Septic Shock Treatment & Management

Patients with sepsis and septic shock require hospital admission. Patients with sepsis who respond to early resuscitation therapy in the emergency department (ED) and show no evidence of end-organ hypoperfusion may be admitted to a general hospital unit, optimally one that has close nursing observation and monitoring. Such patients do not require invasive hemodynamic monitoring and usually do not require admission to an intensive care unit (ICU).

Patients who do not respond to initial ED treatment (ie, who have recurrent hypotension despite adequate fluid challenges) and those who are in septic shock require admission to an ICU for continuous monitoring and continued goal-directed therapy. If an appropriate ICU bed or physician is not available, the patient should be transferred with advanced life support monitoring to another hospital with the available resources.

There is significant controversy surrounding goal-directed therapy (EGDT) in the management of sepsis and septic shock. EGDT was previously evaluated in a small, single, randomized trial at a single institution. ^[68] Subsequently, three newer, large, multicenter randomized trials were performed in the United States (ProCESS [Protocolized Care for Early Septic Shock]), ^[57] Australia (ARISE [Australasian Resuscitation In Sepsis Evaluation]), ^[58] and the United Kingdom (ProMISe [Protocolised Management In Sepsis]). ^[59]

In the ProCESS trial, 1341 patients with septic shock in 31 academic hospital EDs received treatment based on one of three approaches: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or standard care. ^{[69, 70]} No significant differences between groups were found for 90-day mortality, 1-year mortality, or the need for organ support.

Similar findings were reported from both the ARISE and the ProMISe trials. Important to note, measuring lactate, targeting ScvO₂ values, and insertion of a central venous catheter were not associated with improved outcomes. What was important was the direct and aggressive individualized care each patient received, including early bacteriologic cultures of appropriate sites (eg, blood, urine, sputum), early and correct institution of broad-spectrum antibiotics, restoration of blood pressure, and reversal of evidence of end-organ perfusion. These findings are reasonable when considered within the context of acute care medicine resuscitation principles. Namely, stabilize the patient, reverse the cause of shock, and do no additional harm.

Results from a small 2017 study suggested that in patients with septic shock who did not respond to high doses of conventional vasopressors, angiotensin II may be an emerging treatment to increase blood pressure. ^{[71, 72]} The study had limitations and further research is needed. Results are awaiting US Food and Drug Administration (FDA) consideration for approval.

Goals and principles of treatment in septic shock

The treatment of patients with septic shock has the following major goals:

• Start adequate antibiotic therapy (proper dosage and spectrum) as early as possible

• Identify the source of infection, and treat with antimicrobial therapy, surgery, or both (source control)

• Resuscitate the patient, using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation (hypoperfusion)

• Maintain adequate organ system function by maintaining blood flow and arterial pressure, guided by cardiovascular monitoring, and interrupt the progression to multiple organ dysfunction syndrome (MODS) by appropriate antibiotics and surgical debridement, as needed

Management principles, based on the current literature, include the following:

• Early recognition

• Source control

• Early and adequate antibiotic therapy

• Early hemodynamic resuscitation and continued support

• Proper ventilator management with low tidal volume in patients with acute respiratory distress syndrome (ARDS)

Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes antimicrobial therapy targeting the most likely pathogen, removal or drainage of the infected foci, treatment of complications, and interventions to prevent and treat effects of harmful host responses. Source control is an essential component of sepsis management.

Venous access

In all cases of septic shock, adequate venous access must be ensured for volume resuscitation. When sepsis is suspected, 2 large-bore (16-gauge) intravenous (IV) lines should be placed if possible to allow administration of aggressive fluid resuscitation and broad-spectrum antibiotics. Central venous access is useful when administering vasopressor agents and in establishing a stable venous infusion site but is not mandatory.

If the hypotension does not respond to a crystalloid fluid bolus of 30 mL/kg (1-2 L) over 30-60 minutes or if fluids cannot be infused rapidly enough, a central venous catheter should be placed in the internal jugular or subclavian vein. This catheter allows administration of medication centrally and provides multiple ports for rapid fluid administration, antibiotics, and vasopressors if needed. It also allows measurement of central venous pressure (CVP), a surrogate for volume status, if CVP measurement capability is available.

If an intravascular access device is suspected as the source of sepsis or septic shock, alternative vascular access must be obtained, and the suspect device must then be removed.

Urinary catheterization

An indwelling urinary catheter should be placed. In all patients with sepsis, urine output (UOP), a marker for adequate renal perfusion and cardiac output, should be closely monitored, as should renal function; mortality is greatly increased in patients with urosepsis and sepsis or septic shock. Normal UOP in an adult is 0.5 mL/kg/hr or more, ^{[11, 60]} equivalent to about 30-50 mL/hr for most adults.

Any abnormalities in UOP should prompt assessment of the adequacy of circulating blood volume, cardiac output, and blood pressure; these should be corrected if inadequate. As with sepsis in other sites, early and appropriate initiation of antimicrobial therapy—as well as identification and management of any urinary tract disorders—is essential. ^[54]

Intubation and mechanical ventilation

Most patients with sepsis develop respiratory distress as a manifestation of sepsis or septic shock. The lung injury is characterized pathologically as diffuse alveolar damage (DAD) and ranges from acute lung injury (ALI)—or mild ARDS, by the Berlin Definition ^[10] —to moderate or severe ARDS (see Background). These patients need intubation and mechanical ventilation for optimal respiratory support. Intubation should be considered early in the course of progressing sepsis and septic shock.

Direct delivery of oxygen into the trachea at a fraction of inspired oxygen (FIO₂) of 1 is far superior to delivery via a nonrebreather oxygen mask. Mechanical ventilation, with appropriate sedation, also eliminates the work of breathing as well as decreases the metabolic demands of breathing, which accounts for about 30% of total metabolic demand at baseline. ^[73]

Alveolar overdistention and repetitive opening and closing of alveoli during mechanical ventilation have been associated with an increased incidence of ARDS. Low−tidal volume ventilatory strategies have been used to minimize this type of alveolar injury. The recommended tidal volume is 6 mL/kg, with plateau pressures kept at or below 30 mL water. ^{[11, 60]} Positive end-expiratory pressure (PEEP) is required to prevent alveolar collapse at end-expiration. ^[74]

The major focus of resuscitation is on supporting cardiac and respiratory functions. The other organ systems may also require attention and support during this critical period. Patients generally require intubation and assisted ventilation because respiratory failure either is present at the onset of illness or may develop during its course. Correction of the shock state and abnormal tissue perfusion is the next step in the treatment of patients with septic shock.

In 2004, the first set of formal treatment guidelines for septic shock were published. ^[75] These guidelines, known as the Surviving Sepsis Campaign, were formulated by an international consensus group that was composed of experts from 11 organizations, including the Society of Critical Care Medicine (SCCM), the American College of Chest Physicians (ACCP), the European Society of Intensive Care Medicine (ESICM), and the American College of Emergency Physicians (ACEP). These guidelines are reviewed and updated periodically.

The Surviving Sepsis Campaign guidelines were last updated in 2012, and the current versions reflect the opinion of a reasonable approach to the treatment of septic shock. ^[11] The reader is encouraged to check the Sepsis Campaign’s Website periodically for new information. Specifically, with the recently large clinical trials in the management of septic shock completed, specific recommendations may be degraded. Those are highlighted below.

The first 6 hours of resuscitation of a critically ill patient with sepsis or septic shock are critical. ^[11] The following should be completed within 3 hours:

• Obtain the lactate level (Although recommended, the three recent trials showed that lactate-guided therapy had no impact on survival. Still, lactate levels parallel septic shock severity and have prognostic implication.)

