Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Sepsis is a clinical syndrome characterized by systemic inflammation due to infection. There is a continuum of severity ranging from sepsis to septic shock. Although wide-ranging and dependent upon the population studied, mortality has been estimated to be ≥10 percent and ≥40 percent when shock is present [1,2].
In this topic review, the management of sepsis and septic shock is discussed. Our approach is consistent with 2016 guidelines issued by the Surviving Sepsis Campaign [3,4]. While we use the Society of Critical Care Medicine/European Society of Intensive Care Medicine definitions, such definitions are not unanimously accepted. For example, the Center for Medicare and Medicaid Services (CMS) still continues to support the previous definition of systemic inflammatory response syndrome, sepsis, and severe sepsis. Definitions, diagnosis, pathophysiology, and investigational therapies for sepsis, as well as management of sepsis in the asplenic patient are reviewed separately. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Pathophysiology of sepsis" and "Investigational and ineffective therapies for sepsis" and "Clinical features and management of sepsis in the asplenic patient".)
IMMEDIATE EVALUATION AND MANAGEMENT — Securing the airway (if indicated) and correcting hypoxemia, and establishing venous access for the early administration of fluids and antibiotics are priorities in the management of patients with sepsis and septic shock [3,4].
Stabilize respiration — Supplemental oxygen should be supplied to all patients with sepsis and oxygenation should be monitored continuously with pulse oximetry. Intubation and mechanical ventilation may be required to support the increased work of breathing that typically accompanies sepsis, or for airway protection since encephalopathy and a depressed level of consciousness frequently complicate sepsis [5,6]. Techniques, and sedative and induction agents are discussed separately. (See "Induction agents for rapid sequence intubation in adults outside the operating room" and "Advanced emergency airway management in adults" and "Rapid sequence intubation for adults outside the operating room" and "The decision to intubate" and "Direct laryngoscopy and endotracheal intubation in adults".)
Establish venous access — Venous access should be established as soon as possible in patients with suspected sepsis. While peripheral venous access may be sufficient in some patients, particularly for initial resuscitation, the majority will require central venous access at some point during their course. However, the insertion of a central line should not delay the administration of resuscitative fluids and antibiotics. A central venous catheter (CVC) can be used to infuse intravenous fluids, medications (particularly vasopressors), and blood products, as well as to draw blood for frequent laboratory studies. While a CVC can be used to monitor the therapeutic response by measuring the central venous pressure (CVP) and the central venous oxyhemoglobin saturation (ScvO2), evidence from randomized trials suggest that their value is limited [7-12]. (See "Complications of central venous catheters and their prevention" and 'Monitor response' below.)
Initial investigations — An initial brief history and examination, as well as laboratory, microbiologic, and imaging studies are often obtained simultaneously while access is being established and the airway stabilized. This brief assessment yields clues to the suspected source and complications of sepsis, and therefore, helps guide empiric therapy and additional testing (table 1). (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Clinical presentation' and 'Empiric antibiotic therapy (first hour)' below.).
Quickly obtaining the following is preferable (within 45 minutes of presentation) but should not delay the administration of fluids and antibiotics:
●Complete blood counts with differential, chemistries, liver function tests, and coagulation studies including D-dimer level. Results from these studies may support the diagnosis, indicate the severity of sepsis, and provide baseline to follow the therapeutic response.
●Serum lactate – An elevated serum lactate (eg, >2 mmol/L or greater than the laboratory upper limit of normal) may indicate the severity of sepsis and is used to follow the therapeutic response [3,4,13-15].
●Arterial blood gas (ABG) analysis – ABGs may reveal acidosis, hypoxemia, or hypercapnia.
●Peripheral blood cultures (aerobic and anaerobic cultures from at least two different sites), urinalysis, and microbiologic cultures (eg, sputum, urine, intravascular catheter, wound or surgical site, body fluids) from readily accessible sites – For patients with a vascular catheter, blood should be obtained both from the catheter and from peripheral sites.
●Imaging targeted at the suspected site of infection is warranted (eg, chest radiography, computed tomography of chest and/or abdomen).
●Procalcitonin – While we are not proponents of measuring procalcitonin, it has become increasingly popular. Its diagnostic value and value in deescalating antibiotic therapy are controversial and poorly supported by evidence.
INITIAL RESUSCITATIVE THERAPY — The cornerstone of initial resuscitation is the rapid restoration of perfusion and the early administration of antibiotics.
●Tissue perfusion is predominantly achieved by the aggressive administration of intravenous fluids (IVF), usually crystalloids (balanced crystalloids or normal saline) given at 30 mL/kg (actual body weight) within the first three hours following presentation.
●Empiric antibiotic therapy is targeted at the suspected organism(s) and site(s) of infection and preferably administered within the first hour.
Our approach is based upon several major randomized trials that used a protocol-based approach (ie, early goal-directed therapy [EGDT]) to treating sepsis [7-12]. Components of the protocols usually included the early administration of fluids and antibiotics (within one to six hours) using the following targets to measure the response: central venous oxyhemoglobin saturation (ScvO2) ≥70 percent, central venous pressure (CVP) 8 to 12 mmHg, mean arterial pressure (MAP) ≥65 mmHg, and urine output ≥0.5 mL/kg/hour. Although all trials [8-10] (except for one ), did not show a mortality benefit to EGDT, it is thought that the lack of benefit was explained by an overall improved outcome in both control and treatment groups, and to improved clinical performance by trained clinicians in academic centers during an era that followed an aggressive sepsis education and management campaign. In support of this hypothesis is that central line placement was common (>50 percent) in control groups so it is likely that CVP and ScvO2 were targeted in these patients. Furthermore, the mortality in studies that did not report a benefit to EGDT [8-10] approximated that of the treatment arm in the only study that reported benefit .
●One single center randomized trial of 263 patients with suspected sepsis reported a lower mortality in patients when ScvO2, CVP, MAP, and urine output were used to direct therapy compared with those in whom only CVP, MAP, and urine output were targeted (31 versus 47 percent) . Both groups initiated therapy, including antibiotics, within six hours of presentation. There was a heavy emphasis on the use of red cell transfusion (for a hematocrit >30) and dobutamine to reach the ScvO2 target in this trial.
●Three subsequent multicenter randomized trials of patients with septic shock, ProCESS , ARISE , and ProMISE  and two meta-analyses [11,12] all reported no mortality benefit (mortality ranged from 20 to 30 percent), associated with an identical protocol compared with protocols that used some of these targets or usual care.
The importance of timely treatment, particularly with antibiotics, was illustrated in a database study of nearly 50,000 patients with sepsis and septic shock who were treated with various types of protocolized treatment bundles (that included fluids and antibiotics, blood cultures, and serum lactate measurements) . Compared with those in whom a three-hour bundle (blood cultures before broad spectrum antibiotics, serum lactate level) was completed within the three-hour time frame, a higher in-hospital mortality was reported when a three-hour bundle was completed later than three hours (odds ratio [OR] 1.04 per hour). Increased mortality was associated with the delayed administration of antibiotics but not with a longer time to completion of a fluid bolus (as part of a six hour bundle) (OR 1.04 per hour versus 1.10 per hour).
