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]:

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]:

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].

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.

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].

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].

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].

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].

The coagulation system plays an important role in the sepsis-induced inflammatory cascade. Coagulation is the inflammatory reaction to tissue injury and is activated independent of the type of microbe (e.g., gram-positive and gram-negative bacteria, viruses, fungi, or parasites). Coagulation contributes to the outcome in sepsis by down-regulating fibrinolysis and the anticoagulant systems. The collaboration between clotting and inflammation, which works to wall off damaged and infected tissues, is an important host survival strategy. Coagulation induced by inflammation can in turn contribute to further inflammation. A key to determining survival in sepsis is to limit the damage while retaining the benefits of localized clotting and controlled clearance of pathogens [7,56,57].

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].

Before the onset of shock, the patient's condition is usually hyperdynamic. The skin is warm and flushed, pulse volume is increased, and pulse pressure is wide. Cardiac output is typically elevated, and systemic vascular resistance (SVR) is usually decreased. Despite the increase in cardiac output, serum lactate levels are often elevated. Anaerobic metabolism occurs because of inadequate nutrient blood flow [30].

Altered mental status may be the most common and most overlooked manifestation of sepsis. This causes elderly patients to be at particularly high risk. Early changes include withdrawal, confusion, irritability, or agitation. In patients with severe infection, one may see disorientation, lethargy, seizures, or frank obtundation [61,62].

The principal recommendations for fluid resuscitation are [10]:

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.

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.

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.

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.

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]:

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].