#94344: Diagnosis and Management of Sepsis

Sepsis is a systemic pathophysiologic and clinical syndrome caused by infection and manifest by signs of inflammation, host immune response, and organ dysfunction. The causes of sepsis are myriad, and the scope of illness is broad. Most cases of sepsis syndrome arise from bacterial infection, but certain viral (e.g., Ebola and other hemorrhagic fevers) and fungal (e.g., candidiasis, histoplasmosis) infections induce a sepsis syndrome as well.

Infection may be defined as invasion of normally sterile host tissue by a micro-organism. Clinically, infection is recognized by the constellation of symptoms and signs that result from the host's immune response to an invading micro-organism. Bacteremia is defined as demonstrable evidence (e.g., by culture) of viable bacteria within the general circulation.

Historically, there has been some confusion and a lack of consensus with respect to the various stages of systemic infection and how best to manage patients along the spectrum of illness and complications induced by sepsis. This lack of consensus prompted the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) to convene a conference for the purpose of agreeing on definitions for sepsis and its sequelae. The ACCP/SCCM published their definitions in 1992[1].

A second task force, international in scope, was convened in 2001. The purpose of this conference (sponsored by the ACCP, SCCM, the European Society of Intensive Care Medicine, the American Thoracic Society, and the Surgical Infection Society) was to modify, where appropriate, the original ACCP/SCCM definitions to reflect current understanding of the pathophysiology of sepsis. Although the signs and symptoms of sepsis were expanded to reflect clinical bedside experience, the task force found insufficient evidence to support alternative definitions of sepsis [2]. This international effort spawned the global Surviving Sepsis Campaign, comprised of 29 sponsoring clinical specialty societies that convene at regular intervals to review the clinical literature and provide evidence-based guidelines for management of severe sepsis [3,4].

Task force guidelines redefined sepsis as a systemic inflammatory response arising from known or suspected infection, leading to widespread tissue injury and manifested by two or more of the following conditions [1,2]:

This emphasis on the systemic signs of inflammation as the marker for sepsis requires the recognition that other, noninfectious, pathophysiologic conditions also cause tissue injury and inflammation with systemic ramifications. Systemic inflammatory response syndrome (SIRS) includes any serious, ongoing inflammatory process resulting in end-organ damage and multisystem failure. SIRS encompasses a continuum of escalating inflammatory responses to infectious or noninfectious stimuli; end-organ dysfunction and mortality increase with each stage of the advancing inflammatory process. While sepsis is a common and important form, SIRS may also develop in response to noninfectious insults, including trauma, burns, pancreatitis, anaphylaxis, adrenal insufficiency, pulmonary embolism, myocardial infarction, massive hemorrhage, and cardiopulmonary bypass [1,5,6].

Severe sepsis has been defined as sepsis associated with organ dysfunction and tissue hypoperfusion. Signs of tissue hypoperfusion are hypotension (systolic blood pressure <90 mm Hg or a drop in systolic pressure of >40 mm Hg), lactic acidosis, oliguria, and acute alteration in mental status. Organ dysfunction results from falling blood pressure and widespread microvascular injury caused by circulating toxic byproducts of infection and the inflammatory immune response. Common manifestations include acute lung injury, renal failure, disseminated intravascular coagulation (DIC), and laboratory signs of liver dysfunction. In clinical practice, "septic shock" (a subset of sepsis) is present when there is persistent hypotension requiring vasopressor therapy, after adequate fluid resuscitation has been administered [1,7].

In 2014, the European and American societies of critical care medicine convened a third task force (Sepsis 3) to re-examine current concepts and definitions of sepsis and septic shock based on current understanding of the pathobiology, epidemiology, and management of sepsis. After a synthesis of evidence, the task force determined that previous definitions (as presented by the previous task forces) lacked precision because of excessive focus on inflammation. The task force also concluded that the conceptual model of sepsis invariably following a continuum through severe sepsis to shock is misleading; that the SIRS criteria have inadequate specificity and sensitivity for defining sepsis; and that the term "severe sepsis" is redundant. The Sepsis 3 report, with new consensus definitions for sepsis and septic shock, was published in 2016 [8]. The Sepsis 3 definitions are intended to provide greater clarity and specificity while emphasizing the life-threatening nature of sepsis syndrome. The goal is to achieve greater clinical recognition and consistency in diagnosis, therapy, and clinical investigation of sepsis.

The Sepsis 3 task force emphasized that sepsis is the primary cause of death from infection and thus requires early recognition, urgent attention, and prompt treatment. Following infection, the clinical characteristics of sepsis may emerge gradually over time, shaped by the interplay of pathogen factors and host factors such as genetic determinants, age, comorbidities, and environment. Sepsis is differentiated from infection by the presence of an aberrant or dysregulated host response accompanied by organ dysfunction. Sepsis-induced organ dysfunction may be occult; therefore, its presence should be considered in any patient presenting with infection. Conversely, unrecognized infection may be the cause of new-onset organ dysfunction. Any unexplained acute-onset organ dysfunction should thus raise the possibility of underlying infection. Pre-existing illness, chronic comorbidities, medication, and medical interventions may modify signs and symptoms of sepsis. At times, systemic infection may disrupt critical organ function without generating signs of systemic inflammatory host response [8].