Intravenous fluids (first three hours) — In patients with sepsis, intravascular hypovolemia is typical and may be severe, requiring rapid fluid resuscitation. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)
Volume — Intravascular hypovolemia is typical and may be severe in sepsis. Rapid, large volume infusions of IVF (30 mL/kg) are indicated as initial therapy for severe sepsis or septic shock, unless there is convincing evidence of significant pulmonary edema. This approach is based upon several randomized trials that reported no difference in mortality when mean infusion volumes of 2 to 3 liters were administered in the first three hours [8-10] compared with larger volumes of three to five liters, which was considered standard therapy at the time . However, some patients may require higher than recommended volumes, particularly those who demonstrate clinical and/or hemodynamic indicators of fluid-responsiveness. (See 'Monitor response' below.)
Fluid therapy should be administered in well-defined (eg, 500 mL), rapidly infused boluses. The clinical and hemodynamic response and the presence or absence of pulmonary edema must be assessed before and after each bolus. Intravenous fluid challenges can be repeated until blood pressure and tissue perfusion are acceptable, pulmonary edema ensues, or fluid fails to augment perfusion.
Choice of fluid — Evidence from randomized trials and meta-analyses have found no convincing difference between using albumin solutions and crystalloid solutions (eg, normal saline, Ringer's lactate) in the treatment of sepsis or septic shock, but they have identified potential harm from using pentastarch or hydroxyethyl starch [17-26]. There is no role for hypertonic saline .
In our practice, we generally use a crystalloid solution instead of albumin solution because of the lack of clear benefit and higher cost of albumin. However, some experts administer albumin as an additive or maintenance fluid if there is a perceived need to avoid or treat the hyperchloremia that occurs when large volumes of crystalloid are administered, although the data to support this practice are weak.
Data discussing IVF choice among patients with sepsis include the following:
●Crystalloid versus albumin – Among patients with sepsis, several randomized trials and meta-analyses have reported no difference in mortality when albumin was compared with crystalloids, although one meta-analysis suggested benefit in those with septic shock [18,25,26]. In the Saline versus Albumin Fluid Evaluation (SAFE) trial performed in critically ill patients, there was no benefit to albumin compared with saline even in the subgroup with severe sepsis, who comprised 18 percent of the total group . Among the crystalloids, there are no guidelines to suggest that one form is more beneficial than the other.
●Crystalloid versus hydroxyethyl starch (HES) – In the Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, compared with Ringer’s acetate, use of HES resulted in increased mortality (51 versus 43 percent) and renal replacement therapy (22 versus 16 percent) . Similar results were found in additional trials of patients without sepsis.
●Crystalloid versus pentastarch – The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial compared pentastarch to modified Ringer's lactate in patients with severe sepsis and found no difference in 28-day mortality . The trial was stopped early because there was a trend toward increased 90-day mortality among patients who received pentastarch.
Data discussing IVF choice in non-septic patients are provided separately. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Choice of replacement fluid'.)
Empiric antibiotic therapy (first hour) — Prompt identification and treatment of the site(s) of infection is the primary therapeutic intervention, with most other interventions being purely supportive.
Identification of suspected source — Empiric antibiotics should be targeted at the suspected source(s) of infection which is typically identified from the initial brief history and preliminary laboratory findings and imaging (table 1) (see 'Initial investigations' above). However, additional diagnostic testing or interventions may be required to identify the anatomic site(s) of infection. (See 'Septic focus identification and source control' below.)
Timing — Optimal doses of appropriate intravenous antibiotic therapy should be initiated within one hour of presentation, preferably after cultures have been obtained. (See 'Initial investigations' above.)
Although the feasibility of a one hour target has not been assessed, the rationale for choosing it is based upon several observational studies that report poor outcomes with delayed (even beyond one hour), inadequately dosed, or inappropriate (ie, treatment with antibiotics to which the pathogen was later shown to be resistant in vitro) antimicrobial therapy [28-37].
●In a retrospective analysis of over 17,000 patient with sepsis and septic shock, delay in first antibiotic administration was associated with increased in-hospital mortality with a linear increase in the risk of mortality for each hour delay in antibiotic administration .
●A prospective cohort study of 2124 patients demonstrated that inappropriate antibiotic selection was surprisingly common (32 percent) . Mortality was markedly increased in these patients compared with those who had received appropriate antibiotics (34 versus 18 percent).
The early administration of antimicrobials is challenging with several patient- and institutional-related factors that influence delay . Institutional protocols should address timeliness as a quality improvement measure .
Choosing a regimen — The choice of antimicrobials can be complex and should consider the patient's history (eg, recent antibiotics received, previous organisms), comorbidities (eg, diabetes, organ failures), immune defects (eg, human immune deficiency virus), clinical context (eg, community- or hospital-acquired), suspected site of infection, presence of invasive devices, Gram stain data, and local prevalence and resistance patterns [40-42]. The general principles and examples of potential empiric regimens are given in this section but antimicrobial choice should be tailored to each individual.
For most patients with sepsis without shock, we recommend empiric broad spectrum therapy with one or more antimicrobials to cover all likely pathogens. Coverage should be directed against both gram-positive and gram-negative bacteria and, if indicated, against fungi (eg, Candida) and rarely viruses (eg, influenza). Broad spectrum is defined as therapeutic agent(s) with sufficient activity to cover a range of gram negative and positive organisms (eg, carbapenem, piperacillin-tazobactam). Many patients with septic shock should receive combination therapy with at least two antimicrobials from two different classes (ie, combination therapy) depending on the organisms that are considered likely pathogens and local antibiotic susceptibilities. Combination therapy is defined as multiple antibiotics given with the intent of covering a known or suspected pathogen with more than one agent.
Among organisms isolated from patients with sepsis, the most common include Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus pneumoniae, such that coverage of these organisms should be kept in mind when choosing an agent .
However, when the organism is unknown, the clinician should be mindful of other potential pathogens when risk factors are present and consider the following:
●Methicillin-resistant S. aureus – There is growing recognition that methicillin-resistant S. aureus (MRSA) is a cause of sepsis not only in hospitalized patients, but also in community dwelling individuals without recent hospitalization [44,45]. For these reasons, we suggest empiric intravenous vancomycin (adjusted for renal function) be added to empiric regimens, particularly in those with shock or those at risk for MRSA. Potential alternative agents to vancomycin (eg, daptomycin for non-pulmonary MRSA, linezolid, ceftaroline) should be considered for patients with refractory or virulent MRSA, or with a contraindication to vancomycin. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia", section on 'Bacteremia due to MRSA' and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Methicillin-resistant Staphylococcus aureus'.)
