Systemic inflammatory response syndrome and sepsis

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CHAPTER 232

Systemic inflammatory response syndrome and sepsis

Mark T. Keegan, MB, MRCPI, MSc

The systemic inflammatory response syndrome (SIRS) and sepsis are complex syndromes resulting from an inciting insult that causes systemic inflammation, leading to widespread tissue injury. In the case of sepsis, the initial insult is an infection. Sepsis is the leading cause of death in critically ill patients. In the Unites States, sepsis occurs in 750,000 people every year, and more than 200,000 of them die. The incidence of sepsis is increasing, and it is especially common in the elderly. Both SIRS and sepsis may be seen in the perioperative period and are common causes of admission to the surgical intensive care unit.

The American College of Chest Physicians and the Society of Critical Care Medicine published consensus-derived definitions of SIRS, sepsis, and organ failure in 1992 (Table 232-1). In 2001, a list of signs and laboratory findings that should prompt a clinician to consider sepsis in the differential diagnosis was proposed. In addition to tachypnea, tachycardia, and alterations in temperature and white blood cell count, these findings include chills, poor capillary refill, decreased skin perfusion, thrombocytopenia, hypoglycemia, oliguria, alteration in mental status, and skin mottling.

Table 232-1

Consensus Definitions for Sepsis and Organ Failure

Term	Definition
SIRS	Two or more of the following • Temperature >38° C or <36° C • Heart rate >90 beats/min • Respiratory rate >20 breaths/min or PaCO₂ <32 mm Hg • WBC count >12 × 10⁹/L or <4 × 10⁹/L or >10% immature band forms
Sepsis	The presence of SIRS and either of the following • An infection suspected or documented by the presence of pathogenic microorganisms on culture or Gram stain of blood, sputum, urine, or normally sterile body fluids • The focus of infection identified by visual inspection (e.g., wound with purulent discharge)
Severe sepsis*	Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities include, but are not limited to, lactic acidosis, oliguria, or mental status changes
Sepsis-induced hypotension*	Systolic blood pressure <90 mm Hg, or reduction of >40 mm Hg, in the absence of other causes for hypotension
Septic shock*	Sepsis-induced hypotension despite adequate fluid resuscitation plus perfusion abnormalities including, but not limited to, lactic acidosis, oliguria, and mental status changes; patients who receive vasopressor or inotropic agents to maintain blood pressure are considered to be in shock even if they are not hypotensive

WBC, white blood cell.

^*Or systemic inflammatory response syndrome (SIRS), depending on whether or not infection is present.

SIRS occurs in the absence of infection and may be secondary to surgical insult, trauma, or inflammatory conditions, such as pancreatitis. Sepsis is the result of a complex interaction among the patient’s immune, inflammatory, and coagulation systems and an infecting organism. In both SIRS and sepsis, at the site of injury or infection, a local inflammatory response is antagonized by a local antiinflammatory response (Figure 232-1). Such proinflammatory and antiinflammatory responses often become systemic. Both excessive and inadequate host-immune responses can lead to progression of disease and organ dysfunction. Further, a large inciting stimulus or a virulent infectious agent may cause organ dysfunction even in the presence of a competent immune system. Neutrophils play a key role in the development of sepsis. An initial toxic stimulus (e.g., bacterial endotoxin) leads to production of proinflammatory cytokines, such as interleukin 1 and tumor necrosis factor. Migration of neutrophils to vascular endothelium subsequently occurs, with concomitant activation of clotting and generation of secondary inflammatory mediators.

Figure 232-1 Mechanisms of disease after bacterial infection. Barred lines indicate inhibition; lines with arrows, activation or consequences. C5a., Complement component 5a; NO, nitric oxide; Nod, nucleotide-binding oligomerization domain; PGRP, peptidoglycan recognition proteins; sCD14, soluble CD14; sTNFR, soluble tumor necrosis factor (TNF) receptor. (From Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78.)