• Obtain blood cultures before administering antibiotics

• Administer broad-spectrum antibiotics

• Administer 30 mL/kg of crystalloid solution for hypotension or for lactate levels of 4 mmol/L or higher (Again, although most patients presenting with sepsis are in a functional hypovolemic state, requiring fluid resuscitation, careful monitoring of right ventricular volume overload is essential if large quantiles of fluid are to be given quickly, to avoid inducing acute cor pulmonale.) Important to note, the figure 30 mL/kg was chosen as an approximation of the average initial fluid resuscitation given on most clinical trials of septic shock resuscitation. Regrettably, this volume level has since been set as a quality measure of adequacy of sepsis resuscitation, which, by definition, is not accurate. The ProCESS trial demonstrated that similar survival occurred when the bedside clinician gave the initial amount of fluids he or she thought the patient needed based on clinical signs of peripheral perfusion, compared with the group given a fixed initial fluid resuscitation. Thus, the most accurate method for fluid resuscitation is to monitor the response to fluid infusions given rapidly and stop once adequacy of resuscitation has occurred or when the patient no longer is volume responsive. The Surviving Sepsis Guidelines now recommend using dynamic measures of volume responsiveness to guide fluid resuscitation. These measures include arterial pulse pressure variation and left ventricular stroke volume variation if the patient is on mechanical ventilatory support or respiration-induced changes in inferior or superior vena caval diameter of the change in cardiac output to a transient passive leg raising maneuver.

The following should be completed within 6 hours:

• Administer vasopressors for hypotension that does not respond to initial fluid resuscitation to maintain a mean arterial pressure (MAP) of 65 mm Hg or higher (Recent studies showed the validity of the 70-75 mm Hg lower mean arterial pressure target or 80-85 mm Hg in those patients with preexisting hypertension.)

• If hypotension persists despite volume resuscitation or the initial lactate level is 4 mmol/L or higher, then measure central venous pressure (CVP) (aiming for ≥8 mm Hg), measure central venous oxygen saturation (ScvO₂) (aiming for ≥70%), and normalize lactate levels (These recommendations will probably be modified in lieu of the findings that CVP does not represent an effective target. See below about the venoarterial PCO₂ gradient analysis as being a more specific measure of tissue hypoperfusion.)

The Royal College of Obstetricians and Gynaecologists (RCOG) recommends following the Surviving Sepsis Campaign guidelines for managing pregnant women with sepsis or septic shock. ^[76] Treatment strategies include early recognition and resuscitation measures, supportive care, removal of the septic focus, administration of blood products as needed, and thromboprophylaxis, as well as the involvement of a multidisciplinary team. ^{[11, 76]} (See Shock and Pregnancy.)

Although not part of the guidelines, much attention to measuring not only effective oxygen delivery but also organ blood flow has emerged as reasonable parameters to grade shock severity. Clearly, a low ScvO₂ can occur from reduced cardiac output, but it can also occur from severe anemia (or hemoglobinopathies) and hypoxemia. Similarly, a normal or high ScvO₂ may reflect metabolic block, shunt, or sampling errors.

To address many of these errors one should calculate the arterial–to–central venous PO₂ gradient (Pa-vO₂). Since viable tissues produce carbon dioxide as an endpoint of metabolism, end-capillary PCO₂ increases as tissue blood flow decreases. The central venous–to–arterial PCO₂ gap (Pv-aCO₂) assesses blood flow. Finally, lactate, although insensitive as a marker of ischemia, is still an excellent measure of tissue injury and the inflammatory state. Thus, the Pv-aCO₂/Pa-vO₂ ratio can be used to assess the severity of circulatory shock in sepsis. ^{[77, 78]}

Respiratory support

An initial assessment of airway and breathing is vital in a patient with septic shock. Supplemental oxygen should be administered to all patients with suspected sepsis. Early intubation and mechanical ventilation should be strongly considered for patients with any of the following:

• Oxygen requirement

• Dyspnea or tachypnea

• Persistent hypotension

• Evidence of poor peripheral perfusion

Circulatory support

Patients with suspected septic shock require an initial crystalloid fluid challenge of 30 mL/kg (1-2 L) over 30-60 minutes, with additional fluid challenges. (A fluid challenge consists of rapid administration of volume over a particular period, followed by assessment of the response.) (See Fluid Resuscitation.)

Administration of crystalloid solution is titrated to a goal of adequate tissue perfusion. CVP should not be used to target resuscitation; it should be used as a stopping rule. If, during fluid resuscitation, CVP rapidly increases by more than 2 mm Hg, absolute CVP greater than 8-12 mm Hg, or signs of volume overload (dyspnea, pulmonary rales, or pulmonary edema on the chest radiograph) occur, fluid infusion as primary therapy needs to be stopped. Patients with septic shock often require a total of 4-6 L or more of crystalloid solution. However, CVP measurement should not be entirely relied upon, because it does not correlate with intravascular volume status or cardiac volume responsiveness. ^[79]

Some studies have used noninvasive means of estimating CVP—for example, ultrasonography to measure inferior vena cava diameter as a surrogate for volume status. Nagdev et al used the difference between inspiratory and expiratory caval diameter (the caval index) to predict CVP and found that a 50% difference predicted a CVP lower than 8 mm Hg with both a sensitivity and a specificity greater than 90%. ^[80] Similarly, variations in this diameter change with respiration correlated with volume responsiveness.

UOP should also be monitored as a measure of dehydration. UOP lower than 30-50 mL/h should prompt further fluid resuscitation or other measures to increase cardiac output in a non–fluid-responsive patient. Important to note, during fluid resuscitation for sepsis, increased intra-abdominal fluid accumulation and ileus often occur and can induce increases in intra-abdominal pressure. If intra-abdominal pressure is greater than 12 mm Hg, intra-abdominal hypertension exists. Since renal perfusion pressure can be approximated as mean arterial pressure minus CVP or intra-abdominal pressure (whichever is higher), low UOP may reflect low renal perfusion pressure. In general, targeting a renal perfusion pressure of 70-75 mm Hg sustains adequate renal blood flow in sepsis unless preexisting hypertension is present, in which case targeting a higher renal perfusion pressure of 80-85 mm Hg is indicated. ^[81]

Given that third-spacing of intravascular fluid is a hallmark of septic shock, it makes sense that administration of colloid solution might be beneficial. However, although colloid resuscitation with albumin has not been shown in many meta-analyses to have any advantage over isotonic crystalloid resuscitation (isotonic sodium chloride solution or lactated Ringer solution) in this setting, ^[82] Delaney et al found adjunctive albumin resuscitation to provide a statistically significant mortality benefit in relation to other regimens. ^[83]

In the Saline versus Albumin Fluid Evaluation (SAFE) trial, in which about 1200 of 7000 ICU patients who required fluid resuscitation had at the time what was deemed severe sepsis, no overall difference between the 2 treatment groups was seen. ^[84] However, the investigators noted a trend toward improved outcome in patients with severe sepsis who received 4% albumin rather than normal saline. The data are inconclusive, especially with regard to the initial resuscitation phase for septic shock in the ED; therefore, crystalloid fluid resuscitation is recommended.

The current Surviving Sepsis guidelines recommend rapid administration of an initial fluid challenge with 30 mL/kg of crystalloid solution. ^[11] Albumin should be used only when substantial amounts of crystalloid solution are required. Hydroxyethyl starch solutions are not recommended. ^[11] (See Goals of Hemodynamic Support.) Several recent retrospective and smaller prospective clinical trials have underscored the risk that 0.9 N NaCl has as a primary resuscitation fluid. It causes hyperchloremic metabolic acidosis and is associated with an increased mortality relative to balanced salt solutions (eg, plasmalyte). ^[85]

Correction of anemia and coagulopathy

Hemoglobin levels as low as 7 g/dL are well tolerated by patients, and transfusion is not required unless the patient has poor cardiac reserve or demonstrates evidence of myocardial ischemia. Thrombocytopenia and coagulopathy are common in patients with sepsis; these patients do not require replacement with platelets or fresh frozen plasma (FFP) unless they develop active clinical bleeding.

If hemoglobin levels fall below 7 g/dL, red blood cell (RBC) transfusion is recommended to a target hemoglobin range of 7-9 g/dL. ^[11] Even in the absence of apparent bleeding, patients with sepsis should receive platelet transfusion if platelet counts fall below 10 × 10⁹/L (10,000/µL). Platelet transfusion may also be considered when bleeding risk is increased and platelet counts are below 20 × 10⁹/L (20,000/µL). ^[11] Patients who are to undergo surgery or other invasive procedures may require higher platelet counts (eg, ≥50 × 10⁹/L [50,000/µL]).