In our practice, if Pseudomonas is an unlikely pathogen, we favor combining vancomycin with one of the following:
●Pseudomonas – Alternatively, if Pseudomonas is a likely pathogen, we favor combining vancomycin with two of the following, depending on local antibiotic susceptibility patterns (see "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections"):
•Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or
•Monobactam (eg, aztreonam)
●Non pseudomonal gram-negative organisms (eg, E. coli, K. pneumoniae) – Gram-negative pathogens have historically been covered with two agents from different antibiotic classes. However, several clinical trials and two meta-analyses have failed to demonstrate superior overall efficacy of combination therapy compared to monotherapy with a third generation cephalosporin or a carbapenem [32,46-50]. Furthermore, one meta-analysis found double coverage that included an aminoglycoside was associated with an increased incidence of adverse events (nephrotoxicity) [49,50]. For this reason, in patients with suspected gram negative pathogens, we recommend use of a single agent with proven efficacy and the least possible toxicity, except in patients who are either neutropenic or whose sepsis is due to a known or suspected Pseudomonas infection, where combination therapy can be considered . (See "Pseudomonas aeruginosa bacteremia and endocarditis" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)
●Invasive fungal infections – The routine administration of empirical antifungal therapy is not generally warranted in non-neutropenic critically-ill patients. Invasive fungal infections occasionally complicate the course of critical illness, especially when the following risk factors are present: surgery, parenteral nutrition, prolonged antimicrobial treatment or hospitalization (especially in the intensive care unit), chemotherapy, transplant, chronic liver or renal failure, diabetes, major abdominal surgery, vascular devices, septic shock or multisite colonization with Candida spp. However, studies do not support the routine use of empiric antifungals in this population:
•In a meta-analysis of 22 studies (most often comparing fluconazole to placebo, but also using ketoconazole, anidulafungin, caspofungin, micafungin, and amphotericin B), untargeted empiric antifungal therapy possibly reduced fungal colonization and the risk of invasive fungal infection but did not reduce all-cause mortality .
•In a study of critically-ill patients ventilated at least five days, empiric antifungal treatment (mostly fluconazole) was not associated with a decreased risk of mortality or occurrence of invasive candidiasis .
•In a multicenter randomized trial (EMPIRICUS) of 260 non-neutropenic critically-ill patients with Candida colonization (at multiple sites), multiple organ failure, and ICU-acquired sepsis, empiric treatment for 14 days with micafungin did not result in improved infection-free survival at 28 days but did decrease the rate of new fungal infection .
However, if Candida or Aspergillus is strongly suspected or if neutropenia is present, echinocandin (for Candida) or voriconazole (for Aspergillus) are often preferred. (See "Treatment and prevention of invasive aspergillosis" and "Treatment of candidemia and invasive candidiasis in adults".)
●Other – Other regimens should consider the inclusion of agents for specific organisms such as Legionella (macrolide or fluoroquinolone) or difficult to treat organisms (eg, Stenotrophomonas), or for specific conditions (eg, neutropenic bacteremia)
Dosing — Clinicians should pay attention to maximizing the dose in patients with sepsis and septic shock using a full "high-end" loading dose where possible. This strategy is based upon the known increased volume of distribution that can occur in patients with sepsis due to the administration of fluid [54-56] and that higher clinical success rates have been reported in patients with higher peak concentrations of antimicrobials [57-59]. Continuous infusions of antibiotics as compared with intermittent dosing regimens remains investigational at this time .
MONITOR RESPONSE — After fluids and empiric antibiotics have been administered, the therapeutic response should be assessed frequently. We suggest that clinical, hemodynamic, and laboratory parameters be followed as outlined in the sections below. In our experience, most patients respond within the first 6 to 24 hours to initial fluid therapy, however, resolution can be protracted and take days or weeks. The response mostly influences further fluid management but can also affect antimicrobial therapy and source control.
Monitoring catheters — For many patients, a central venous catheter (CVC) and an arterial catheter are placed, although they are not always necessary. For example, an arterial catheter may be inserted if blood pressure is labile, sphygmomanometer readings are unreliable, restoration of perfusion is expected to be protracted (especially when vasopressors are administered), or dynamic measures of fluid responsiveness are selected to follow the hemodynamic response. A CVC may be placed if the infusion of large volumes of fluids or vasopressors are anticipated, peripheral access is poor, or the central venous pressure (CVP) or the central venous oxyhemoglobin saturation (ScvO2) are chosen as methods of monitoring the hemodynamic response. (See "Arterial catheterization techniques for invasive monitoring" and "Novel tools for hemodynamic monitoring in critically ill patients with shock" and "Overview of central venous access".)
We believe that pulmonary artery catheters (PACs) should not be used in the routine management of patients with sepsis or septic shock since they have not been shown to improve outcome [61-63]. PACs can measure the pulmonary artery occlusion pressure (PAOP) and mixed venous oxyhemoglobin saturation (SvO2). However, the PAOP has proven to be a poor predictor of fluid responsiveness in sepsis and the SvO2 is similar to the ScvO2, which can be obtained from a CVC [64,65]. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)
Clinical — All patients should be followed clinically for improved mean arterial pressure (MAP), urine output, heart rate, respiratory rate, skin color, temperature, pulse oximetry, and mental status. Among these, a MAP ≥65 mmHg (MAP = [(2 x diastolic) + systolic]/3) (calculator 1), and urine output ≥0.5 mL/kg per hour are common targets used in clinical practice. They have not been compared to each other nor have they been proven to be superior to any other target or to clinical assessment. Data supporting their use are discussed above. (See 'Initial resuscitative therapy' above.)
The ideal target for MAP, is unknown. One trial that randomized patients to a target MAP of 65 to 70 mmHg (low target MAP) or 80 to 85 mmHg (high target MAP) reported no mortality benefit to targeting a higher MAP [66,67]. Patients with a higher MAP had a greater incidence of atrial fibrillation (7 versus 3 percent), suggesting that targeting a MAP >80 mmHg is potentially harmful. Another pilot randomized trial that compared a lower MAP target (60-65 mmHg) to a higher target (75-80 mmHg) reported that among patients aged 75 years or older, a higher MAP target was associated with increased hospital mortality (60 versus 13 percent) . An analysis of data from both trials reported that targeting a higher MAP had no effect on mortality but was associated with a greater risk of supraventricular cardiac arrhythmias .
Hemodynamic — Static or dynamic predictors of fluid responsiveness should be employed in order to determine further fluid management. Guidelines state a preference for dynamic measures  since they are more accurate than static measures (eg, CVP) at predicting fluid responsiveness. However whether their use improved clinically impactful outcomes such as mortality remains unproven.
●Static – Traditionally, in addition to MAP, the following static CVC measurements were used to determine adequate fluid management:
•CVP at a target of 8 to 12 mmHg
•ScvO2 ≥70 percent (≥65 percent if sample is drawn off a PAC)
While one early trial of patients with septic shock reported a mortality benefit to these parameters in a protocol-based therapy, trials published since then (ProCESS, ARISE, ProMISe) have reported no mortality benefit in association with their use [7-10]. (See 'Initial resuscitative therapy' above.)