Multiple organ dysfunction syndrome (MODS) may result from SIRS or sepsis. Organ dysfunction tends to follow a predictable course—independent of the inciting insult—unless the process is halted by therapeutic interventions. Intravascular volume depletion and vasodilation initially lead to hypotension. The acute respiratory distress syndrome (ARDS) may also occur relatively early. Subsequently, acute kidney injury, ileus, mental status changes, and hepatic dysfunction may occur. As the process continues, direct myocardial depression and bone marrow suppression may develop.

Common sites of infection, in descending order of frequency, include the lung, the abdominopelvic region, urinary tract, and soft tissue. In 20% to 30% of patients, a definite site of infection is not identified, and blood cultures may be positive only 30% of the time.

Sepsis and SIRS are associated with a vasodilated state; intravascular volume depletion results from “third spacing.” The classic picture shows a hyperdynamic, high cardiac output state with a low systemic vascular resistance. However, this hemodynamic pattern may be absent in the early stages before adequate volume resuscitation has taken place or when sepsis-associated myocardial depression leads to a decrease in stroke volume.

Severe sepsis and septic shock are medical emergencies requiring prompt intervention. Guidelines for management have been developed by a multinational multidisciplinary collaboration of experts as part of an education initiative known as the Surviving Sepsis Campaign, the latest iteration being the 2012 version. Many institutions have incorporated these therapies into “sepsis bundles” to promote best practice. Suggested algorithms for investigating potential sepsis and managing patients with sepsis are provided in Figures 232-2 and 232-3. Elements of sepsis management include initial resuscitation, diagnosis, antibiotic therapy, source control, and supportive therapy.

Figure 232-2 Decision tree for the diagnosis of septic shock. sTREM1, Soluble triggering receptor expressed on myeloid cells. (From Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78.)

Figure 232-3 Principles of the treatment of septic shock. Pink boxes refer to interventions; brackets, timing of interventions. (Modified from Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78.)

Initial resuscitation

Fluid resuscitation and identification of the infection with surgical site control, if possible, are hallmarks of treatment. Intravenously administered large-volume fluid resuscitation is required to reverse organ hypoperfusion. In adults, the deficit is often more than 6 L, and both crystalloids and colloids may be administered, preferably according to a protocol. The multicenter SAFE (Saline versus Albumin Fluid Evaluation) study failed to show a benefit of colloid (albumin) over crystalloid (saline) in most patient populations; in patients with traumatic brain injury, albumin was found in a posthoc analysis to be harmful. Arterial and central venous catheters for measuring central venous pressure and venous oximetry are often placed to guide resuscitation. “Early goal-directed” resuscitation has been demonstrated to improve outcomes in septic shock, although the details are debated. Reasonable targets for fluid resuscitation include a central venous pressure of 8 to 12 mm Hg, a mean arterial pressure of at least 65 mm Hg, and a central venous O₂ saturation of at least 70% or mixed venous O₂ saturation of at least 65%.

Evidence supports, during the first 6 h of resuscitation, transfusion of packed red blood cells to a hematocrit of at least 30%, administration of dobutamine (up to 20 μg·kg⁻¹·min⁻¹), or both to achieve hemodynamic goals if they are not met by fluid administration alone. Although nonspecific, measurement of serum lactate, C-reactive protein, and procalcitonin concentrations may be useful markers.

Diagnosis

Appropriate cultures should be obtained before antimicrobial therapy is initiated, assuming that performance of such cultures does not significantly delay antibiotic administration. Two sets of blood cultures should be drawn in addition to appropriate cultures of other potential sites of infection. Imaging studies should be performed expeditiously, weighing the risk of transport, if required, against the potential benefit of the study.

Antibiotic therapy and source control

Antibiotic therapy, directed against likely pathogens, should be intravenously administered as soon as possible and within the first hour after severe sepsis or septic shock is recognized. Antimicrobial agents that effectively penetrate into the presumed site of infection should be chosen. The initial therapy should cover a wide spectrum of pathogens, with subsequent daily reassessment based on culture data and clinical response. Antimicrobial options are presented in Table 232-2. Identification of an anatomic site of infection should prompt consideration of intervention to control the source (e.g., drainage of empyema or intraabdominal abscess, débridement of infected necrotic tissue, removal of an infected device.)