Other points to consider with respect to the administration of blood products include the following ^{[11, 60]} :

• Erythropoietin is not recommended for specific treatment of anemia associated with sepsis; rather, it should be given to such patients for other acceptable indications (eg, anemia associated with renal failure)

• FFP is not recommended for the correction of laboratory clotting abnormalities unless bleeding is present or invasive procedures are planned

• Antithrombin agents are not recommended for treatment of sepsis and septic shock

• Recombinant activated protein C (rhAPC) is no longer available for treating patients with sepsis or septic shock

Antimicrobial therapy

IV antibiotic therapy should be initiated within the first hour after the recognition of septic shock or sepsis; delays in administration are associated with increased mortality. ^{[5, 11, 60]} Selection of antibiotic agents is empiric, based on an assessment of the patient’s underlying host defenses, the potential source of infection, and the most likely responsible organisms. (See Empiric Antimicrobial Therapy.)

When the source is unknown, the antibiotic chosen must be a broad-spectrum agent that covers gram-positive, gram-negative, and anaerobic bacteria. In addition, consideration must be given to pathogens with antibiotic resistance, such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas species, and gram-negative organisms with extended-spectrum beta-lactamase (ESBL) activity.

Patients who are at risk for these types of infection are those with recent, prolonged, or multiple hospitalizations. The 2012 Surviving Sepsis Campaign guidelines recommend combination empiric therapy for neutropenic patients as well as for those with difficult-to-treat, multidrug-resistant microorganisms, such as Acinetobacter and Pseudomonas. ^[11]

Temperature control

Fever generally requires no treatment, except in patients who have limited cardiovascular reserve as a consequence of increased metabolic requirements. Antipyretic drugs and physical cooling methods, such as sponging or cooling blankets, may be used to lower the patient’s temperature.

External cooling is another method of fever control that has been reported to be safe and to decrease vasopressor requirements and early mortality in patients with septic shock. In a multicenter, randomized, controlled study comprising febrile patients with septic shock who required vasopressors, mechanical ventilation, and sedation, the group that received external cooling, as compared with the group that did not, exhibited the following ^[86] :

• Significantly lower body temperature after 2 hours

• Significantly more common occurrences of shock reversal in the ICU

• Significantly lower day-14 mortality

Although a 50% decrease in the vasopressor dose was significantly more common after 12 hours of external cooling treatment, the same result was not found after 48 hours of this therapy. ^[86]

Metabolic and nutritional support

Patients with septic shock develop electrolyte abnormalities. Potassium, magnesium, and phosphate levels should be measured and corrected if deficient.

Patients with septic shock generally have high protein and energy requirements. Although a brief period (several days) without nutrition does not cause deleterious effects, prolonged starvation must be avoided.

Early nutritional support is of critical importance in patients with septic shock. The oral or enteral route is preferred, unless the patient has an ileus or other intestinal abnormality. Gastroparesis is commonly observed and can be treated by administering motility agents or placing a small-bowel feeding tube.

Diminished bowel sounds are not a contraindication to a trial of enteral nutrition, though motility agents or a small-bowel feeding tube may be necessary. The benefits of enteral nutrition are as follows:

• Protection of gut mucosa

• Prevention of translocation of organisms from the gastrointestinal (GI) tract

• Reduction of the complication rate

• Lower cost

The 2012 Surviving Sepsis Campaign guidelines recommend using nutritional support without specific immunomodulating supplementation. ^[11]

Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation, which ultimately causes cellular, and then organ system, dysfunction. Therefore, the goals of hemodynamic therapy are restoration and maintenance of adequate tissue perfusion so as to prevent multiple organ dysfunction.

Careful clinical and invasive monitoring is required for assessment of global and regional perfusion. Shock at the bedside is defined by an MAP lower than 60 mm Hg or a decrease in MAP of 40 mm Hg from baseline.

Elevation of the blood lactate level on serial measurements of lactate can indicate inadequate tissue perfusion. In addition, mixed venous oxyhemoglobin saturation serves as an indicator of the balance between oxygen delivery and consumption. A decrease in maximal venous oxygen (MVO₂) can be secondary to decreased cardiac output; however, maldistribution of blood flow in patients experiencing septic shock may artificially elevate the MVO₂ levels. An MVO₂ of less than 65% generally indicates decreased tissue perfusion.

Regional perfusion in patients with septic shock is evaluated by assessing the adequacy of organ function. Indications of inadequate perfusion may include any of the following:

• Evidence of myocardial ischemia

• Renal dysfunction, manifested by decreased UOP or increased creatinine levels

• Central nervous system (CNS) dysfunction, indicated by a decreased level of consciousness

• Hepatic injury, shown by increased levels of transaminases

• Splanchnic hypoperfusion, manifested by stress ulceration, ileus, or malabsorption

Hemodynamic support in septic shock is provided by restoring the adequate circulating blood volume, and, if necessary, optimizing perfusion pressure and cardiac function with vasoactive and inotropic support to improve tissue oxygenation.

Hypovolemia is an important factor contributing to shock and tissue hypoxia; therefore, all patients with sepsis require supplemental fluids. The amount and rate of infusion are guided by an assessment of the patient’s volume and cardiovascular status.

Monitor patients for signs of volume overload, such as dyspnea, elevated jugular venous pressure, crackles on auscultation, and pulmonary edema on the chest radiograph. Improvements in mental status, heart rate, MAP, capillary refill, and UOP indicate adequate volume resuscitation.

Volume resuscitation can be achieved with either crystalloid or colloid solutions. The crystalloid solutions are 0.9% sodium chloride and lactated Ringer solution; the colloid solutions are albumin, dextrans, and pentastarch. Although most clinical trials have not shown either type of resuscitation fluid to be superior in septic shock, a meta-analysis by Delaney et al found a significant reduction in mortality associated with albumin-containing solutions as compared with other fluid resuscitation regimens. ^[83]

It should be kept in mind, however, that crystalloid fluids not only must be given in considerably (2-4 times) greater volumes than colloid fluids but also take longer to achieve the same end points. On the other hand, colloid solutions are much more expensive than crystalloid solutions.

The 2012 Surviving Sepsis Campaign guidelines recommend rapid administration of an initial fluid challenge with 30 mL/kg of crystalloid solution. ^[11] Albumin infusion should be used only when substantial amounts of crystalloid solution are required. Hydroxyethyl starch solutions are not recommended.

In some patients, clinical assessment of the response to volume infusion may be difficult. In such cases, it may be facilitated by monitoring the response of CVP or pulmonary artery occlusion pressure (PAOP) to fluid boluses because if either pressure increases, then fluid infusion should be stopped and the patient’s cardiovascular status reassessed. Fluid administration should be continued as long as hemodynamic improvement continues. ^{[11, 60]} Hemodynamic improvement is defined as increased organ perfusion, decreasing serum lactate and metabolic acidosis, and improved end-organ function. Fluid responsiveness can be accurately assessed at the bedside using dynamic measures of volume responsiveness, such as pulse pressure or stroke volume variation during positive-pressure breathing or the change in cardiac output to a passive leg-raising maneuver.

A sustained rise of more than 5 mm Hg in cardiac filling pressure after a fluid volume is infused indicates that the compliance of the vascular system is decreasing as further fluid is being infused. Such patients are susceptible to volume overload, and further fluid should be administered with care.

Data from several studies suggest that the incidence of pulmonary edema is essentially the same with crystalloid solutions as with colloid solutions when cardiac filling pressures are maintained at a lower level. However, if higher filling pressures are required for maintenance of optimal hemodynamics, crystalloid solutions may increase extravascular fluid fluxes through a decrease in plasma oncotic pressure.