●Dynamic – Respiratory changes in the vena caval diameter, radial artery pulse pressure, aortic blood flow peak velocity, left ventricular outflow tract velocity-time integral, and brachial artery blood flow velocity are considered dynamic measures of fluid responsiveness. There is increasing evidence that dynamic measures are more accurate predictors of fluid responsiveness than static measures, as long as the patients are in sinus rhythm and passively ventilated with a sufficient tidal volume. For actively breathing patients or those with irregular cardiac rhythms, an increase in the cardiac output in response to a passive leg-raising maneuver (measured by echocardiography, arterial pulse waveform analysis, or pulmonary artery catheterization) also predicts fluid responsiveness. Choosing among these is dependent upon availability and technical expertise, but a passive leg raising maneuver may be the most accurate and broadly available. Future studies that report improved outcomes (eg, mortality, ventilator free days) in association with their use are needed. Further details are provided separately. (See "Novel tools for hemodynamic monitoring in critically ill patients with shock".)
●Lactate clearance – Although the optimal frequency is unknown, we follow serum lactate (eg, every six hours) in patients with sepsis until the lactate value has clearly fallen. While guidelines promote normalization of lactate , only lactate-guided resuscitation has not been convincingly associated with improved outcomes.
The lactate clearance is defined by the equation [(initial lactate – lactate >2 hours later)/initial lactate] x 100. The lactate clearance and interval change in lactate over the first 12 hours of resuscitation has been evaluated as a potential marker for effective resuscitation [13,69-73]. One meta-analysis of five low quality trials reported that lactate–guided resuscitation resulted in a reduction in mortality compared with resuscitation without lactate . Other meta-analyses reported modest mortality benefit when lactate clearance strategies were used compared with usual care or ScvO2 normalization [72,73]. However, many of the included trials contain heterogeneous populations and varying definitions of lactate clearance as well as additional variables that potentially affected the outcome.
In addition, after the restoration of perfusion, lactate is a poor marker of tissue perfusion . As a result, lactate values are generally unhelpful following restoration of perfusion, with one exception that a rising lactate level should prompt reevaluation of perfusion. (See "Venous blood gases and other alternatives to arterial blood gases".)
Newer point of care analyzers are commercially available that may allow clinicians to follow lactate levels at the bedside more readily [75-77].
●Arterial blood gases – It is prudent to follow arterial blood gas parameters including the arterial partial pressure of oxygen:fraction of inspired oxygen ratio as well as severity and type of acidosis (resolution of metabolic acidosis and avoidance of hyperchloremic acidosis). Worsening gas exchange may indicate pulmonary edema from fluid resuscitation or other complications including pneumothorax from central catheter placement, acute respiratory distress syndrome, or venous thromboembolism.
●Routine laboratories – Follow up laboratory studies, in particular platelet count, serum chemistries, and liver function tests are often performed (eg, every six hours) until values have reached normal or baseline. Hyperchloremia should be avoided, but if detected, switching to low chloride-containing (ie, buffered) solutions may be indicated. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Buffered crystalloid'.)
●Microbiology – Follow up indices of infection are also indicated, including complete blood count and additional cultures. Results may prompt alteration of antibiotic choice and/or investigations directed toward source control. (See 'Septic focus identification and source control' below.)
SEPTIC FOCUS IDENTIFICATION AND SOURCE CONTROL — In our experience, a focused history and examination is the most valuable method for source detection. Following initial investigations and empiric antimicrobial therapy, further efforts aimed at identifying and controlling the source(s) of infection should be performed in all patients with sepsis. In addition, for those who fail despite therapy or those who fail having initially responded to therapy, further investigations aimed at adequacy of the antimicrobial regimen or nosocomial super infection should be considered.
●Identification – Additional investigations targeted at the suspected source(s) should be considered in patients with sepsis, within the first 12 hours. This may include imaging (eg, computed tomography, ultrasonography) and sample acquisition (eg, bronchoalveolar lavage, aspirating fluid collections or joints), and may incur risk if an intervention is involved and the patient remains unstable. If invasive Candida or Aspergillus infection is suspected, serologic assays for 1,3 beta-D-glucan, galactomannan, and anti-mannan antibodies, if available, may provide early evidence of these fungal infections. These assays are discussed separately. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Non-culture methods' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)
●Source control – Source control (ie, physical measures to eradicate a focus of infection and eliminate or treat microbial proliferation and infection) should be undertaken since undrained foci of infection may not respond to antibiotics alone (table 2). As examples, potentially infected vascular access devices should be removed (after other vascular access has been established). Other examples include removing other infected implantable devices/hardware, when feasible, abscess drainage (including thoracic empyema and joint), percutaneous nephrostomy, soft tissue debridement or amputation, colectomy (eg, for fulminant Clostridium difficile-associated colitis), and cholecystostomy.
The optimal timing of source control is unknown but guidelines suggest no more than 6 to 12 hours after diagnosis since survival is negatively impacted by inadequate source control . Although the general rule of thumb is that source control should occur as soon as possible [78-80], this is not always practical or feasible. In addition, the decision should take into consideration the risk of the intervention and its complications (eg, death, fistula formation) and the likelihood of success, particularly when there is diagnostic uncertainty regarding the source.
PATIENTS WHO FAIL INITIAL THERAPY — Patients having persistent hypoperfusion despite adequate fluid resuscitation and antimicrobial treatment should be reassessed for fluid responsiveness (see 'Hemodynamic' above) adequacy of the antimicrobial regimen and septic focus control (see 'Septic focus identification and source control' above) as well as the accuracy of the diagnosis and the possibility that unexpected complications or coexisting problems have occurred (eg, pneumothorax following CVC insertion) (see "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock"). Other options including vasopressors, glucocorticoids, inotropic therapy, and blood transfusion are discussed in this section.
Vasopressors — Intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema. Based upon meta-analyses of small randomized trials and observational studies, a paradigm shift in practice has occurred such that most experts prefer to avoid dopamine in this population and favor norepinephrine as the first-choice agent (table 3 and table 4). Although guidelines suggest additional agents including vasopressin (up to 0.03 units/minute to reduce the dose of norepinephrine) or epinephrine (for refractory hypotension), practice varies considerably. Guidelines state a preference for central venous and arterial access especially when vasopressor administration is prolonged or high dose, or multiple vasopressors are administered through the same catheter ; while this is appropriate, waiting for placement should not delay their administration and the risks of catheter placement should also be taken into account.
●First agent – Data that support norepinephrine as the first-line single agent in septic shock are derived from numerous trials that have compared one vasopressor to another [81-87]. These trials included norepinephrine versus phenylephrine , norepinephrine versus vasopressin [89-92], norepinephrine versus terlipressin [93,94], norepinephrine versus epinephrine , and vasopressin versus terlipressin . While some of the comparisons found no convincing difference in mortality, length of stay in the ICU or hospital, or incidence of kidney failure [92,97], two 2012 meta-analyses reported increased mortality among patients who received dopamine during septic shock compared with those who received norepinephrine (53 to 54 percent versus 48 to 49 percent) [84,98]. Although the causes of death in the two groups were not directly compared, both meta-analyses identified arrhythmic events about twice as often with dopamine than with norepinephrine.