The definition of sepsis is a syndrome defined as life-threatening organ dysfunction caused by dysregulated host immune responses to infection [8]. This new definition emphasizes the loss of adaptive homeostasis in response to infection, the potential lethality of infection when any degree of organ dysfunction is present, and the importance of urgent assessment and prompt treatment. Because even modest organ dysfunction has been found to confer a mortality risk in excess of 10%, sepsis is inherently a serious condition and the term "severe sepsis" is no longer considered useful [8].

The presence and extent of organ dysfunction can be assessed with various scoring systems that rely on clinical and laboratory parameters, such as the following [3,8,9]:

The scoring system currently used in most critical care units is the Sequential Organ Failure Assessment (SOFA) score, which grades abnormality by organ system and accounts for clinical interventions [9]. A higher SOFA score is associated with an increased probability of mortality. Organ dysfunction can be identified by an acute change in SOFA score ≥2 points consequent to the infection [8].

Working from a model derived from a large data base, the task force was able to identify and validate a simple "bedside" clinical measure that can be used to identify which patients with suspected infection are at risk for developing sepsis, referred to as the quick SOFA (qSOFA). This measure consists of three elements [8]:

Data analysis has demonstrated that patients with infection who are positive for two or more of these elements are likely to have a prolonged intensive care unit (ICU) stay (i.e., three or more days) or die in the hospital. Physicians and nurses can employ the qSOFA in the office, emergency department, or hospital ward to quickly identify which patients with an infection are on the clinical threshold of sepsis and thus at risk of further clinical deterioration. The task force suggests that positive qSOFA criteria be used to prompt clinicians to further investigate for organ dysfunction, to initiate or escalate therapy as appropriate, and to consider referral to critical care [8].

While the data analysis supports the use of qSOFA as a predictor of poor outcomes in patients, no analysis was performed to support the use of qSOFA as a screening tool, and numerous studies since publication of the Sepsis 3 report have yielded contradictory results as to its usefulness. For example, studies have shown that qSOFA is more specific but less sensitive than having two of four SIRS criteria for early identification of infection-induced organ dysfunction. Although the presence of a positive qSOFA can alert the clinician to the possibility of sepsis in all resource settings, the 2021 Surviving Sepsis Campaign guidelines for the management of sepsis and septic shock include a strong recommendation against using qSOFA compared with systemic inflammatory response syndrome (SIRS) criteria, national early warning score (NEWS), or modified early warning score (MEWS) as a single screening tool for sepsis or septic shock [10].

Sepsis 3 defines septic shock as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Within the clinical construct of sepsis, the patient with septic shock can be identified by the presence of the following two criteria [8]:

The hospital mortality rate for patients meeting these criteria is in excess of 40%, or four times greater than for patients with sepsis [8].

The first description of multiple organ failure appeared in 1973 in a discussion of three patients who died of distal organ failure that followed ruptured aortic aneurysms. Multiple organ failure was subsequently described as multiple, progressive, or sequential systems organ failure. It was noted that shock or infection alone did not cause the distal organ dysfunction. Other severe insults could set in motion an underlying reaction that would lead to widespread endothelial damage, edema resulting from increased vascular permeability, and impaired availability of oxygen [11,12,13].

Sepsis, septic shock, and multiple organ failure are major causes of morbidity and mortality in the United States. The Centers for Disease Control and Prevention (CDC) estimates that each year 1.7 million adults develop sepsis, at least 350,000 die as a result of sepsis, and 1 in 3 patients who dies in a hospital has sepsis [14]. Approximately 9.3% of all deaths in the United States can be attributed to sepsis, which equals the number of deaths resulting from myocardial infarction and far exceeds the mortality rates from acquired immune deficiency syndrome (AIDS) or breast cancer. The aggregate hospital cost of care for patients with septicemia totaled nearly $23.7 billion (6.2%) in 2013 [15,16,17].

A study of hospital emergency department visits between 1999 and 2005 found that of the 750,000 hospitalizations, more than two-thirds may have initially presented to an emergency department. Cases of suspected sepsis account for more than 570,000 emergency department visits annually. The average length of stay in the emergency department is 4.7 hours. However, more than 20% of patients with sepsis had a length of stay that exceeded six hours, resulting in a substantial burden on facilities nationwide in providing sepsis care [18,19].

The incidence of septicemia more than doubled between 1993 and 2009, increasing by an annual average of 6% [15]. Between 1993 and 2003, 8.4 million cases of sepsis and 2.4 million cases of severe sepsis were reported; the annual age-adjusted sepsis hospitalization and mortality rates increased from 5.6% to 8.2%, whereas the fatality rate decreased by 1.4% [20]. The percentage of severe sepsis cases among all sepsis cases increased from 25.6% to 43.8% during the same time period [20]. Sepsis is more common among men than women, and the fatality rate is greater in men and nonwhite populations [21].

Prior to 2017, national estimates of sepsis burden relied on the use of administrative codes, which demonstrated increasing incidence and decreasing mortality [22]. However, studies have demonstrated that coding for sepsis has steadily increased over the past decade, while coding for the most common underlying infections has been stable or decreasing. These analyses suggested that code-based case identification might be unreliable for surveillance purposes because of coding practice biases and changes in diagnosis over time [22]. In order to improve hospital surveillance of sepsis, the CDC developed a case definition based on objective clinical data elements conceptually analogous to Sepsis-3 and optimized for surveillance directly from electronic health records [22]. An analysis of data from 409 participating hospitals showed that sepsis was present in 6% of adult hospitalizations, and neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009 and 2014 [23].