EGDT may be considered for sepsis and septic shock ^[68] ; however, this approach remains controversial, and further studies are under way. One of these studies was just completed and published in 2014, the ProCESS trial, ^[57] which was a randomized trial of protocol-based care for early septic shock. This trial enrolled 1341 patients and compared a protocol-based EGDT (N=439) to two other arms: protocol-based standard therapy (N=446) and usual care (N=456). The results showed no significant 60-day mortality differences among the three arms, 21%, 18.2%, and 18.9%, respectively. Because these mortality rates were lower than the original EGDT study, ^[68] the authors performed a subgroup analysis including the sickest third of patients based on lactate levels and APACHE II scores, which showed similar or higher mortality than that from the original study, ^[68] but no benefit from EGDT was detected in this high-disease-severity population.

Following ProCESS, two additional EGDT studies, one from Australia-New Zealand called ARISE ^[58] and the other from the United Kingdom called ProMISe, ^[59] both found the exact same results, suggesting that strict protocolized resuscitation from septic shock is not as important as close bedside titration of care based on sound physiologic principles, independent of measures of lactate or ScvO₂.

Another study recently published, the OPTIMISE study, ^[87] was a pragmatic, randomized, observer-blinded trial that compared a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid/inotrope (dopexamine) (N=368) with usual care within 6 hours following major gastrointestinal surgery (N=366). The outcome measured was a composite of 30-day mortality plus moderate or major complications; no composite outcome differences were observed between the two groups. The authors also performed an updated meta-analysis with the addition of their new data and found a potential reduction in complication rates, but not in mortality.

However, at the same time, a French study showed that in previously nonhypertensive patients, targeting a mean arterial pressure of 65-75 mm Hg was as good, if not better, than targeting a mean arterial pressure 80-85 mm Hg. ^[81] In those patients with preexisting hypertension, there was less AKI and less need for hemodialysis but also more cardiovascular compilations, presumably because the higher mean arterial pressure group received higher doses of vasopressor agents.

Further, the large retrospective study of all of Australia and New Zealand ICU care from 2000-2012 demonstrated a clear progressive decline in septic shock mortality rates from 35% to 18% over this period, with equal trends across all age groups and treatment settings. ^[47]

If the patient does not respond to resuscitation with several liters (usually ≥4 L) of isotonic crystalloid solution or if evidence of volume overload is present, the depressed cardiovascular system can be stimulated by means of vasopressor therapy.

Vasopressor administration is required for persistent hypotension once adequate intravascular volume expansion has been achieved. Persistent hypotension is typically defined as systolic blood pressure lower than 90 mm Hg or MAP lower than 65 mm Hg with altered tissue perfusion. The mean blood pressure required for adequate splanchnic and renal perfusion (MAP, 60 or 65 mm Hg) is based on clinical indices of organ function.

The goal of vasopressor therapy is to reverse the pathologic vasodilation and altered blood flow distribution that occur as a result of the activation of adenosine triphosphate (ATP)-dependent potassium channels in vascular smooth muscle cells and the synthesis of the vasodilator nitric oxide (NO).

First-line agents: Norepinephrine vs dopamine

The recommended first-line agent for septic shock is norepinephrine, preferably administered through a central catheter. ^{[11, 60]} Norepinephrine has predominant alpha-receptor agonist effects and results in potent peripheral arterial vasoconstriction without significantly increasing heart rate or cardiac output. The dosage range for norepinephrine is 5-20 µg/min, and it is not based on the weight of the patient.

Norepinephrine is preferred to dopamine for managing septic shock because dopamine is known to cause unfavorable flow distribution (more arrhythmias). In this setting, norepinephrine has been shown to be both significantly safer and somewhat more effective.

In a systematic review of randomized controlled trials, norepinephrine was significantly superior to dopamine in improving both in-hospital and 28-day mortality in septic shock patients. ^[88] In a meta-analysis that evaluated these 2 agents in the setting of septic shock, the investigators determined that in comparison with dopamine, epinephrine was associated with a decreased risk of death and a lower incidence of arrhythmic events. ^[89]

In theory, norepinephrine is the ideal vasopressor in the setting of warm shock, wherein peripheral vasodilation exists in association with normal or increased cardiac output. The typical patient with warm shock has warm extremities but exhibits systemic hypotension and tachycardia, the results of decreased systemic vascular resistance.

Dopamine should be used only in certain highly specific situations, such as when there is a low risk of tachyarrhythmias and in the presence of coexistent bradycardia. Treatment usually begins at 5-10 µg/kg/min IV, and the infusion is adjusted according to the blood pressure and other hemodynamic parameters. Often, patients may require high dosages of dopamine (up to 20 µg/kg/min). Low-dose dopamine is not recommended for renal protection. ^{[11, 60]}

Second-line agents

Second-line vasopressors appropriate for patients who have persistent hypotension despite maximal doses of norepinephrine or dopamine include sythenthetic human angiotensin II, epinephrine, phenylephrine, and vasopressin.

In December 2017, synthetic human angiotensin II (Giapreza) was approved by the FDA for adults with septic or other distributive shock. Approval was based on the ATHOS-3 clinical trial (n = 321) in patients with vasodilatory shock and critically low blood pressure. Eligible patients had vasodilatory shock despite intravenous volume resuscitation with at least 25 mL/kg over the previous 24 hours and the administration of high-dose vasopressors. Significantly more patients responded to treatment with the angiotensin II injection added to conventional therapy compared with those on conventional therapy plus placebo. At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (P = .01). ^[71]

Epinephrine clearly increases MAP in patients unresponsive to other vasopressors, mainly by virtue of its potent inotropic effects on the heart; thus, it should probably be the first alternative agent considered in patients with septic shock who show a poor clinical response to norepinephrine or dopamine. ^{[11, 60]} Adverse effects include tachyarrhythmias, myocardial and splanchnic ischemia, and increased systemic lactate concentrations.

Phenylephrine exerts a pure alpha-receptor agonist effect, which results in potent vasoconstriction, albeit at the expense of depressed myocardial contractility and heart rate. Phenylephrine may be considered a first-line agent in patients with extreme tachycardia; its pure alpha-receptor activity will not result in increased chronotropy. ^[90]

Vasopressin, or antidiuretic hormone (ADH), has been proposed for use in septic shock because it is an endogenous peptide with potent vasoactive effects and its circulating levels are depressed in septic shock. According to the 2012 Surviving Sepsis Campaign guidelines, vasopressin should not be the single initial vasopressor but should be reserved for salvage therapy. ^[11] After first-line treatment, 0.03 U/min of vasopressin may be added to norepinephrine, with an anticipated effect equivalent to that of norepinephrine alone. ^{[11, 60]}

Characteristics of the vasopressors

Norepinephrine

Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. It can increase blood pressure successfully in patients with sepsis who remain hypotensive after fluid resuscitation and dopamine. The dosage may range from 0.2 to 1.5 µg/kg/min, and dosages as high as 3.3 µg/kg/min have been used because of the alpha-receptor downregulation in sepsis.

In patients with sepsis, indices of regional perfusion (eg, urine flow) and lactate concentration have improved after norepinephrine infusion. Several studies have found that a significantly greater percentage of patients treated with norepinephrine were resuscitated successfully, in comparison with patients treated with dopamine. ^{[88, 89]} Therefore, norepinephrine should be used early and should not be withheld as a last resort in patients with sepsis who are in shock.

Concerns about compromising splanchnic tissue oxygenation have not been borne out by the data; the studies have confirmed no deleterious effects on splanchnic oxygen consumption and hepatic glucose production, provided that adequate cardiac output is maintained.

Synthetic human angiotensin II

Angiotensin II, the major bioactive component of the renin-angiotensin-aldosterone system (RAAS), serves as one of the body’s central regulators of blood pressure. It raises blood pressure by vasoconstriction and increased aldosterone release; direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein–coupled angiotensin II receptor type 1 on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction. It is indicated for adults with septic or other distributive shock.

It is initiated at 20 ng/kg/min IV by continuous infusion. Monitor blood pressure response every 5 minutes and titrate by increments of up to 15 ng/kg/min as needed to achieve or maintain target blood pressure, not exceeding 80 ng/kg/min during the first 3 hours of treatment. Maintenance ranges from 1.25 ng/kg/min and should not exceed 40 ng/kg/minute.