Table 232-2

Antimicrobial Choices in Sepsis

Patient Population/Site of Infection	Likely Pathogen	Recommended Antimicrobial Agent or Agents
Immunocompetent	Gram-positive Gram-negative	Give ureidopenicillins + one of the following β-Lactamase inhibitors Carbapenems Third- and fourth-generation cephalosporins Add antipseudomonal fluoroquinolone if Pseudomonas aeruginosa is a likely pathogen. Add vancomycin or linezolid if there is concern for MRSA. Add linezolid if there is concern for VRE.
Immunocompromised	Gram-positive Gram-negative Fungal	Treat as for an immunocompetent patient, with inclusion of vancomycin or linezolid and antipseudomonal agent. Add antifungal (amphotericin B, caspofungin, or voriconazole) if patient is at high risk for fungal infection.
Intravascular catheter–related infections	Gram-positive Gram-negative Fungal	Provide broad-spectrum antimicrobial coverage In settings with a significant MRSA prevalence, vancomycin should be administered. Add antipseudomonal agent in immunocompromised patients. Add intravenously administered amphotericin B or fluconazole if fungemia is suspected.
VAP, HCAP, HAP*	Streptococcus pneumoniae, Haemophilus influenzae, MSSA, enteric gram-negative bacilli	In the absence of risk factors that necessitate use of broad-spectrum antibiotics, fluoroquinolone, ampicillin/sulbactam, or ceftriaxone can be given. With recognized risk factors, use antipseudomonal cephalosporin (cefipime, ceftazidime), antipseudomonal carbapenem (imipenem, meropenem), or piperacillin/tazobactam AND antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin) or aminoglycoside. Add vancomycin or linezolid if there is concern for MRSA. Add macrolide or fluoroquinolone if there is concern for Legionella pneumophila.
Severe community-acquired pneumonia	Typical organisms (S. pneumoniae, H. influenzae, S. aureus) and atypical organisms (Mycoplasma pneumoniae, Chlamydia pneumoniae, L. pneumophila)	Give third-generation cephalosporin and intravenously administered macrolide or nonpseudomonal fluoroquinolone. Give antipseudomonal fluoroquinolone if Pseudomonas aeruginosa is a likely pathogen.
Fungal infections	Candida spp., Aspergillus	Caspofungin, amphotericin B, voriconazole, itraconazole, or fluconazole may be chosen depending on individual patient and organism factors.

HAP, Hospital-acquired pneumonia; HCAP, health care–associated pneumonia; MSSA, methicillin-sensitive Staphylococcus aureus; VAP, ventilator-associated pneumonia; VRE, vancomycin-resistant Enterococcus.

^*Certain patients (e.g., those with recent antibiotic therapy, prolonged hospitalization, or immunosuppression or on dialysis) require broad-spectrum antibiotics targeting gram-positive, gram-negative, and atypical organisms, such as Legionella pneumophila and MRSA. (methicillin-resistant Staphylococcus aureus)

Vasopressors and inotropes

Mean arterial pressure should be maintained at a minimum of 65 mm Hg, though preexisting comorbid conditions (e.g., longstanding hypertension) may alter this pressure goal. Surviving Sepsis Campaign recommendations for hemodynamic support are provided in Box 232-1. Norepinephrine is recommended as the first-choice vasopressure in septic shock, though epinephrine may be used as an alternative when the patient is poorly responsive to the initial choice. Patients with sepsis may have a relative vasopressin deficiency that contributes to vasodilatation, and intravenously administered vasopressin is increasingly used by many as a vasoconstrictor. Phenylephrine is devoid of β-adrenergic effects and is not recommended as a first-line agent because it is likely to decrease stroke volume. Vasopressor agents should be administered through a central venous catheter as soon as a catheter is available. When myocardial dysfunction is suggested by elevated cardiac filling pressures and low cardiac output, dobutamine should be administered to attain a normal (though not supranormal) cardiac index.

Box 232-1 Surviving Sepsis Campaign 2012 Recommendations for Hemodynamic Therapy

Crystalloids should be the initial resuscitation fluid in severe sepsis and septic shock. Albumin should be added when substantial amounts of crystalloids are required. Hydroxyethyl starches are not recommended.