The reported incidence rates of sepsis increase with advanced age. Two-thirds of all sepsis cases occur in people 65 years of age and older, with case fatality rates as high as 40% [16]. In a study of the burden of sepsis among Medicare recipients for the period 2012 to 2018, six-month mortality rates remained high for septic shock (60%), severe sepsis (36%), sepsis attributed to a specific organism (31%), and unspecified sepsis (27%) [24]. In the same period, the estimated annual cost of sepsis care (inpatient and subsequent skilled nursing facility) for all Medicare patients increased from $27.7 to $41.5 billion.

Mortality from sepsis of gram-negative etiology is the cause of 20% to 50% of the overall total number of septic deaths. The figures are now similar for sepsis of gram-positive etiology [25]. Mortality has been reported as high as 60% in patients with underlying medical problems. Among patients who develop the complications of shock and organ failure, mortality can reach 90% [26]. Extent of organ failure contributes to the prognosis, with a greater survival rate in patients with fewer than three failing organs. The risk of death increases as each organ fails [26].

Sepsis is among the leading causes of hospitalization and ranks as the most expensive inpatient conditions treated in U.S. hospitals [15,27]. Hospitalized patients with sepsis include those with community-onset infection/sepsis and those with hospital-onset sepsis. Data from the 2008 National Hospital Discharge Survey show that the rate of hospitalization for sepsis increased from 11.8 to 24 per 10,000 population during the period 2000 through 2008 [27]. Compared with other conditions, the hospital stay for sepsis was 75% longer and the likelihood of dying during hospitalization was eight times higher. In a large cohort study of 2.2 million adult patients hospitalized in 2009–2015, hospital-onset sepsis complicated 1 in 200 hospitalizations and accounted for 1 in 8 sepsis cases [28]. Patients with hospital-onset sepsis had more comorbidities, longer hospital length of stay, and higher risk of death (33% vs 17%) than patients with community-onset sepsis. Among patients admitted without sepsis, hospital-onset sepsis tripled the risk of dying in the hospital. The estimated annual cost of hospitalization for sepsis and septicemia in 2013 was $14.6 billion and increasing at the rate of 11.9% each year [15,27].

Despite immense clinical effort and high treatment expenditures, mortality rates remain high. Those who survive often sustain permanent organ damage, some degree of physical disability, and long-term cognitive impairment [29].

The risk of sepsis complicating an infection is determined by virulence of the pathogen and host factors that increase susceptibility and/or impede host defense mechanisms. Factors considered important in the development of sepsis include: recent use of broad-spectrum antibiotics; immunosuppressive drugs, such as cancer chemotherapy; invasive procedures; organ transplantation; burns or other trauma; anatomic obstruction; intestinal ulceration; extremes of age; and progressive clinical conditions, such as malignancy, diabetes, or AIDS [30].

To the extent that a patient seeks medical care at an early stage of infection, risk factors for sepsis might also include how well the healthcare provider has recognized the nature of the clinical issue and taken into account the patient's vulnerabilities. In a retrospective cohort study involving 46,000 hospitalized patients with sepsis in two large healthcare delivery systems, half the patients had outpatient clinical encounters in the week prior to hospitalization and one-third were diagnosed with an acute infection [31]. Outpatient primary care and subspecialty providers play an important role in identifying patients who are at risk for sepsis and in need of close follow-up.

The majority of infections that progress to sepsis begin outside of hospitals; however, as noted, most patients with sepsis have had recent encounters with the healthcare system even before becoming ill. Using a data set from the CDC Emerging Infections Program, a retrospective cohort study was designed to identify patient characteristics and risk factors for sepsis. Among 1,078 adult patients hospitalized with sepsis across 10 states, the median age was 64 years and 973 (90%) were classified as community-onset sepsis [32]. Of the total, 654 patients (60.7%) had healthcare exposures before hospital admission for sepsis and 447 (41.5%) had received medical treatment (e.g., antimicrobial drugs, chemotherapy, wound care, dialysis, surgery) in the 30 days prior to admission. An etiologic diagnosis for sepsis was established in 57% of cases; the most common pathogens identified were Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae. Controlling for other factors, the 30-day mortality was significantly higher in patients with cirrhosis, immunosuppression, and vascular disease. These findings indicate that most adult patients with sepsis have health facility exposures or medical treatment in the weeks before hospital admission for sepsis, encounters that may offer opportunities to intervene in ways that alter the disease course for patients at risk of severe outcomes [32].

Healthcare-associated infections are a major cause of sepsis among severely ill patients. Increased risk of nosocomial infection is associated with the presence of underlying chronic disease, alteration in host defenses, prolonged hospital stay, and the presence of invasive catheters or monitoring devices [33]. Pulmonary, urinary tract, gastrointestinal, and wound infections predominate [30,34,35]. In hospitalized adult patients, the etiology of sepsis has shifted from being predominantly gram-negative nosocomial infections (Escherichia coli, Klebsiella spp., Enterobacter spp., and Pseudomonas aeruginosa) to gram-positive infections (Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes). The incidence of sepsis caused by gram-positive infections has increased by 26.3% per year over the last three decades [36]. As of 2024, however, the rates of sepsis and septic shock due to gram-positive organisms are rising again because of the more frequent use of invasive procedures and lines in critically ill patients. As a result, gram-positive and gram-negative micro-organisms are now about equally likely to be causative pathogens in septic shock [30]. Multidrug-resistant pathogens, such as S. aureus, now account for more than half of all sepsis cases. S. aureus is singly responsible for 40% of ventilator-associated pneumonia episodes and most cases of nosocomial pneumonia [36,37]. Group B streptococcus is a leading cause of neonatal sepsis in the United States [38].