Thromboembolism was observed in clinical trials. It should be administered with concurrent venous thromboembolic prophylaxis.

Dopamine

A precursor of norepinephrine and epinephrine, dopamine has varying effects, according to the doses infused. At lower doses, it has a much greater effect on beta receptors; at higher doses, it has more alpha-receptor effects and increases peripheral vasoconstriction.

Dosages range from 2 to 20 µg/kg/min. A dosage lower than 5 µg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. ^[11] At a dosage of 5-10 µg/kg/min, beta₁ -adrenergic effects induce an increase in cardiac contractility and heart rate. At dosages of about 10 µg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and elevation in blood pressure. ^[11]

Dopamine is often effective for restoring mean arterial pressure in patients with septic shock who remain hypotensive after volume resuscitation. The blood pressure increases primarily as a result of the drug’s inotropic effect, which is useful in patients who have concomitant reductions in cardiac function. However, as mentioned above, in a comparison of norepinephrine to dopamine for the management of arterial pressure in septic shock, failure of dopamine to reach mean arterial pressure targets occurred in 30% of the treatment arm, necessitating adding norepinephrine.

Dopamine may be particularly useful in the setting of cold shock, where peripheral vasoconstriction exists (cold extremities) and cardiac output is too low to maintain tissue perfusion. Undesirable effects include tachycardia, increased pulmonary shunting, the potential to decrease splanchnic perfusion, and an increase in pulmonary arterial wedge pressure (PAWP).

Low-dose (renal-dose) dopamine has been studied. Dopamine at a dosage of 2-3 µg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers; however, several well-designed clinical trials have not found such regimens to have any beneficial effects on renal blood flow and function in the setting of circulatory shock of any etiology.

Multiple studies also have not shown prophylactic or therapeutic low-dose dopamine administration to have any beneficial effect in patients with sepsis who are critically ill. In view of the real side effects of dopamine infusion, the use of renal-dose dopamine should be abandoned.

Epinephrine

Epinephrine can increase MAP by increasing cardiac index and stroke volume, as well as by increasing systemic vascular resistance and heart rate. This agent may increase oxygen delivery and oxygen consumption. The use of epinephrine is recommended only in patients who are unresponsive to traditional agents. The undesirable effects of epinephrine include the following:

• An increase in systemic and regional lactate concentrations

• The potential to produce myocardial ischemia and promote development of arrhythmias

• Reduced splanchnic flow

Phenylephrine

Phenylephrine is a selective alpha₁ -adrenergic receptor agonist that is used primarily in anesthesia to increase blood pressure. Although the data are limited, studies have found phenylephrine to increase MAP in patients who were septic and hypotensive with increased oxygen consumption. However, concern remains about this agent’s potential to reduce cardiac output and lower heart rate in patients with sepsis. Phenylephrine may be a good choice when tachyarrhythmias limit therapy with other agents.

Vasopressin

Vasopressin is synthesized in the hypothalamus and excreted by the posterior pituitary. In contrast to endogenous catecholamines (eg, norepinephrine), whose serum levels are universally high in septic shock, vasopressin stores are limited and its levels are low. ^[91] Furthermore, catecholamine effectiveness on vascular smooth muscle cells is inhibited by the activation of ATP-dependent potassium channels and NO.

Exogenous administration of vasopressin results in vasoconstriction via activation of V1 receptors on vascular smooth muscle cells that have the effect of inhibiting ATP-dependent potassium channels and, in theory, restoring the effectiveness of catecholamines. Vasopressin is also thought to inhibit NO synthase and therefore counteract the vasodilatory effect of NO. In addition, vasopressin increases renal perfusion by causing vasodilation of afferent renal arterioles, in contrast to the renal vasoconstriction caused by catecholamines.

Several small clinical trials have shown that low-dose vasopressin increases MAP and decreases the requirement for catecholamines while maintaining mesenteric and renal perfusion. ^[91] However, a large, randomized trial (the Vasopressin and Septic Shock Trial [VASST]) did not find mortality to be significantly lower in patients who received vasopressin in addition to norepinephrine than in those who received norepinephrine alone, even though vasopressin reduced the requirement for norepinephrine. ^[92]

Overall, the major adverse effects attributed to vasopressin (myocardial ischemia, cardiac arrest, mesenteric, and digital ischemia) were not significantly increased in the trial; however, patients with known coronary artery disease or congestive heart failure were excluded from the study. ^[92] The incidence of digital ischemia was higher with vasopressin use. Because the mean time to receiving the drug in VASST was 12 hours, this study does not address the use of vasopressin in early sepsis resuscitation.

Although myocardial performance is altered during sepsis and septic shock, cardiac output generally is maintained in patients with volume-resuscitated sepsis. Data from the 1980s and 1990s suggested a linear relation between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that the oxygen delivery likely was insufficient to meet the metabolic needs of the patient.

However, subsequent investigations challenged the concept of pathologic supply dependency, suggesting that elevating cardiac index and oxygen delivery (hyperresuscitation) was not associated with improved patient outcome. Therefore, the role of inotropic therapy is uncertain, unless the patient has inadequate cardiac index, MAP, mixed venous oxygen saturation (SmvO₂), and UOP despite adequate volume resuscitation and vasopressor therapy.

Patients with sepsis or septic shock have hypermetabolism, maldistribution of blood flow, and, possibly, suboptimal oxygen delivery; therefore, attempts at detecting and correcting tissue hypoxia must be made. Lactic acidosis is an indication of either global ischemia (inadequate oxygen delivery) or regional (organ-specific) ischemia. Calculation of pH in the gastric mucosa via gastric tonometry may detect tissue hypoxia in the splanchnic circulation; however, this technique has not been validated extensively and is not widely available.

Dobutamine is an inotropic agent that stimulates beta receptors and results in increased cardiac output. In theory, it can enhance tissue oxygen delivery in patients with septic shock who have received adequate fluid resuscitation and vasopressor support. In EGDT, dobutamine is recommended if there is evidence of tissue hypoperfusion (central venous oxygen saturation [ScvO₂] < 70 mm Hg) after CVP, MAP, and hematocrit goals have been met.

The 2012 Surviving Sepsis Campaign guidelines recommend administration of dobutamine dosages up to 20 µg/kg/min only in the presence of myocardial dysfunction or persistent hypoperfusion despite adequate fluid resuscitation and adequate MAP. ^[11]

Although initial aggressive resuscitation to maximize oxygen delivery improves outcome, manipulation of oxygen delivery to deliver supraphysiologic oxygen to tissues via blood transfusion, fluid boluses, or inotropic therapy once organ dysfunction has developed has not improved outcome in critically ill patients. Hayes et al reported a higher mortality in patients with sepsis who were maintained on high levels of oxygen delivery. ^[93] Thus, inotropic therapy is not recommended for increasing the cardiac index to supranormal levels. ^{[11, 60]}

In patients with septic shock, the inability to increase oxygen consumption and to decrease lactate levels most likely is a consequence of impaired oxygen extraction or inability to reverse anaerobic metabolism. Boosting oxygen delivery to supranormal levels does not reverse these pathophysiologic mechanisms after the development of organ injury.