However, we believe the initial choice of vasopressor in patients with sepsis is often individualized and determined by additional factors including the presence of coexistent conditions contributing shock (eg, heart failure), arrhythmias, organ ischemia, or agent availability. For example, in patients with significant tachycardia (eg, fast atrial fibrillation, sinus tachycardia >160/minute), agents that completely lack beta adrenergic effects (eg, vasopressin) may be preferred if it is believed that worsening tachycardia may prompt further decompensation. Similarly, dopamine (DA) may be acceptable in those with significant bradycardia; but low dose DA should not be used for the purposes of “renal protection.”
The impact of agent availability was highlighted by one study of nearly 28,000 patients from 26 hospitals, which reported that during periods of norepinephrine shortages, phenylephrine was the most frequent alternative agent chosen by intensivists (use rose from 36 to 54 percent) . During the same period, mortality rates from septic shock rose from 36 to 40 percent. Whether this was directly related to phenylephrine use remains unknown.
●Additional agents – The addition of a second or third agent to norepinephrine may be required (eg, epinephrine, dobutamine, or vasopressin) with little data to support agent selection. For patients with refractory septic shock associated with a low cardiac output, an inotropic agent may be added. In a retrospective series of 234 patients with septic shock, among several vasopressor agents added to norepinephrine (dobutamine, dopamine, phenylephrine, vasopressin), inotropic support with dobutamine was associated with a survival advantage (epinephrine was not studied) . (See "Use of vasopressors and inotropes", section on 'Epinephrine' and "Use of vasopressors and inotropes", section on 'Dobutamine'.)
Additional information regarding vasopressor use is provided separately. (See "Use of vasopressors and inotropes".)
Additional therapies — Most physicians agree that additional therapies such as glucocorticoids, inotropic agents, or red blood cell (RBC) transfusion are not warranted routinely in those who present with sepsis or septic shock but can be reserved for refractory cases or special circumstances.
Glucocorticoids — Guidelines recommend against the routine use of glucocorticoids in patients with sepsis. However, corticosteroid therapy is appropriate in patients with septic shock that is refractory to adequate fluid resuscitation and vasopressor administration. This topic is discussed in detail separately. (See "Glucocorticoid therapy in septic shock".)
Inotropic therapy — A trial of inotropic therapy may be warranted in patients who fail to respond to adequate fluids and vasopressors, particularly those who also have diminished cardiac output (table 4) [7,101-103]. Inotropic therapy should not be used to increase the cardiac index to supranormal levels . Dobutamine is a suitable first-choice agent; epinephrine is a suitable alternative. (See "Use of vasopressors and inotropes", section on 'Dobutamine'.)
Red blood cell transfusions — Based upon clinical experience, randomized studies, and guidelines on transfusion of blood products in critically ill patients, we typically reserve red blood cell transfusion for patients with a hemoglobin level ≤7 g per deciliter. Exceptions include suspicion of concurrent hemorrhagic shock or active myocardial ischemia.
Support for a restrictive transfusion strategy (goal hemoglobin >7 g/dL) is derived from direct and indirect evidence from randomized studies of patients with septic shock:
●One multicenter randomized study of 998 patients with septic shock reported no difference in 28-day mortality between patients who were transfused when the hemoglobin was ≤7 g/dL (restrictive strategy) and patients who were transfused when the hemoglobin was ≤9 g/dL (liberal strategy) . The restrictive strategy resulted in 50 percent fewer red blood cell transfusions (1545 versus 3088 transfusions) and did not have any adverse effect on the rate of ischemic events (7 versus 8 percent).
●One randomized trial initially reported a mortality benefit from a protocol that included transfusing patients to a goal hematocrit >30 (hemoglobin level 10 g/dL) . However, similarly designed studies published since then reported no benefit to this strategy [8-10]. These studies are discussed below.
In further support of a restrictive approach to transfusion in patients with septic shock is the consensus among experts that transfusing to a goal of >7 g/dL is also preferred in critically ill patients without sepsis [106-108], the details of which are provided separately. (See "Use of blood products in the critically ill", section on 'Red blood cells'.)
PATIENTS WHO RESPOND TO THERAPY — Once patients have demonstrated a response to therapy, attention should be directed towards continuing to control the septic focus, and de-escalation of fluids and antibiotics, as appropriate. This may occur within hours or days, depending upon the indicators of response and the individual patient. (See 'Clinical' above and 'Hemodynamic' above and 'Laboratory' above.)
Identification and control of the septic focus — Following initial investigations and empiric antimicrobial therapy, further efforts aimed at identifying and controlling the source of infection should be performed in all patients with sepsis. (See 'Septic focus identification and source control' above.)
De-escalation fluids — Patients who respond to therapy (ie, clinical hemodynamic and laboratory targets are met; usually hours to days) should have the rate of fluid administration reduced or stopped, vasopressor support weaned, and, if necessary, diuretics administered. While early fluid therapy is appropriate in sepsis, fluids may be unhelpful or harmful when the circulation is no longer fluid responsive. Careful and frequent monitoring is essential because patients with sepsis may develop cardiogenic and noncardiogenic pulmonary edema (ie, acute respiratory distress syndrome [ARDS]).
In patients with ARDS or sepsis, a restrictive approach to intravenous fluid administration has been shown to decrease the duration of mechanical ventilation and ICU stay, compared to a more liberal approach [109,110]. In addition, small retrospective studies have reported that fluid overload is common in patients with sepsis and is associated with the increased performance of medical interventions (eg, diuresis, thoracentesis); the effect of fluid overload and such interventions on mortality and functional recovery in sepsis is unclear [111-113]. (See "Acute respiratory distress syndrome: Supportive care and oxygenation in adults", section on 'Fluid management'.)
De-escalation and duration of antibiotics — It is appropriate that de-escalation and duration of antimicrobial agents be assessed daily . When uncertain, it is also appropriate to obtain an infectious diseases consultation to facilitate good antimicrobial stewardship.
●De-escalation – Once pathogen identification and susceptibility data return and/or patients clinically improve, we recommend that antimicrobial therapy be narrowed (typically a few days). When possible, antimicrobial therapy should also be pathogen- and susceptibility-directed (also known as targeted/definitive therapy). However, since no pathogen is identified in approximately 50 percent of patients, de-escalation of empiric therapy requires a component of clinical judgement. For example, vancomycin is typically discontinued, if no Staphylococcus is cultured.
While there is no consensus on de-escalation criteria, most experts use follow-up clinical (improved vital signs), laboratory and imaging data, and a fixed course of broad-spectrum therapy (eg, 3 to 5 days).
There are no high quality trials testing safety of de-escalation of antibiotic therapy in adult patients with sepsis or septic shock [115-118]. However, most observational trials report equivalent or improved outcomes with this strategy.