Vascular and monitoring catheters and infusion sets may become contaminated and lead to the development of nosocomial infections and sepsis. The risk of catheter-related sepsis is increased when the IV catheter is placed in a central vein, particularly if the catheter remains in place longer than three to five days or if the catheter is used for blood sampling [39]. For this reason, consideration should be given to changing the catheter and possibly the insertion site after 72 hours. The risk of contamination of arterial catheters is higher than that observed with venous catheters. Contamination can occur if the system is entered frequently for blood sampling, if the infusate remains in place for more than 48 hours, or if inflammation develops near the catheterized artery [40]. Urinary catheters left in the bladder longer than two weeks often cause infection. Therefore, increased surveillance for signs of urinary tract infections when catheters remain in place beyond a few days is necessary [41].

Central venous catheters (CVCs) are increasingly used in the pediatric population, leading to an increase in CVC-related complications. Implanted ports may be the device of choice when long indwelling times are expected, with consideration given to the patient's age and need for sedation and analgesia during the insertion procedure. Radiograph following the insertion procedure is recommended to ensure correct catheter positioning. Full sterile barrier precautions, strict protocols for catheter care, and prompt removal of the catheter when it is no longer needed are recommended to prevent infectious complications [42].

Bacterial contamination of platelet units (estimated at 1 in 1,000–3,000) results in many occurrences of transfusion-associated sepsis in the United States each year. In 2004, the AABB (formerly the American Association of Blood Banks) adopted a standard requiring member blood banks and transfusion services to implement detection measures and limit bacterial contamination in all platelet components [43].

Patients who live with malignancy are commonly hospitalized due to infection. Immunosuppresive treatments (or the malignancy itself) can lead to severe infection, which is a frequent cause of death among cancer patients. One in six patients with sepsis has underlying disease [44].

The natural defense of the body to an infection, or other assault, involves a number of cellular and humoral factors. They include B and T lymphocytes, macrophages, neutrophils, platelets, tumor necrosis factor (TNF), interleukins, the coagulation factors, and probably several other products [45,46,47]. There are five rather distinct phases that describe how these biologic products work together to overcome the assault and, paradoxically, how they can interact to cause SIRS and potentially lead to critical organ failure [45,48].

A complex, dynamic, and bidirectional interaction occurs between pathogens and the body's immune defense mechanisms during the course of invasive infection. If the defenses are breached successfully, the result can be sepsis [26].

When the etiology of sepsis began to shift from a predominance of gram-negative bacteria to a predominance of gram-positive, drug-resistant bacteria, it led to a re-evaluation of basic assumptions about the pathogenesis of sepsis (e.g., there may or may not be differences in the host response to gram-negative organisms compared with the response to gram-positive organisms) [52,53]. It is important to note that discrimination between gram-negative and gram-positive organisms is based on the recovery of specific pathogens from blood or the presumed site of infection rather than from any specific immunologic criterion. In 30% to 50% of sepsis cases, the inciting organism is not identified [25,30,37].

Any patient with sepsis who has evidence of dysfunction in one organ in the absence of an obvious cause such as traumatic injury may have incipient dysfunction of other organs. The manifestations of sepsis may be seen in the cardiovascular, pulmonary, central nervous, renal, gastrointestinal, and hematologic systems of the body (most frequently in the lungs and circulatory system) [26].

The following signs and symptoms should not be thought of merely as the manifestations of sepsis but as clear evidence that MODS may be developing. The host response may be more important in the genesis of MODS than the specific bacterium, virus, or traumatic injury. In most patients, the extent of systemic changes corresponds to the extent of shock [26,59,60].

Methods to identify critically ill patients who are likely to die as a result of sepsis have become clearer, and increased awareness that sepsis is more common and lethal than previously understood has helped to promote the development of an organized approach to care. While the early diagnosis of sepsis continues to be a challenge (primarily because a rapid, sensitive, and specific diagnostic test is lacking), research indicates that improvements in outcomes are possible when treatment protocols are applied in a timely manner [58].

As discussed, an international consortium of critical care specialty societies has worked to standardize the definition and clinical parameters of sepsis and to develop evidence-based guidelines for optimal management of sepsis and septic shock. This is an ongoing effort, the goal of which is to improve care and reduce mortality worldwide. Clinical care guidelines have been developed by the Surviving Sepsis Campaign and published by the Society of Critical Care Medicine (SCCM) in 2008, 2013, 2016, and 2021. Detailed management strategies are provided for rapid diagnostic evaluation and antimicrobial treatment, fluid resuscitation, and the use of vasopressors in septic shock [3,4,10]. Initial funding of the Surviving Sepsis Campaign was provided by the SCCM. The ongoing work and the campaign's guidelines have no direct or indirect connection to industry support. The 2021 international guideline for the management of sepsis and septic shock are available online at https://www.sccm.org/SurvivingSepsisCampaign/Home [10]. The 2021 guideline recommendations are graded for strength ("strong" or "weak") and for quality of evidence.

MANAGEMENT OF SEPSIS

Fluid Resuscitation and Diagnosis

The SCCM guideline emphasizes that sepsis and septic shock are medical emergencies; treatment and resuscitation should begin immediately upon recognition. Intravenous fluid resuscitation of a patient with sepsis-induced shock (defined as tissue hypoperfusion) should be initiated as soon as the hypoperfusion is recognized (i.e., not delayed pending admission to an ICU).