Empiric antimicrobial therapy should be initiated early in patients experiencing septic shock (within 1 hour of recognition of septic shock) and sepsis without septic shock, if possible. ^{[11, 60]}

The Surviving Sepsis Campaign guidelines recommend including 1 or more agents that are not only active against the likely organisms but also capable of penetrating “in adequate concentrations into the presumed source of sepsis,” with daily reevaluation of the anti-infective therapy for potential de-escalation. ^{[11, 60]}

Generally, a 7- to 10-day treatment course is followed. Longer treatment regimens may be warranted in the presence of a slow clinical response, undrainable foci of infection, and immunologic deficiencies (eg, neutropenia). The use of procalcitonin or similar biomarkers may facilitate discontinuance of antibiotics in patients with clinical improvement and no further evidence of infection. ^[11]

Combination empiric therapy is recommended for patients with the following ^[11] :

• Difficult-to-treat, multidrug-resistant microorganisms (eg, Pseudomonas and Acinetobacter species)

• Severe infections associated with respiratory failure and septic shock

• Septic shock and bacteremia from pneumococci

However, combination therapy should be limited to 3-5 days, after which period treatment should switch to the most appropriate monotherapy once the results of the susceptibility profile are available. ^{[11, 60]}

The following points must always be considered:

• Early broad-spectrum empiric antibiotic therapy is essential; the coverage spectrum will be narrowed later, when culture results become available

• Waiting until cultures are back is an invalid reason to withhold antibiotics

• Only 30% of patients with presumed septic shock have positive blood cultures ^{[3, 4, 5, 37]}

• About 25% of presumed septic shock patients remain culture-negative from all sites, but mortality is similar to that for culture-positive counterparts ^{[3, 4, 5, 37]}

• Promptly discontinue antimicrobial therapy if the patient’s condition is determined to be from a noninfectious source ^{[11, 60]}

Antibiotic selection

The selection of appropriate agents is based on the patient’s underlying host defenses, the potential sources of infection, and the most likely culprit organisms. Antibiotics must be broad-spectrum agents and must cover gram-positive, gram-negative, and anaerobic bacteria because organisms from any of these different classes can produce the same clinical picture of distributive shock.

If the patient is “antibiotic-experienced,” strong consideration should be given to using an aminoglycoside rather than a quinolone or cephalosporin for gram-negative coverage. Knowing the antibiotic resistance patterns of both the hospital itself and its referral base (ie, nursing homes) is very important.

Antibiotics should be administered parenterally, in doses adequate to achieve bactericidal serum levels. Many studies have found that clinical improvement correlates with the achievement of serum bactericidal levels rather than with the number of antibiotics given.

In the selection of empiric antibiotics, the increasing prevalence of MRSA must be taken into account, and an agent such as vancomycin or linezolid should be included. This is especially true in patients with a history of IV drug use, those with indwelling vascular catheters or devices, or those with recent hospitalizations. Antianaerobic coverage is indicated in patients with intra-abdominal or perineal infections.

Certain organisms, chiefly Enterobacteriaceae (eg, Escherichia coli and Klebsiella pneumoniae), contain a beta-lactamase enzyme that hydrolyzes the beta-lactam ring of penicillins and cephalosporins and thus inactivates these antibiotics (ESBL-producing bacteria). This phenomenon has become an increasing concern as its prevalence has increased. Beta-lactam antibiotics that have remained effective against ESBL-producing organisms include cephamycins (eg, cefotetan) and carbapenems (eg, imipenem, meropenem, and ertapenem). ^[94]

In immunocompetent patients, monotherapy with carbapenems (eg, imipenem and meropenem), third- or fourth-generation cephalosporins (eg, cefotaxime, cefoperazone, ceftazidime, and cefepime), or extended-spectrum penicillins (eg, ticarcillin and piperacillin) is usually adequate, without the need for a nephrotoxic aminoglycoside. ^[95] Patients who are immunocompromised or at high risk for multidrug-resistant organisms typically require dual broad-spectrum antibiotics with overlapping coverage.

Within these general guidelines, no single combination of antibiotics is clearly superior to any other.

Three additional antibiotics, oritavancin (Orbactiv), dalbavancin (Dalvance), and tedizolid (Sivextro), are approved by the FDA for the treatment of acute bacterial skin and skin structure infections. These agents are active against Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S aureus [MSSA, MRSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group (includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), among others. For complete drug information, including dosing, see the following monographs:

• Oritavancin

• Dalbavancin

• Tedizolid

Community-acquired pneumonia

For inpatients with pneumonia who are not admitted to the ICU, the guidelines formulated by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recommend administering the following ^[66] :

• A respiratory fluoroquinolone, especially in penicillin-allergic patients

• A beta-lactam agent (cefotaxime, ceftriaxone, or ampicillin) plus a macrolide; ertapenem may be used for selected patients, and doxycycline may be an alternative to the macrolide

• Antibiotic therapy for a minimum of 5 days for community-acquired pneumonia; the treatment duration may be increased in complicated cases or in cases where the initial therapy did not provide a clinical response against the identified organism

For inpatients with pneumonia who are admitted to the ICU, the IDSA/ATS guidelines offer the following minimal recommendations ^[66] :

• Administer a beta-lactam (eg, cefotaxime, ceftriaxone, ampicillin-sulbactam) plus either azithromycin or a fluoroquinolone; penicillin-allergic patients may receive a respiratory fluoroquinolone and aztreonam

• For pseudomonal infections, administer (1) an antipneumococcal, antipseudomonal beta-lactam agent (eg, piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus ciprofloxacin or levofloxacin; (2) the beta-lactam above plus an aminoglycoside and azithromycin; or (3) the beta-lactam above plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, use aztreonam instead of the above beta-lactam)

• Add vancomycin or linezolid for patients with community-acquired MRSA (CA-MRSA) infection

Other IDSA/ATS recommendations include the following ^[2] :

• Influenza A – Early treatment (≤48 hr after symptoms onset) with oseltamivir or zanamivir; although these 2 agents are not recommended for use in uncomplicated influenza with symptoms longer than 48 hours, they may be used for reduction of viral shedding in inpatients or for influenza pneumonia

• H5N1 infection – In suspected cases, administer oseltamivir and antibacterial agents against S pneumoniae and S aureus, which can cause secondary bacterial pneumonia in influenza patients

Intra-abdominal infections

For community-acquired abdominal infections, the IDSA and the Surgical Infection Society (SIS) indicate that empiric antibiotic therapies should be active against enteric gram-negative aerobic and facultative bacilli as well as enteric gram-positive streptococci. ^[2]

Empiric coverage is not needed for Enterococcus, nor is empiric antifungal therapy needed for Candida, unless these infections are severe. Antibiotics with activity against E faecalis include ampicillin, piperacillin-tazobactam, and vancomycin. Fluconazole is used for isolated C albicans; an echinocandin (eg, caspofungin, micafungin, or anidulafungin) is used for fluconazole-resistant Candida. ^[2] In critically ill patients, an echinocandin is recommended over a triazole (eg, fluconazole or itraconazole). ^[2]

Agents that cause healthcare-associated intra-abdominal infections include Candida, Enterococcus, and MRSA. Empiric antibiotic therapy for those infections should be based on local susceptibility results.

In adults with community-acquired infection or hospital-associated intra-abdominal infection of high severity (eg, Acute Physiology And Chronic Health Evaluation [APACHE] II score >15), broad-spectrum agents are used against gram-negative activity (eg, metronidazole plus meropenem, imipenem-cilastatin, doripenem, piperacillin-tazobactam, ciprofloxacin, or levofloxacin; alternatively, metronidazole plus ceftazidime or cefepime). ^[2]

Antibiotics that are not recommended for treating intra-abdominal infections, because of the greater prevalence of resistance, include ampicillin-sulbactam and quinolones (high resistance in community-acquired E coli), as well as cefotetan and clindamycin (high resistance in Bacteroides fragilis). ^[2] In addition, aminoglycosides, because of their toxicity and the availability of other agents, are not recommended for routine use in community-acquired abdominal infections.

Corticosteroid insufficiency has been associated with severe illness. ^[96] The American College of Critical Care Medicine (ACCCM) uses the term “critical illness-related corticosteroid insufficiency” (CIRCI) to describe hypothalamic-pituitary-adrenal (HPA) axis dysfunction in critically ill patients and recommends avoiding use of the terms “absolute” or “relative” adrenal insufficiency in such patients. ^[65]

Although there is theoretical and experimental animal evidence favoring the use of large doses of corticosteroids (eg, methylprednisolone, hydrocortisone, and dexamethasone) in patients with sepsis and septic shock, the clinical medical literature does not support the routine use of such doses in these patients.