●Duration – For most patients, the duration of therapy is typically 7 to 10 days [119-122], although longer courses are appropriate in patients who have a slow clinical response, an undrainable focus of infection, bacteremia with S. aureus, some fungal (eg, deep Candida infections) or viral infections (eg, herpes or cytomegalovirus), endocarditis, osteomyelitis, large abscesses, highly resistant gram-negative pathogens with marginal or limited sensitivities, neutropenia, or immunologic deficiencies [123-128]. In patients who are neutropenic, antibiotic treatment should continue until the neutropenia has resolved or the planned antibiotic course is complete, whichever is longer. In non-neutropenic patients in whom infection is thoroughly excluded, antibiotics should be discontinued as early as is feasible to minimize colonization or infection with drug-resistant microorganisms and superinfection with other pathogens. Occasionally, shorter courses may be appropriate (eg, patients with pyelonephritis or urinary sepsis who have rapid resolution of source control) [129-132].
●Role of procalcitonin – Although many institutions and guidelines support the use of procalcitonin to limit antibiotic (empiric or therapeutic) use in critically ill patients with suspected infection or documented infection, the evidence to support this practice is limited. While one randomized open-label trial of critically ill patients with infection reported a mortality benefit when the duration of antibiotic use was guided by normalization of procalcitonin levels , several randomized trials and meta-analyses found that using procalcitonin-guided algorithms to guide antimicrobial de-escalation did not result in any mortality benefit [134-139]. However, most trials report a reduction in the duration of antibiotic therapy (on average one day). Another retrospective analysis suggested that use of procalcitonin was associated with lower hospital and ICU length of stay, but no clinically meaningful outcomes were measured in this study . Other studies suggest that procalcitonin may distinguish infectious from noninfectious conditions and may therefore facilitate the decision to de-escalate empiric therapy [134,141-143].
SUPPORTIVE THERAPIES — Details regarding supportive therapies needed for the care of critically ill patients, including those with sepsis are provided separately:
●Blood product infusion (see "Use of blood products in the critically ill")
●Nutrition (see "Nutrition support in critically ill patients: An overview")
●Stress ulcer prophylaxis (see "Stress ulcer prophylaxis in the intensive care unit")
●Neuromuscular blocking agents (see "Use of neuromuscular blocking medications in critically ill patients")
●Venous thromboembolism prophylaxis (see "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults")
●Intensive insulin therapy (see "Glycemic control and intensive insulin therapy in critical illness")
●External cooling or antipyretics (see "Fever in the intensive care unit", section on 'Management')
●Mechanical ventilation, sedation, weaning (see "Mechanical ventilation of adults in acute respiratory distress syndrome" and "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal" and "Methods of weaning from mechanical ventilation")
●Investigational therapies for sepsis and acute respiratory distress syndrome (eg, intravenous immune globulin, antithrombin, thrombomodulin, heparin, cytokine and toxin inactivators, as well as hemofiltration, statins, beta-2 agonists, beta blockade, and vitamin C/thiamine/hydrocortisone combination) (see "Investigational and ineffective therapies for sepsis" and "Acute respiratory distress syndrome: Investigational or ineffective pharmacotherapy in adults")
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in children and adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Sepsis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●For patients with sepsis and septic shock, therapeutic priorities include securing the airway, correcting hypoxemia, and establishing vascular access for the early administration of fluids and antibiotics. Simultaneously obtaining the following is preferable (within 45 minutes) but should not delay the administration of fluids and antibiotics: routine laboratory studies, serum lactate, arterial blood gases, blood cultures (aerobic and anaerobic) from two distinct venipuncture sites and from indwelling vascular access devices, cultures from easily accessible sites (eg, sputum, urine), and imaging of suspected sources. (See 'Immediate evaluation and management' above.)
●For patients with sepsis and septic shock, we recommend the infusion of intravenous fluids (30mL/kg) within the first three hours of presentation, rather than vasopressors, inotropes, or red blood cell transfusions (Grade 1B). Fluid boluses are the preferred method of administration and should be repeated until blood pressure and tissue perfusion are acceptable, pulmonary edema ensues, or there is no further response. Crystalloid solutions (eg, normal saline or Ringer’s lactate) are our preferred resuscitation fluid. We recommend that a hyperoncotic starch solution NOT be administered (Grade 1A). (See 'Initial resuscitative therapy' above and 'Intravenous fluids (first three hours)' above.)
●For patients with sepsis, we recommend that optimal doses of empiric broad spectrum intravenous therapy with one or more antimicrobials be administered within one hour of presentation (Grade 1B). Broad spectrum is defined as therapeutic agent(s) with sufficient activity to cover a broad range of gram negative and positive organisms and, if suspected, against fungi and viruses. For patients with septic shock, we suggest combination therapy, defined as multiple antibiotics (at least two) from different classes given with the intent of covering a known or suspected pathogen with more than one antibiotic. Agent selection depends upon patient's history, comorbidities, immune defects, clinical context, suspected site of infection, presence of invasive devices, Gram stain data, and local prevalence and resistance patterns. The routine administration of antifungal therapy is not warranted in non-neutropenic patients. (See 'Empiric antibiotic therapy (first hour)' above and 'Initial resuscitative therapy' above.)
●For most patients with sepsis and septic shock, we recommend that fluid management be guided using clinical targets including mean arterial pressure 65 mmHg to 70 mmHg (calculator 1) and urine output ≥0.5 mL/kg/hour (Grade 1B). In addition, while dynamic measures of fluid responsiveness (eg, respiratory changes in the radial artery pulse pressure) are preferred, static measures of determining adequacy of fluid administration (eg, central venous pressure 8 to 12 mmHg or central venous oxygen saturation ≥70 percent) may be more readily available. Serum lactate should be followed (eg, every six hours), until there is a definitive clinical response. It is prudent that other measures of the overall response to infection also be followed (eg, routine laboratory studies, arterial blood gases, microbiology studies). (See 'Monitor response' above.)
●For patients with sepsis who remain hypotensive despite adequate fluid resuscitation (eg, 3L in first three hours), we recommend vasopressors (Grade 1B); the preferred initial agent is norepinephrine (table 4). For patients who are refractory to intravenous fluid and vasopressor therapy, additional therapies, such as glucocorticoids, inotropic therapy, and blood transfusions, can be administered on an individual basis. We typically reserve red blood cell transfusion for patients with a hemoglobin level <7 g per deciliter. (See 'Additional therapies' above and "Use of vasopressors and inotropes", section on 'Choice of agent in septic shock'.)
●Following initial investigations and empiric antimicrobial therapy, further efforts aimed at identifying and controlling the source(s) of infection (ideally within 6 to 12 hours) should be performed in all patients with sepsis (table 2 and table 1). In addition, for those who fail despite therapy or those who fail having initially responded to therapy, further investigations aimed at adequacy of the antimicrobial regimen or nosocomial super infection should be considered. (See 'Septic focus identification and source control' above.)