The Society for Critical Care Medicine recommends that, in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first three hours.

(https://journals.lww.com/ccmjournal/Fulltext/2017/03000/Surviving_Sepsis_Campaign___International.15.aspx Last Accessed: May 20, 2024)

Strength of Recommendation/Level of Evidence: Strong recommendation, low quality of evidence

The principal recommendations for fluid resuscitation are [10]:

• Crystalloids should be used as first-line fluid for resuscitation for adults with sepsis or septic shock (grade strong, moderate-quality evidence).

• In the setting of sepsis-induced hypoperfusion, at least 30 mL/kg of intravenous crystalloid fluid should be given within the first three hours (grade weak, low-quality evidence).

• It is suggested that albumin be added when patients require substantial amounts of crystalloids (grade weak, moderate-quality evidence).

• Fluid resuscitation should initially target a MAP of 65 mm Hg in patients with septic shock requiring vasopressors (grade strong, moderate-quality evidence).

It is recommended that, following initial fluid resuscitation, additional fluid administration be guided by frequent reassessment of hemodynamic status. A reasonable set of treatment goals suggested for the first six hours of resuscitation are [4,10]:

• Central venous pressure of at least 8 mm Hg (12 mm Hg in mechanically ventilated patients)

• MAP of 65 mm Hg or greater

• Urine output of 0.5 mL/kg/hour or greater

• Central venous or mixed venous oxygen saturation of at least 70% or 65%, respectively

Antibiotic Therapy and Source Control

The Society for Critical Care Medicine recommends that appropriate routine microbiologic cultures (including blood) be obtained before starting antimicrobial therapy in patients with suspected sepsis or septic shock if doing so results in no substantial delay in the start of antimicrobials.

(https://journals.lww.com/ccmjournal/Fulltext/2017/03000/Surviving_Sepsis_Campaign___International.15.aspx Last Accessed: May 20, 2024)

Strength of Recommendation/Level of Evidence: Best practice statement

The SCCM recommends obtaining appropriate cultures before beginning antimicrobial therapy, but the process of doing so should not delay antibiotic administration. At least two sets (aerobic and anaerobic) of blood cultures should be obtained, including one drawn through any indwelling vascular catheter or device in place prior to onset of infection. Cultures from other suspected sites should be obtained as well. The guideline committee also recommends that imaging studies be performed to confirm the source of infection, assuming the patient's condition allows it [3,4,10].

Intravenous antimicrobial therapy should be started as early as possible, ideally within the first hour of recognition of sepsis or septic shock (grade strong, moderate-quality evidence). Clinical studies have shown that delay in antimicrobial therapy for serious infection and sepsis prolongs morbidity, lengthens hospital stay, and increases mortality [66]. A retrospective cohort study involving 2,731 patients with sepsis showed that initiation of antimicrobial therapy within the first hour of documented hypotension was associated with increased survival to discharge. Moreover, each hour of delay conferred an approximately 12% decreased probability of survival [67].

The initial choice of antibiotics will depend on the most likely pathogens associated with the source of infection as well as the prevalent micro-organisms in the local community and hospitals. The clinician should assess risk factors for multidrug-resistant pathogens, including prior hospitalization, health facility residence, recent antimicrobial use, and evidence of prior infection with resistant organism. The anticipated susceptibility profile of prevalent local pathogens and the ability of the antibiotic to penetrate to the source of the infection must also be considered. A combination of drugs with activity against all likely pathogens should be administered initially, but the regimen should be reassessed in light of culture results, the goal being to identify a single, narrow-spectrum antibiotic that will best control the infection [63,68]. It has been found that combining an extended-spectrum beta-lactam antibiotic (e.g., penicillins, cephalosporins) with an aminoglycoside (e.g., gentamicin) was no more effective in reducing mortality than using the beta-lactam agent alone. In addition, the combination carries an increased risk of renal damage [63,68]. A common approach is to initiate empiric therapy with a carbapenem or extended-spectrum penicillin/beta-lactamase inhibitor (e.g., ticarcillin/tazobactam) to cover gram-negative enteric bacilli and Pseudomonas, often in combination with vancomycin to cover S. aureus pending culture results.

The empirical antimicrobial regimen should be narrowed as soon as the pathogen has been identified and sensitivities are known. The duration of therapy will depend on the nature of the infection and other considerations specific to a given case. As a general rule, a 5- to 8-day course of bactericidal antimicrobial therapy is considered adequate for most serious infections associated with sepsis [10]. In the event that the syndrome is due to something other than an infectious cause, such as trauma, antibiotics should be discontinued as soon as possible.

Source control requires that a specific anatomic diagnosis of infection (e.g., skin/soft tissue infection, pyelonephritis, cholangitis, peritonitis) be identified, or excluded, as soon as possible and preferably within the first six hours after presentation. Radiographic imaging is often necessary and should be undertaken promptly as soon as the patient's condition permits and antimicrobial therapy has been administered. Source control may be achieved by percutaneous drainage of an infected cyst or abscess, debridement of infected tissue, or removal of an infected device or catheter (removal should be prompt after other vascular access has been established) [10,63]. If necessary, surgical exploration and drainage should be undertaken within 12 hours of diagnosis (grade strong, low-quality evidence) [4].