High-dose corticosteroids should not be used in patients with sepsis or septic shock. A meta-analysis of prospective, randomized, controlled trials of glucocorticoid use did not find any benefit from corticosteroids and suggested that their use could be harmful. ^[97] A review of 3 meta-analyses found that use of low-dose corticosteroids did not improve survival in septic shock and sepsis and that they were associated with side effects that included superinfections, bleeding, and hyperglycemia. ^[98]

Some trials have documented positive results from stress-dose administration of corticosteroids in patients with severe and refractory shock. ^[99] Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.

Other studies have shown that lower-dose steroids may be beneficial for patients with relative adrenal insufficiency. In a study by Annane et al that included 299 patients with septic shock who were randomly assigned to receive low-dose steroids (hydrocortisone, 50 mg q6hr, and fludrocortisone, 50 µg/day) or placebo, 77% were nonresponders; for nonresponders who received steroids, there was a 10% absolute benefit with respect to mortality (63% vs 53%). ^[100]

In this study, all patients had been intubated, had been persistently hypotensive despite crystalloid resuscitation and vasopressor administration, and had had evidence of end-organ failure. ^[100] Nonresponders were defined as those whose cortisol level increased by less than 10 µg/dL in a cortisol stimulation test and thus were considered adrenally insufficient. This test involves measuring cortisol levels before and 30 minutes after IV administration of 0.25 mg of cosyntropin (ie, adrenocorticotropic hormone [ACTH]).

Although performing the cortisol stimulation test in the ED setting may not be practical, given time and resource constraints, it is worth noting that more than 75% of patients with vasopressor-refractory hypotension were adrenally insufficient. ^[100] This finding suggested that the majority of patients with vasopressor-refractory shock would benefit from steroid administration, regardless of the results of the cortisol stimulation test. A common choice is hydrocortisone 100 mg IV; a good alternative is dexamethasone 10 mg IV.

In a subsequent study, Annane et al published a systematic review of corticosteroid use for severe sepsis and septic shock, the pooled results of which showed that the subgroup of studies using prolonged, low-dose corticosteroid therapy demonstrated a beneficial effect on short-term mortality. ^[101] However, no clear benefit was shown with the use of high-dose corticosteroids for severe sepsis or septic shock. ^[101]

In the CORTICUS (Corticosteroid Therapy of Septic Shock) study, a large randomized trial of hydrocortisone versus placebo in patients with septic shock, no difference in mortality was noted between the groups, even though the patients who received steroids had a more rapid resolution of shock, as measured by a shorter duration of vasopressor therapy ^[102] and a faster improvement in Sequential Organ Failure Assessment (SOFA) scores. ^[103] However, the incidence of superinfection and recurrent sepsis was higher in those who received steroids.

Additionally, the result of the cortisol stimulation test had no bearing on outcome in the CORTICUS trial, ^[102] which raises questions about the value of this test in determining who will benefit from steroid treatment. However, the CORTICUS study enrolled all patients with septic shock, regardless of vasopressor response. Consequently, patients in this study had a lower mortality than those in the Annane study.

Guidelines recommendations and summary of key points regarding steroids

The 2012 Surviving Sepsis Campaign guidelines emphasize that steroids should not be administered to patients with septic shock unless hemodynamic stability cannot be achieved with fluid resuscitation and vasopressor agents. ^[11] In addition, these guidelines ^{[11, 60]} and those of the ACCCM ^[65] recommend the following:

• Do not use the ACTH stimulation test to identify the subset of adult patients with septic shock (or ARDS) who should receive hydrocortisone ^{[11, 60, 65]}

• Do not administer dexamethasone when hydrocortisone is available; fludrocortisone is optional if hydrocortisone is used, but when hydrocortisone is not available and the substituted steroid does not have significant mineralocorticoid activity, consider daily administration of oral fludrocortisone (50 µg once daily) ^{[11, 60]}

The ACCCM also has the following treatment recommendations ^[65] :

• For patients with septic shock, administer hydrocortisone 200 mg/day IV in 4 divided doses or as a 100-mg bolus followed by continuous infusion at 10 mg/hr (240 mg/d); in patients with early severe ARDS, the optimal initial treatment regimen is continuous infusion of methylprednisolone 1 mg/kg/day

• Although the optimal treatment period for corticosteroids in patients with septic shock and early ARDS remains to be determined, a regimen of 7 days or longer should be used in patients with septic shock—provided that signs of sepsis or shock do not recur—before tapering, and a regimen of 14 days or longer should be used in patients with early ARDS before tapering

• Do not use dexamethasone therapy for septic shock or ARDS

The following key points summarize use of corticosteroids in septic shock:

• Older, traditional trials of corticosteroids in sepsis were unsuccessful, probably because of high dosages and poor patient selection

• More recent trials with low-dose (physiologic) dosages in select patient populations (those with vasopressor dependence and, possibly, relative adrenal insufficiency) may have resulted in improved outcome

• Corticosteroids (hydrocortisone) should be considered only for patients with vasopressor-dependent septic shock ^[65] ; wean steroid therapy when vasopressor therapy is no longer needed ^{[11, 60]}

• Consider moderate-dose corticosteroids in the management of patients with early severe ARDS (arterial oxygen tension [PaO₂]/fraction of inspired oxygen [FIO₂] < 200), as well as before day 14 in patients with unresolving ARDS ^[65] ; investigators still need to determine what role corticosteroid treatment may have in less severe ARDS (PaO₂/FIO₂ >200) ^[65]

• A cortisol stimulation test may be performed to identify patients with relative adrenal insufficiency, defined as failure to increase levels by more than 9 µg/dL

• Do not administer corticosteroids to treat sepsis when shock is not present ^{[11, 60]}

• Maintenance steroid therapy or stress-dose steroids may be continued as needed on the basis of the patient’s endocrine or corticosteroid-administration history ^{[11, 60]}

A Belgian study of critically ill surgical ICU (SICU) patients found a 10% mortality benefit in those with tighter glycemic control—when the glucose levels were maintained between 80 and 110 mg/dL through intensive insulin therapy. ^[104] However, subsequent large, randomized studies did not replicate the results from the Belgian study ^{[105, 106, 107]} In fact, intensive insulin treatment has been shown to lead to increased episodes of hypoglycemia and increased mortality in ICU patients. ^{[107, 108, 109, 110]}

On the basis of the current evidence, the Surviving Sepsis Campaign guidelines recommend maintaining a glucose level below 180 mg/dL. ^[11]

Deep vein thrombosis

The Severe Sepsis Campaign guidelines have the following recommendations or suggestions regarding prophylaxis of deep vein thrombosis (DVT) in patients with sepsis ^{[11, 60]} :

• In the absence of contraindications (eg, active bleeding or thrombocytopenia), administer either low-dose unfractionated heparin (UFH; 2 or 3 times daily) or low-molecular-weight heparin (LMWH); LMWH may be preferred in very high risk patients (eg, patients with sepsis and previous DVT, trauma, or orthopedic surgery)

• If the patient’s creatinine clearance is less than 30 mL/min, dalteparin may be used

• In the presence of contraindications for heparin use and in the absence of other contraindications, use mechanical DVT prevention devices (eg, graduated compression stockings [GCS] or intermittent compression devices [ICDs])

• In very high risk patients, consider combining pharmacologic and mechanical prophylactic therapy unless contraindications exist or such therapy would be impractical

(See Deep Venous Thrombosis, Thromboembolism, and General Principles of Anticoagulation in Deep Venous Thrombosis.)

Disseminated intravascular coagulation

DIC, a condition in which bleeding and thrombosis occur, can contribute to multiorgan system failure and carries a high mortality. Although controversy exists regarding DIC treatment, the overall management strategy is to treat the underlying cause and provide supportive care (see Correction of anemia and coagulopathy under General Treatment Guidelines).

In 2009, the British Committee for Standards in Haematology (BCSH) published their guidelines recommendations, in which they state that treating the underlying etiology is “the cornerstone” of DIC therapy. ^[111] The BSCH guidelines regarding adjunctive treatment (eg, plasma and platelet transfusion, anticoagulation, use of anticoagulant factor concentrates, and antifibrinolytic therapy) are discussed below.