●For patients with sepsis who have demonstrated a response to therapy, we suggest that the rate of fluid administration should be reduced or stopped, vasopressor support weaned, and if necessary diuretics administered. We also recommend that antimicrobial therapy be narrowed once pathogen identification and susceptibility data return. Antimicrobial therapy should be pathogen- and susceptibility-directed for a total duration of 7 to 10 days, although shorter or longer courses are appropriate for select patients. (See 'Patients who respond to therapy' above.)
- Elixhauser A, Friedman B, Stranges E. Septicemia in U.S. Hospitals, 2009. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf (Accessed on February 15, 2013).
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017; 43:304.
- Howell MD, Davis AM. Management of Sepsis and Septic Shock. JAMA 2017; 317:847.
- Luce JM. Pathogenesis and management of septic shock. Chest 1987; 91:883.
- Ghosh S, Latimer RD, Gray BM, et al. Endotoxin-induced organ injury. Crit Care Med 1993; 21:S19.
- Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368.
- ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683.
- ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496.
- Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372:1301.
- Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015; 41:1549.
- PRISM Investigators. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. N Engl J Med 2017.
- Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 2015; 43:567.
- Tang Y, Choi J, Kim D, et al. Clinical predictors of adverse outcome in severe sepsis patients with lactate 2-4 mM admitted to the hospital. QJM 2015; 108:279.
- Haas SA, Lange T, Saugel B, et al. Severe hyperlactatemia, lactate clearance and mortality in unselected critically ill patients. Intensive Care Med 2016; 42:202.
- Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med 2017; 376:2235.
- Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247.
- Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370:1412.
- Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012; 367:124.
- Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125.
- Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med 2014; 161:347.
- Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ 2014; 349:g4561.
- Rochwerg B, Alhazzani W, Gibson A, et al. Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med 2015; 41:1561.
- Raghunathan K, Bonavia A, Nathanson BH, et al. Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock. Anesthesiology 2015; 123:1385.
- Xu JY, Chen QH, Xie JF, et al. Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care 2014; 18:702.
- Jiang L, Jiang S, Zhang M, et al. Albumin versus other fluids for fluid resuscitation in patients with sepsis: a meta-analysis. PLoS One 2014; 9:e114666.
- Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med 2017; 5:180.
- Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38:1045.
- Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31:2742.
- Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000; 118:146.
- Harbarth S, Garbino J, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003; 115:529.
- Leibovici L, Paul M, Poznanski O, et al. Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrob Agents Chemother 1997; 41:1127.
- Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589.
- Schramm GE, Johnson JA, Doherty JA, et al. Methicillin-resistant Staphylococcus aureus sterile-site infection: The importance of appropriate initial antimicrobial treatment. Crit Care Med 2006; 34:2069.
- Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136:1237.
- Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med 2014; 42:1749.
- Whiles BB, Deis AS, Simpson SQ. Increased Time to Initial Antimicrobial Administration Is Associated With Progression to Septic Shock in Severe Sepsis Patients. Crit Care Med 2017; 45:623.
- Peltan ID, Mitchell KH, Rudd KE, et al. Physician Variation in Time to Antimicrobial Treatment for Septic Patients Presenting to the Emergency Department. Crit Care Med 2017; 45:1011.
- Amaral AC, Fowler RA, Pinto R, et al. Patient and Organizational Factors Associated With Delays in Antimicrobial Therapy for Septic Shock. Crit Care Med 2016; 44:2145.
- Johnson MT, Reichley R, Hoppe-Bauer J, et al. Impact of previous antibiotic therapy on outcome of Gram-negative severe sepsis. Crit Care Med 2011; 39:1859.
- Verhoef J, Hustinx WM, Frasa H, Hoepelman AI. Issues in the adjunct therapy of severe sepsis. J Antimicrob Chemother 1996; 38:167.
- Sibbald WJ, Vincent JL. Round table conference on clinical trials for the treatment of sepsis. Crit Care Med 1995; 23:394.
- Savage RD, Fowler RA, Rishu AH, et al. Pathogens and antimicrobial susceptibility profiles in critically ill patients with bloodstream infections: a descriptive study. CMAJ Open 2016; 4:E569.
- Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:1445.
- Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 2005; 352:1436.
- Rubinstein E, Lode H, Grassi C. Ceftazidime monotherapy vs. ceftriaxone/tobramycin for serious hospital-acquired gram-negative infections. Antibiotic Study Group. Clin Infect Dis 1995; 20:1217.
- Cometta A, Calandra T, Gaya H, et al. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program. Antimicrob Agents Chemother 1996; 40:1108.
- Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004; 4:519.
- Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004; 328:668.
- Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2014; :CD003344.
- Cortegiani A, Russotto V, Maggiore A, et al. Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. Cochrane Database Syst Rev 2016; :CD004920.
- Bailly S, Bouadma L, Azoulay E, et al. Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients. Am J Respir Crit Care Med 2015; 191:1139.
- Timsit JF, Azoulay E, Schwebel C, et al. Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial. JAMA 2016; 316:1555.
- Pletz MW, Bloos F, Burkhardt O, et al. Pharmacokinetics of moxifloxacin in patients with severe sepsis or septic shock. Intensive Care Med 2010; 36:979.
- van Zanten AR, Polderman KH, van Geijlswijk IM, et al. Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study. J Crit Care 2008; 23:422.
- Blot S, Koulenti D, Akova M, et al. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Crit Care 2014; 18:R99.
- Zelenitsky S, Rubinstein E, Ariano R, et al. Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob Agents 2013; 41:255.
- Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998; 279:125.
- Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother 1999; 43:623.
- Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials. Am J Respir Crit Care Med 2016; 194:681.
- Harvey S, Harrison DA, Singer M, et al. Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet 2005; 366:472.
- Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003; 290:2713.
- National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wheeler AP, Bernard GR, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:2213.
- Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med 2000; 162:134.
- Walley KR. Use of central venous oxygen saturation to guide therapy. Am J Respir Crit Care Med 2011; 184:514.
- Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014; 370:1583.
- Lamontagne F, Meade MO, Hébert PC, et al. Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med 2016; 42:542.
- Hylands M, Moller MH, Asfar P, et al. A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension. Can J Anaesth 2017; 64:703.
- Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303:739.
- Liu V, Morehouse JW, Soule J, et al. Fluid volume, lactate values, and mortality in sepsis patients with intermediate lactate values. Ann Am Thorac Soc 2013; 10:466.
- Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010; 182:752.
- Gu WJ, Zhang Z, Bakker J. Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med 2015; 41:1862.
- Simpson SQ, Gaines M, Hussein Y, Badgett RG. Early goal-directed therapy for severe sepsis and septic shock: A living systematic review. J Crit Care 2016; 36:43.
- Forsythe SM, Schmidt GA. Sodium bicarbonate for the treatment of lactic acidosis. Chest 2000; 117:260.
- Karon BS, Scott R, Burritt MF, Santrach PJ. Comparison of lactate values between point-of-care and central laboratory analyzers. Am J Clin Pathol 2007; 128:168.