Vasopressors and Inotropic Therapy

If hypotension persists after intravascular volume repletion, then vasopressors may be required to restore and maintain adequate blood pressure and tissue perfusion (goal MAP ≥65 mg Hg). Such patients are considered to have the combination of vasodilation and reduced cardiac contractility, a condition best managed with a combined inotrope-vasopressor agent. In order to monitor arterial pressure accurately, it is suggested that all patients requiring vasopressors have an arterial catheter placed as soon as practical, if resources are available [10].

Historically, norepinephrine, dopamine, and epinephrine were three inotrope-vasopressor used to correct hypotension in septic shock [63]. Based on comparison studies and a meta-analysis of six randomized trials, norepinephrine is considered superior to dopamine and is now the recommended first choice for vasopressor therapy in septic shock (grade strong, high-quality evidence) [4,10,69]. In settings where norepinephrine is not available, epinephrine or dopamine can be used as an alternative. Special attention should be given to patients at risk for arrhythmias when using dopamine and epinephrine [10]. For adults with septic shock on norepinephrine with inadequate MAP levels, vasopressin should be added instead of escalating the dose of norepinephrine (grade weak, moderate-quality evidence) [10]. If combination therapy is not effective, epinephrine may be added. For patient safety and effectiveness, intravenous vasopressor therapy should be administered via a central venous catheter.

As an alternative second drug, or to decrease the required effective dose of norepinephrine, vasopressin (up to 0.03 units/minute) may be added to norepinephrine [3,4,10]. Vasopressin should not be administered as the initial agent in septic shock.

Phenylephrine is a pure vasopressor that may be used in very select cases of septic shock [3,4]. It reduces cardiac stroke volume, which can have deleterious effects in the patient with low cardiac output, and thus is not recommended as initial or additive therapy. Phenylephrine is reserved for the unusual case in which tachyarrhythmia limits norepinephrine use or the patient has known high cardiac output. Intravenous phenylephrine should be administered only by properly trained individuals familiar with its use [63,70,71].

Inotropic therapy may involve the use of dobutamine if the cardiac output remains low. If dobutamine is used, it should be combined with the vasopressors (grade weak, low-quality evidence) [10]. All patients requiring vasopressors should have an arterial line placed for monitoring blood pressure [63,70].

Monitoring Serum Lactate

If elevated, serum lactate provides a marker of tissue hypoperfusion, and serial measurements (of lactate clearance) can be used to monitor progress in resuscitation of the patient with sepsis or early septic shock. In cases in which elevated lactate levels are used as a marker of tissue hypoperfusion, it is recommended that resuscitation efforts target serum lactate with the goal to achieve normalization as rapidly as possible (grade weak) [3,4,10].

Corticosteroids

Prior to the 1990s, there was evidence that the overall 28-day mortality was not impacted by the use of corticosteroids; consequently, their use was not advised. A review of studies conducted between 1992 and 2003 concluded that corticosteroids did not change the 28-day mortality in patients with sepsis and septic shock, but that the use of low-dose corticosteroids did reduce the all-cause mortality [72]. A 2019 update of this review concluded with moderate-certainty evidence that corticosteroids probably reduce 28-day and hospital mortality among patients with sepsis [73]. According to the 2021 guideline, corticosteroids are not recommended in adult patients with sepsis if hemodynamic stability has been achieved with fluid resuscitation and vasopressor therapy.

The patient with persistent hypotension despite fluids and vasopressors should be assessed for adrenal responsiveness and may benefit from corticosteroid therapy. The 2021 SCCM guideline suggests using IV corticosteroids for adults with septic shock and an ongoing requirement for vasopressor therapy (grade weak, moderate-quality evidence) [10]. The typical corticosteroid used in adults with septic shock is IV hydrocortisone at a dose of 200 mg/day given as 50 mg intravenously every six hours or as a continuous infusion [10,74]. It is suggested that this is commenced at a dose of norepinephrine or epinephrine ≥0.25 mcg/kg/min at least four hours after initiation.

Recombinant Human Activated Protein C

Drotrecogin alpha (activated), or recombinant human activated protein C (rhAPC), has been studied in patients with sepsis due to its antithrombotic, anti-inflammatory, and profibrinolytic properties. It was voluntarily withdrawn from the market in 2011 due to studies showing no improvement in mortality with treatment [75].

Blood Product Administration

In some cases, blood product administration may be required. The 2021 guideline recommends RBC transfusion if the hemoglobin level falls below 70 g/L; however, RBC transfusion should not be guided by hemoglobin concentration alone. Assessment of the patient's overall clinical status and consideration of extenuating circumstances (e.g., acute myocardial ischemia, severe hypoxemia) is required [10]. The routine use of erythropoietin is not recommended for treatment of anemia in patients with sepsis unless other conditions are present, such as the compromise of red blood cell production induced by renal failure.

Patients who require invasive procedures or surgery typically require a platelet count that is in excess of 50,000/mm³[63]. The routine use of fresh frozen plasma is not recommended unless there is active bleeding or planned surgery. Direct administration of antithrombin agents for the treatment of sepsis or septic shock is not advised [63].

