of morbidity or mortality. Thus, the ProCESS trial emphasizes that the early recognition of sepsis, administration of antimicrobials, adequate volume resuscitation, and assessment of the adequacy of circulation are the important elements that improve outcomes, not any specific path of resuscitation. These observations allow providers or sites the flexibility of crafting the best approach to care but show that mandatory central venous catheterization and monitoring of central venous pressure or SCVO2 are not necessary for all patients with sepsis.
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When resuscitating an ED patient with sepsis, first assess and replenish circulating volume, typically with an initial 20 to 30 milligram/kg crystalloid bolus, preferably through large-bore IVs. This amounts to an approximate 1- to 2-L bolus of saline or lactated Ringer's solution in a 70-kg adult, although some patients require more or less. Saline can produce a hyperchloremic metabolic acidosis if used in large-volume resuscitation, causing some to switch to lactated Ringer's if large volumes are planned. Colloids are not needed in early sepsis care, and hydroxyethyl starch can worsen acute kidney injury.
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The most important variable process in volume replacement is determining if a patient is volume responsive. There are several more sophisticated measurements that can be used to make this determination such as cardiac output and stroke volume variation. The latter entails lifting the legs of a supine patient for 60 seconds; improved blood pressure or less variation in the peak blood pressure wave (if an arterial line is present) identifies a volume-responsive patient who will likely benefit from more fluid. If these tools are unavailable, assess the need for further volume expansion with empiric crystalloid boluses until the patient fails to demonstrate a physiologic or hemodynamic response (e.g., rise in systolic or mean pressure, decrease in heart rate, improvement in peripheral pulses or extremity perfusion, increase in urinary output).
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Once the patient fails to respond to further intravenous volume expansion, provide adequate perfusion pressure with vasoactive agents. In general, a mean arterial pressure goal of 65 mm Hg is sought; routine targeting of a higher mean arterial pressure does not aid outcomes, although in some patients, it may be necessary.54 A mean arterial pressure is preferable to a specific systolic blood pressure goal; however, use of systolic pressure is often preferred by clinicians, who often seek a goal of 90 mm Hg or higher.
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Ideally, deliver vasoactive agents through a central venous line to limit extravasation and resultant tissue necrosis. If a central line is unavailable, use a large, secured peripheral IV temporarily for vasopressor administration. In septic shock, norepinephrine at a dose of 0.5 to 30 micrograms/min is the best first choice since the dual α- and β-adrenergic effects result in peripheral vasoconstriction and cardiac inotropy. Dopamine has a higher rate of complications, most notably dysrhythmias and failure, compared with norepinephrine and is no longer routinely recommended.55 Vasopressin is a second-line agent and may allow for the down-titration of the norepinephrine dose.56 Give vasopressin as a constant infusion at a rate of 0.03 or 0.04 U/min. Do not titrate the dose, because higher rates are associated with vasospasm and high morbidity. Epinephrine at a dose of 1 to 20 micrograms/min appears safe and equivalent to norepinephrine when dosed appropriately,57 although the risk of medication dosing errors related to epinephrine concentration may make norepinephrine a superior choice. If tachydysrhythmias are a problem, phenylephrine is an option as a pure α-adrenergic agonist.
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CENTRAL VENOUS OXYGENATION
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After volume repletion and perfusion pressure optimization, if tissue perfusion appears to continue to be compromised (cool extremities, poor pulses, worsening organ function), one may assess oxygen balance. Although not needed routinely, insertion of a continuous central venous oxygen saturation (SCVO2) measuring catheter can aid additional therapy as outlined in the early goal-directed therapy approach.45 If SCVO2 is less than 70%, it implies a relative oxygen supply and demand mismatch.
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An alternative is to guide therapy through the use of lactate clearance, because a relative decrease in lactate over time suggests a restoration of adequate tissue perfusion. Measure lactate using the same method 1 to 2 hours apart; improvement of 10% or more is associated with improved clinical outcomes.
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Give broad-spectrum antibiotics as early as possible for severe sepsis.40 Combination antibiotic therapy as opposed to monotherapy leads to improved outcomes, potentially due to higher rates of bactericidal activity.58 Recommendations for antibiotic regimens are in Table 151–2. Therapy can later be tailored based on clinical response and microbiologic data. Given the rising rates of community-acquired methicillin-resistant S. aureus (CA-MRSA), ensure this is covered along with gram-negative pathogens and anaerobic organisms. Vancomycin is often underdosed in clinical practice, which can impair recovery58; guidelines suggest an initial vancomycin dose of 25 to 30 milligrams/kg in critically ill patients.59 In immunosuppressed patients, consider antifungal or antiviral agents.
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The Surviving Sepsis Campaign recommends giving antibiotics as soon as feasible, ideally within 1 hour of the recognition of severe sepsis and/or within 3 hours of triage. However, these are suggestions, not a standard of care,40 and these recommendations are often not achievable.60 Whether antimicrobials are best given initially or only after hemodynamic stabilization of the patient is unclear; given the poor prognosis associated with delays in either resuscitation or infection therapies, we recommend delivering both concurrently. Ideally, sample any organ infectious source and obtain blood cultures prior to the initiation of antibiotics, but do not delay the initiation of antibiotics to obtain cultures.40
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Infection control is not confined to antimicrobial administration; it also includes addressing potential surgical sources of infection. Drain any source and remove indwelling vascular lines and other medical devices suspected as infected once the patient is stabilized.
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OTHER THERAPIES: VENTILATION, GLYCEMIC CONTROL, ACTIVATED PROTEIN C, AND STEROIDS
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Sepsis is the leading cause of acute respiratory distress syndrome. Data from a large study of patients with acute respiratory distress syndrome found that low tidal volume ventilation (6 mL/kg ideal body weight) leads to superior outcomes compared with large (12 mL/kg) volume ventilation,61 with the latter likely creating barotrauma from overdistension of the alveoli. Thus, low tidal volume ventilation with a positive end expiratory pressure adequate to prevent alveolar collapse is recommended. Although starting at a low tidal volume is recommended,40 it is unclear whether a fixed volume of 6 mL/kg is best for all; some titration is permissible. To accommodate low tidal volumes, patients may be allowed some hypercapnia as long as the accompanying acidosis does not threaten hemodynamic deterioration.
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Multiple trials note a link between hyperglycemia and worsened outcomes in the setting of sepsis, notably in patients without pre-existing diabetes. Although there is evidence of improved outcomes in patients who achieve tight glucose control (target glucose level of 80 to 110 milligrams/dL), the high rate of hypoglycemia occurring with attempts at this targeted glycemia may explain increased harm seen.62 More modest efforts (seeking blood glucose <180 mg/dL) allow for similar outcomes with less variation.62 Glucose control is most important after initial care and is best if protocolized, especially for patients receiving extended sepsis care in the ED.
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Therapies to manipulate the coagulation cascade are unproven; the most promising candidate to date, activated protein C, failed to improve outcomes and is not used.63 Systemic corticosteroids are the only anti-inflammatory agent in use in clinical practice but are controversial. Despite early literature suggesting a mortality benefit,64 recent data failed to confirm these findings.65 Corticosteroids shorten the time to shock reversal and are adjunctive agents in patients with refractory hemodynamic shock (i.e., requiring more than one vasopressor or active upward titration of vasopressors after adequate volume restoration). Stimulation testing using adrenocorticotropic hormone is not clinically helpful. Although even a single dose of etomidate may alter adrenal activity as measured by laboratory tests,66 there is no clear evidence that the use of etomidate to facilitate endotracheal intubation alters any clinically important outcome.