A fluid bolus of 30 mL/kg should be administered in hypoperfusion states with presumed hypovolemia. Fluid challenges should be repeated based on response (change in pulse pressure, stroke volume variation, arterial pressure, heart rate).

Vasopressor therapy should target a MAP of 65 mm Hg.

Norepinephrine is the first-choice vasopressor. Epinephrine should be added or substituted when an additional agent is needed to maintain MAP. Vasopressin may be added to increase MAP or decrease norepinephrine dose. Vasopressin should not be used as a single agent, and its use in doses of >0.03-0.04 unit/min should be reserved for refractory cases.

Dopamine and phenylephrine should be used only in highly selected cases. Dopamine should not be used for renal protection.

Dobutamine should be added if myocardial dysfunction is present or if there are signs of hypoperfusion despite adequate intravascular volume and MAP. There is no benefit to achieving a “supranormal” cardiac index.

MAP, Mean arterial pressure.

Corticosteroids

Relative adrenal insufficiency may be a feature of the “endocrinopathy of critical illness.” Although the results of some studies have suggested that supplementation with corticosteroids in patients with septic shock might be beneficial, recent multicenter trials (e.g., CORTICUS [Corticosteroid Therapy of Septic Shock]) have failed to demonstrate a survival benefit in patients with septic shock who received steroids. If hemodynamic stability is not achieved by the use of fluids, vasopressors, and inotropes alone, the administration of hydrocortisone at 200 mg/day may be considered. Patients who have documented adrenal insufficiency or who are likely to have suppression of the hypothalamic-pituitary-adrenal axis because of long-term steroid use should receive supplemental intravenously administered hydrocortisone during episodes of critical illness.

Recombinant human activated protein c

A randomized controlled trial in adult patients with severe sepsis and septic shock demonstrated a survival advantage with the use of the antiinflammatory, antithrombotic, profibrinolytic agent recombinant human activated protein C (rhAPC). This was the first drug targeting the mechanism of sepsis that appeared to offer a survival benefit. Further studies clarified the indications for rhAPC and the contraindications for its use—patients with severe sepsis and a low risk of death or children because of the risk of hemorrhagic complications. Careful consideration was given to the use and timing of administration of rhAPC in surgical patients because anticoagulation was a predictable side effect of the drug. As more studies were conducted, however, other concerns were demonstrated, and the manufacturer withdrew the product from the market in October 2011.

Supportive therapy

Multiple supportive therapies are often required for patients with sepsis. Noninvasive or invasive mechanical ventilation may be needed for patients with acute respiratory distress syndrome. Mechanical ventilatory support should be based on the principles discussed in Chapter 227. When required, sedation should be guided by protocols that target predetermined end points (e.g., sedation scales), with daily interruption or lightening of sedation with awakening and retitration of sedative agents. Neuromuscular blocking agents should be avoided, if possible, to decrease the likelihood of the development of critical illness polyneuromyopathy, although a short (≤ 48 h) course of neuromuscular blocking agents is recommended for patients with acute respiratory distress syndrome and sepsis. Glycemic control in critically ill patients has been the subject of considerable debate, with evolution of target values over the past decade. The NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) study has greatly influenced the Surviving Sepsis Guidelines in this regard. A use of a protocol-based approach is recommended, commencing with intravenously administered insulin when two consecutive blood glucose levels are greater than 180 mg/dL, and targeting an upper blood glucose level of 180 mg/dL or less.

Renal failure is common in patients with septic shock, and renal replacement therapy should be initiated as appropriate. Continuous renal replacement therapy and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure, but continuous techniques may facilitate management of fluid balance in hemodynamically unstable patients.

In addition to the aforementioned therapies, other proven practices (e.g., deep venous thrombosis and stress ulcer prophylaxis, optimal nutrition support) should be used in patients with sepsis.

Unfortunately, septic shock has a mortality rate between 25% and 50%, which is directly related to the number of organ failures. An important aspect of management is communication of likely outcomes to family members or health care surrogates and, when appropriate, consideration for limitation of support.