MANAGEMENT OF SEVERE CORONAVIRUS DISEASE 2019 (COVID-19) IN THE ICU

In response to the ongoing COVID-19 pandemic, a Surviving Sepsis Campaign Coronavirus Disease 2019 panel of international experts was formed to provide guidance for managing patients with severe or critical COVID-19 [77]. The panel issues updated recommendations as new evidence becomes available. COVID-19 is defined as severe when the patient has clinical signs of pneumonia (e.g., fever, cough, dyspnea, tachypnea) combined with one or more of the following: respiratory rate >30 breaths/min, severe respiratory distress, or oxygen saturation <90% on room air [77]. COVID-19 is classified as critical when the patient has acute respiratory failure requiring ventilation and/or signs of sepsis or septic shock.

For adults with COVID-19 and shock, the Society for Critical Care Medicine suggests using norepinephrine as the first-line vasoactive agent over other agents.

(https://journals.lww.com/ccmjournal/Fulltext/2021/03000/Surviving_Sepsis_Campaign_Guidelines_on_the.21.aspx Last Accessed: May 20, 2024)

Strength of Recommendation: Weak

In March 2021, the Surviving Sepsis Campaign COVID-19 panel issued nine new or updated statements/recommendations for management of patients with COVID-19 in the ICU [78]. For severe or critical COVID-19, the panel recommends the use of systemic corticosteroids (preferably dexamethasone) and venous thromboprophylaxis but recommends against the use of hydroxychloroquine. In addition, the panel suggests against the use of convalescent plasma and therapeutic anticoagulation outside clinical trials. The use of remdesivir, an antiviral drug, is suggested for adults with severe COVID-19 who do not require mechanical ventilation; however, the panel suggests against starting remdesivir in patients with critical COVID-19 outside clinical trials. Because of insufficient evidence, no recommendation has been issued on the use of awake prone positioning [78].

Sepsis is a common and frequently fatal condition affecting children worldwide. The global burden and mortality of sepsis in neonates and children was assessed in a systemic review and meta-analysis of epidemiologic studies published between 1979 and 2016 [79]. The analysis demonstrated an aggregate estimate of 48 cases of childhood sepsis and 22 cases of severe sepsis per 100,000 person-years. Childhood mortality ranged from 1% to 5% for sepsis and 9% to 20% for severe sepsis. The population-level estimate for neonatal sepsis was 2,202 per 100,000 live births, with mortality between 11% and 19%. Extrapolating data on a global scale yielded an estimated annual incidence of 3.0 million cases of sepsis in neonates and 1.2 million cases in children [79]. In the United States alone there are 72,000 children hospitalized for sepsis annually, with a reported mortality rate of 25% [80].

In 2002, an international panel of experts met to revise the definitions of sepsis and septic shock to include and reflect the developmental stages of children and age-specific norms of vital sign and laboratory data. The panel also modified the adult criteria for SIRS and proposed dividing the pediatric population into the following six distinct age groups to account for age-specific risks [81]:

The panel's definition of SIRS for children includes the presence of at least two of the following criteria (one of which must be abnormal temperature or leukocyte count) [81]:

Because many pediatric disease processes present with symptoms of tachycardia and tachypnea, a diagnosis of SIRS should not be based solely on elevated heart and respiratory rates; abnormalities in temperature or leukocyte count must be present. Biomechanical markers of inflammation (e.g., elevated sedimentation rate, C-reactive protein, interleukin-6) have not been proven specific enough to be included in the diagnostic criteria [81].

The following definitions have also been proposed for use in the pediatric population [81]:

The diagnosis of sepsis and impending septic shock in neonates and children should be suspected when the usual inflammatory triad of fever, tachycardia, and vasodilation is accompanied by changes in mentation. Altered mentation may manifest as inability to be aroused, inconsolable irritability, or lack of interaction with parents. Children may present with hyper- or hypothermia, signs of decreased perfusion, and/or decreased urinary output. Because children often maintain their blood pressure until they are severely ill, hypotension is not necessary for the diagnosis (as in adults), but if present, it helps confirm a suspected case of septic shock. It is also important to note that shock in children may occur long before hypotension occurs [81].

Neonatal ICU (NICU) nurses play a key role in the early recognition and prompt treatment of infection/sepsis in the newborn. A published critical care nursing guide for understanding issues of sepsis in the NICU emphasizes the following goals [82]:

Prior to 2020, the most widely utilized guidance for management of sepsis in the pediatric age group was the Surviving Sepsis Campaign guidelines, reviewed and updated every four years [4,80]. Following the 2016 edition, SCCM formed a separate task force dedicated to developing guidelines for managing sepsis in children. Published in 2020, the objective of the SCCM Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children is to provide guidance for clinicians caring for infants, children, and adolescents with sepsis and septic shock [83]. Resources related to these guidelines can be found on the SCCM Surviving Sepsis Campaign website at https://www.sccm.org/SurvivingSepsisCampaign/Guidelines/Pediatric-Patients[84].

Systematic screening for sepsis is recommended in children who present as acutely unwell. Upon clinical suspicion of sepsis, an expedited diagnostic evaluation should be performed within three hours, including an assessment for sepsis-associated organ dysfunction and blood cultures [84]. If signs of shock develop, or clinical evaluation supports sepsis-associated organ dysfunction, management is escalated to a one-hour time frame with the following goals: obtain IV access, collect blood culture, start empiric broad-spectrum antibiotics, measure lactate, and administer fluid bolus(es) if the patient is hypotensive. Vasoactive agents should be added when hypotension persists despite completion of initial fluid resuscitation protocol. Continuous clinical reassessment is recommended for early recognition of ARDS, infectious source control, and titration of vasoactive drugs [84]. Patients refractory to hemodynamic support should be evaluated and treated for adrenal insufficiency. About 25% of children with septic shock have adrenal insufficiency and will benefit from corticosteroid therapy [80].