- Ismail F, Mackay WG, Kerry A, et al. The accuracy and timeliness of a Point Of Care lactate measurement in patients with Sepsis. Scand J Trauma Resusc Emerg Med 2015; 23:68.
- Singer AJ, Taylor M, LeBlanc D, et al. ED bedside point-of-care lactate in patients with suspected sepsis is associated with reduced time to iv fluids and mortality. Am J Emerg Med 2014; 32:1120.
- Azuhata T, Kinoshita K, Kawano D, et al. Time from admission to initiation of surgery for source control is a critical determinant of survival in patients with gastrointestinal perforation with associated septic shock. Crit Care 2014; 18:R87.
- Buck DL, Vester-Andersen M, Møller MH, Danish Clinical Register of Emergency Surgery. Surgical delay is a critical determinant of survival in perforated peptic ulcer. Br J Surg 2013; 100:1045.
- Karvellas CJ, Abraldes JG, Zepeda-Gomez S, et al. The impact of delayed biliary decompression and anti-microbial therapy in 260 patients with cholangitis-associated septic shock. Aliment Pharmacol Ther 2016; 44:755.
- Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103:1826.
- De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779.
- Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994; 272:1354.
- De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med 2012; 40:725.
- Patel GP, Grahe JS, Sperry M, et al. Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Shock 2010; 33:375.
- Mathur SM, Dhunna R, Chakraborty A. Comparison of dopamine and norepinephrine in the management of septic shock using impedance cardiography. Ind J Crit Care Med 2007; 11:186.
- Ruokonen E, Takala J, Kari A, et al. Regional blood flow and oxygen transport in septic shock. Crit Care Med 1993; 21:1296.
- Morelli A, Ertmer C, Rehberg S, et al. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Crit Care 2008; 12:R143.
- Russell JA, Walley KR, Gordon AC, et al. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med 2009; 37:811.
- Lauzier F, Lévy B, Lamarre P, Lesur O. Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial. Intensive Care Med 2006; 32:1782.
- Luckner G, Dünser MW, Stadlbauer KH, et al. Cutaneous vascular reactivity and flow motion response to vasopressin in advanced vasodilatory shock and severe postoperative multiple organ dysfunction syndrome. Crit Care 2006; 10:R40.
- Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA 2016; 316:509.
- Albanèse J, Leone M, Delmas A, Martin C. Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study. Crit Care Med 2005; 33:1897.
- Boccara G, Ouattara A, Godet G, et al. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology 2003; 98:1338.
- Myburgh JA, Higgins A, Jovanovska A, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34:2226.
- Morelli A, Ertmer C, Rehberg S, et al. Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study. Crit Care 2009; 13:R130.
- Havel C, Arrich J, Losert H, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev 2011; :CD003709.
- Vasu TS, Cavallazzi R, Hirani A, et al. Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials. J Intensive Care Med 2012; 27:172.
- Vail E, Gershengorn HB, Hua M, et al. Association Between US Norepinephrine Shortage and Mortality Among Patients With Septic Shock. JAMA 2017; 317:1433.
- Nguyen HB, Lu S, Possagnoli I, Stokes P. Comparative Effectiveness of Second Vasoactive Agents in Septic Shock Refractory to Norepinephrine. J Intensive Care Med 2017; 32:451.
- Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 2004; 32:1928.
- Rhodes A, Bennett ED. Early goal-directed therapy: an evidence-based review. Crit Care Med 2004; 32:S448.
- Bersten AD, Hersch M, Cheung H, et al. The effect of various sympathomimetics on the regional circulations in hyperdynamic sepsis. Surgery 1992; 112:549.
- Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296.
- Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014; 371:1381.
- Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409.
- Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med 2012; 157:49.
- Retter A, Wyncoll D, Pearse R, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol 2013; 160:445.
- National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:2564.
- Silversides JA, Major E, Ferguson AJ, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med 2017; 43:155.
- Kelm DJ, Perrin JT, Cartin-Ceba R, et al. Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock 2015; 43:68.
- Malbrain ML, Marik PE, Witters I, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther 2014; 46:361.
- Mitchell KH, Carlbom D, Caldwell E, et al. Volume Overload: Prevalence, Risk Factors, and Functional Outcome in Survivors of Septic Shock. Ann Am Thorac Soc 2015; 12:1837.
- Weiss CH, Moazed F, McEvoy CA, et al. Prompting physicians to address a daily checklist and process of care and clinical outcomes: a single-site study. Am J Respir Crit Care Med 2011; 184:680.
- Silva BN, Andriolo RB, Atallah AN, Salomão R. De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev 2013; :CD007934.
- Morel J, Casoetto J, Jospé R, et al. De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit. Crit Care 2010; 14:R225.
- Leone M, Bechis C, Baumstarck K, et al. De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med 2014; 40:1399.
- Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, et al. De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 2014; 40:32.
- Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016; 63:e61.
- Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003; 290:2588.
- Choudhury G, Mandal P, Singanayagam A, et al. Seven-day antibiotic courses have similar efficacy to prolonged courses in severe community-acquired pneumonia--a propensity-adjusted analysis. Clin Microbiol Infect 2011; 17:1852.
- Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev 2015; :CD007577.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18.
- Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1.
- Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56.
- Jack L, Bal AM, Harte S, Collier A. International guidelines: the need to standardize the management of candidaemia. Infect Dis (Lond) 2016; 48:779.
- Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation 2015; 132:1435.
- Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36:3075.
- Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med 2015; 372:1996.
- Eliakim-Raz N, Yahav D, Paul M, Leibovici L. Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection-- 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2013; 68:2183.
- Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004; 164:1669.
- Rattan R, Allen CJ, Sawyer RG, et al. Patients with Complicated Intra-Abdominal Infection Presenting with Sepsis Do Not Require Longer Duration of Antimicrobial Therapy. J Am Coll Surg 2016; 222:440.
- de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis 2016; 16:819.
- Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011; 171:1322.
- Shehabi Y, Sterba M, Garrett PM, et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med 2014; 190:1102.
- Matthaiou DK, Ntani G, Kontogiorgi M, et al. An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients. Intensive Care Med 2012; 38:940.
- Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock--a systematic review and meta-analysis. Crit Care 2013; 17:R291.
- Paul M, Dickstein Y, Raz-Pasteur A. Antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis. Clin Microbiol Infect 2016; 22:960.
- Andriolo BN, Andriolo RB, Salomão R, Atallah ÁN. Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev 2017; 1:CD010959.
- Balk RA, Kadri SS, Cao Z, et al. Effect of Procalcitonin Testing on Health-care Utilization and Costs in Critically Ill Patients in the United States. Chest 2017; 151:23.
- Westwood M, Ramaekers B, Whiting P, et al. Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis. Health Technol Assess 2015; 19:v.
- Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-guided antibiotic therapy: a systematic review and meta-analysis. J Hosp Med 2013; 8:530.
- Schuetz P, Kutz A, Grolimund E, et al. Excluding infection through procalcitonin testing improves outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results from the randomized ProHOSP trial. Int J Cardiol 2014; 175:464.