Plasma and platelet transfusion

In general, the BSCH recommends reserving transfusion of platelets or plasma (components) for patients with DIC who are bleeding (rather than administering this therapy on the basis of laboratory findings). Thus, platelet transfusion should be considered in patients with DIC and bleeding (or a high risk of bleeding) who have a platelet count below 50 × 10⁹/L (50,000/µL). ^[111] The Surviving Sepsis Campaign suggests considering platelet transfusion in such patients when platelet counts are below 20 × 10⁹/L (20,000/µL). ^[11]

Other BSCH plasma/platelet transfusion guidelines include the following ^[111] :

• Do not administer prophylactic platelet transfusions in nonbleeding patients unless they are at high risk of bleeding

• Consider administering FFP in patients with DIC and active bleeding who have prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), as well as those who may undergo an invasive procedure; do not administer FFP solely on the basis of laboratory findings

• Consider administering factor concentrates (eg, prothrombin complex concentrate) if FFP cannot be transfused; note that these agents contain only selected factors and will not completely correct the DIC

• Consider administering fibrinogen concentrate or cryoprecipitate in cases of persistent severe hypofibrinogenemia (< 1 g/L) despite FFP therapy

Anticoagulation

Therapeutic doses of heparin should be considered in the following clinical situations of DIC ^[111] :

• When thrombosis predominates (eg, arterial or venous thromboembolism)

• In the presence of severe purpura fulminans with associated inadequate perfusion to the extremities

• In the presence of vascular skin infarction

Continuous infusion of UFH should be considered in patients with DIC who are at high risk of bleeding; for example, weight-adjusted doses (eg, 10 U/kg/hr) “may be used without the intention to prolong the aPTT ratio to 1.5-2.5 times the control.” ^[111] Close monitoring of these patients is required for signs of bleeding and for their aPTT measurements.

DVT prophylaxis with prophylactic doses of heparin or LMWH is recommended for critically ill patients with DIC who are not actively bleeding. ^[111]

Antifibrinolytic therapy

In general, the BSCH does not recommend administering antifibrinolytic agents to patients with DIC. ^[111] In patients who have DIC that is characterized by a primary hyperfibrinolytic state and who present with severe bleeding, administration of lysine analogues (eg, tranexamic acid 1 g q8hr) may be considered.

ARDS and ALI (now often referred to as mild ARDS, in accordance with the Berlin Definition ^[10] ) are major complications of sepsis and septic shock. The incidence of ARDS in septic shock ranges from 20% to 40% and is higher when a pulmonary source of infection exists. (See Acute Respiratory Distress Syndrome and Pediatric Acute Respiratory Distress Syndrome.)

ARDS can be associated with clinical disorders causing direct lung injury, such as gastric acid aspiration, thoracic trauma, pneumonia, and near drowning; or indirect lung injury, including sepsis, acute pancreatitis, drug overdose, reperfusion injury, and severe nonthoracic trauma. Sepsis-associated ARDS carries an abysmal prognosis and carries the highest mortality.

Management of ARDS is primarily supportive; pharmacologic and other innovative therapies have not proved especially beneficial. General supportive care includes adequate treatment of underlying sepsis with appropriate antibiotics and surgical management if indicated. Appropriate fluid management to lower intravascular volume without affecting cardiac output and organ perfusion may be beneficial. The fluid manipulation often requires invasive hemodynamic monitoring.

The goals of mechanical ventilation include the following:

• Improving gas exchange

• Reducing work of breathing

• Avoiding oxygen toxicity

• Minimizing high airway pressures

• Avoiding further lung damage

• Allowing the injured lung to heal

A lung-protective and pressure-limited ventilatory strategy has been shown to improve survival rates and lower rates of barotrauma. Current recommendations are to use a tidal volume of 5-8 mL/kg, to employ a longer inspiratory time, and not to exceed a transpulmonary pressure of 30 cm water. Permissive hypercapnia may ensue may occur with the use of lesser tidal volumes, but it is tolerated.

The use of PEEP may reduce or prevent ventilator-induced lung injury. Sufficient PEEP to recruit atelectatic alveolar units and to increase lung volumes so that respiration happens on the most compliant part of the pressure volume curve is recommended. In clinical practice, this can be achieved by measuring plateau pressures and calculating lung compliance at different levels of PEEP. The use of prone positioning and NO may prove to be beneficial in the short term; these interventions have not been shown to improve survival rates.

High-dose corticosteroids, though not useful in early management, can improve survival in patients whose ARDS is not resolving. In a study by Meduri et al, prolonged administration of methylprednisolone in patients with nonresolving ARDS was associated with improvement and reduced mortality. ^[112] Mortality was 0/16 (0%) for the treatment group and 5/8 (62%) for the placebo group in the ICU. The rate of infections, including pneumonia, was similar in the 2 groups. More evidence is needed regarding steroid use and ARDS.

Patients with focal infections should be sent for definitive surgical treatment after initial resuscitation and antibiotic therapy. ^[2] Little is gained by spending hours stabilizing the patient while an infected focus persists. However, even though urgent management is warranted for hemodynamically stable patients without evidence of acute organ failure, it may be possible to delay invasive procedures up to 24 hours—provided that very close clinical monitoring is instituted and appropriate antimicrobial therapy administered. ^[2]

Any soft-tissue abscess should be drained promptly. Certain conditions will not respond to standard treatment for septic shock until the source of infection is surgically removed. Some of these common foci of infection include intra-abdominal sepsis (perforation or abscess), empyema, mediastinitis, cholangitis, pancreatic abscess, pyelonephritis or renal abscess from ureteric obstruction, infective endocarditis, septic arthritis, infected prosthetic devices, deep cutaneous or perirectal abscess, and necrotizing fasciitis.

Whenever possible, percutaneous drainage of abscesses and other well-localized fluid collections is preferred to surgical drainage. ^[2] For example, a superficial abscess can be drained in the ED. However, any deep abscess or suspected necrotizing fasciitis should be drained in the surgical suite. Other examples of emergency conditions that call for rapid management are diffuse peritonitis, cholangitis, and intestinal infarction. ^{[11, 60]}

In cases of sepsis of unclear etiology, a thorough search for abscesses should be performed, with particular attention paid to the rectal and perianal area.

Patients with impaired host defense mechanisms are at greatly increased risk for sepsis. The main causes of impaired host defense are as follows:

• Chemotherapeutic drugs

• Malignancy

• Severe trauma

• Burns

• Diabetes mellitus

• Renal or hepatic failure

• Advanced age

Ventilatory support and invasive catheters further increase the risk of infection. Avoiding the use of catheters or removing them as soon as possible may prevent sepsis.

Prophylactic antibiotics in the perioperative phase, particularly after GI surgery, may be beneficial. The use of topical antibiotics around invasive catheters and as part of dressings for patients with burns is helpful. Other preventive measures include maintenance of adequate nutrition, administration of pneumococcal vaccine in patients who have undergone splenectomy, and early enteral feeding.

Prevention of sepsis with topical or systemic antibiotics is suggested for high-risk patients. Use of nonabsorbable antibiotics in the stomach to prevent translocation of bacteria and occurrence of bacteremia is a controversial issue.

Numerous trials have been performed, using either topical antibiotics alone or a combination of topical and systemic antibiotics. A systemic review by Nathens found no benefit in medical patients but documented a reduced mortality in surgical trauma patients. ^[113] The beneficial effect was achieved with a combination of systemic and topical antibiotics, predominantly by reducing lower respiratory tract infections in treated patients.

Progression from infection with systemic inflammatory response syndrome (ie, sepsis) to sepsis with organ dysfunction to septic shock with refractory hypotension can often be reversed with early identification, aggressive crystalloid fluid resuscitation, broad-spectrum antibiotic administration, and removal of the infectious source if possible.

Basic measures to prevent nosocomial infections include the following ^[54] :

• Shortening the hospital stay

• Removing indwelling catheters as early as possible

• Avoiding unnecessary invasive procedures

• Using aseptic techniques