Clinically, pediatric septic shock takes two forms. In hyperdynamic shock, the child has rapid capillary refill and bounding pulses. In hypodynamic shock, there is prolonged capillary refill, mottled cool extremities, and diminished pulses. In both types, immediate resuscitation involves maintaining necessary circulation with fluid replacement, assuring proper ventilation, and maintaining threshold heart rates. Suggested therapeutic end points include a capillary refill of less than two seconds, warm extremities, urine output greater than 1 mL/kg/hr, normal blood pressure, normal mental status, and normal pulses with no differential between peripheral and central pulses. Frequent monitoring is required as rapid changes may occur in the status of a child with sepsis [63,85].

The international consensus panel also developed criteria for MODS in the pediatric population based on scoring systems previously described in the literature. These systems include the Pediatric Logistic Organ Dysfunction score, Pediatric-MODS score, and Multiple Organ System Failure score. The panel also considered the criteria used in the open-label rhAPC study in their development of criteria for pediatric MODS [81].

The panel's goal was to identify criteria that would optimize the enrollment of children with severe sepsis in clinical studies. To that end, they specified the following [81]:

Experts generally agree that additional evidence-based studies are needed to understand and accurately define pediatric sepsis by accounting for the physiologic variables, age-specific norms, and risk factors of this population [80,86,87].

There is limited information on the long-term complications of sepsis in those who survive. One systematic review of hospitalized patients who recover from sepsis found that about 40% are re-hospitalized within 90 days, one-third die within the following year, and one-sixth experience persistent physical or cognitive impairments [88]. The most prevalent of reported residual impairments are functional limitations (e.g., inability to bathe and dress independently), cognitive deficits, anxiety, depression, and post-traumatic stress disorder. Factors associated with late sequelae included poor pre-sepsis health status, severity of the acute sepsis episode, and timeliness and quality of initial sepsis care [88]. This review discusses inpatient practices for reducing long-term morbidity and provides a framework for evaluating and treating patients in the 90 days after hospitalization for sepsis [88].

A recommended hospital- and ICU-based approach to improving clinical outcomes centers on three strategies: attention to 2021 SCCM guidelines for sepsis care; protocol management of pain, agitation, and delirium; and early mobilization to prevent or minimize muscle atrophy [88]. Adherence to guidelines for the early identification and treatment of sepsis, including rapid administration of antibiotics, has been shown to decrease in-hospital mortality [89]. Critical care specialists have published the ABCDEF bundle, an evidence-based clinical care guide to optimize ICU patient recovery and outcomes [90]. This guide addresses issues such as pain prevention, spontaneous awakening and breathing trials, choice of sedation, management of delirium, early mobility, and family engagement and empowerment. The ABCDEF bundle helps assure more interactive ICU patients who can participate in higher-order physical and cognitive activities at the earliest in recovery from critical illness [90].

A recommended post-discharge management strategy for patients who recover from sepsis includes the following: identify new physical, mental, and cognitive problems that could benefit from appropriate treatment; review long-term medications and adjust dosage if indicated; and screen for treatable conditions that impact risk of rehospitalization, such as recurrent infection, heart failure, and aspiration [88].

Sepsis and septic shock present the clinician with a difficult management situation. Patients are usually unstable and may rapidly progress to ARDS, MODS, and death. There are several possible causes of sepsis, including traumatic injury, infections, and burns. Gram-negative and gram-positive organisms associated with nosocomial infections account for many cases. Other bacteria, viruses, fungi, and noninfectious etiologies account for the remaining [36,59]. The mortality rate from sepsis is approximately 30%, and it was the 14th leading cause of death in the United States in 2023 [21,91].

The pathophysiology of sepsis involves multiple organ systems and is often related to an abnormal proinflammatory and/or anti-inflammatory response to infection. Effective management requires early empiric antimicrobial therapy, hemodynamic monitoring, appropriate respiratory support, and maintenance of physiologic homeostasis.

Evidence-based practice guidelines are available to assist in the diagnosis and treatment of these disorders. This course outlines some of the current recommendations and suggestions provided by the SCCM and other experts experienced in treating patients with these disorders.

Patient A is a woman, 50 years of age, who was admitted to the emergency department after a motor vehicle accident. She incurred massive abdominal injuries and was transported to the emergency department unconscious and hypotensive upon arrival. She was receiving 35% O₂ via oxygen mask. Her respiratory rate was 28 breaths per minute, and lung sounds were clear bilaterally. She had a sinus tachycardia with a heart rate of 150 beats per minute. Her blood pressure was 80/45 mm Hg. The patient had a 40 pack-year history of cigarette smoking and had been taking medications to control hypertension.

She was transported via stretcher to radiology for a computed tomography scan, which revealed bleeding in the peritoneum. She was taken immediately to surgery. Following surgery, she was taken to the ICU. Three liters of lactated Ringer's solution had been infused in surgery. Estimated blood loss was 2,500 cc, and she received 6 units of whole blood in surgery. Despite fluid resuscitation, the patient was hypotensive during much of the surgical procedure. To assess fluid management, a pulmonary artery catheter was placed while in surgery. A variety of data was obtained upon arrival to the surgical ICU.

Patient A was hemodynamically stable following surgery. She awakened slowly and was able to be extubated and put on a 40% O₂ mask.