Sepsis and septic shock

INTRODUCTION

• Sepsis is a clinical syndrome that has physiologic, biologic, and biochemical abnormalities caused by a dysregulated host response to infection.

• Sepsis and the inflammatory response that ensues can lead to multiple organ dysfunction syndrome and death.

Pathogens • Bacteria have been shown to be the predominant pathogen of sepsis

among patients with pathogens detected, while sepsis caused by viruses is underdiagnosed worldwide.

• The contribution of various infectious organisms to the burden of sepsis has changed over time.

• Gram positive bacteria are most frequently identified in patients with sepsis, although the number of cases of Gram negative sepsis remains substantial.

• The incidence of fungal sepsis has increased over the past decade, but remains lower than bacterial sepsis.

• In approximately one-half of cases of sepsis, an organism is not identified (culture negative sepsis).

• The viruses, which can cause severe disease, include influenza A and B, respiratory syncytial virus, coronavirus, human metapneumovirus, parainfluenza virus types 1 to 3, adenovirus, enteroviruses, and rhinovirus.

• As well as for commonly detected viruses, emerging novel virus infections can also result in sepsis and have raised global health concerns; these include severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East Respiratory Syndrome-coronavirus (MERS-CoV), and SARS-CoV-2, which caused the outbreak of the coronavirus disease 2019 (COVID-19).

Pathogens

DEFINITIONS

Sepsis exists on a continuum of severity ranging from infection and bacteremia to sepsis and septic shock, which can lead to multiple organ dysfunction syndrome (MODS) and death.

Septic shock • Septic shock is a type of vasodilatory or distributive shock.

• Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone.

• Clinically, this includes patients who fulfill the criteria for sepsis who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L (>18 mg/dL).

• Per predictions from the SOFA score, patients who fulfill these criteria for septic shock have a higher mortality than those who do not (≥40 versus ≥10 percent).

COVID-19

• Patients critically ill with COVID-19 satisfy the diagnostic criteria for sepsis and exhibit a phenotype and pathology with both similarities and differences to that of sepsis caused by other pathogens.

• Patients with severe COVID-19 suffer from multi-organ dysfunction, representing the common manifestations that characterize sepsis

CLINICAL PRESENTATION

• Patients with suspected or documented sepsis typically present with hypotension, tachycardia, fever, and leukocytosis.

• As severity worsens, signs of shock (eg, cool skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury, altered mental status).

• Importantly, the presentation is nonspecific such that many other conditions (eg, pancreatitis, acute respiratory distress syndrome) may present similarly.

Laboratory signs

Laboratory features are nonspecific and may be associated with abnormalities due to the underlying cause of sepsis or to tissue hypoperfusion or organ dysfunction from sepsis.

They include the following:

• Leukocytosis (white blood cell [WBC] count >12,000 microL) or leukopenia (WBC count <4000 microL).

• Normal WBC count with greater than 10 percent immature forms.

• Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes.

• Plasma C-reactive protein more than two standard deviations above the normal value.

• Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] <300).

• Acute oliguria (urine output <0.5 mL/kg/hour for at least two hours despite adequate fluid resuscitation).

• Creatinine increase >0.5 mg/dL or 44.2 micromol/L.

• Coagulation abnormalities (international normalized ratio [INR] >1.5 or activated partial thromboplastin time [aPTT] >60 seconds).

• Thrombocytopenia (platelet count <100,000 microL).

• Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L).

• Adrenal insufficiency (eg, hyponatremia, hyperkalemia), and the euthyroid sick syndrome can also be found in sepsis.

• Hyperlactatemia–An elevated serum lactate (eg, >2 mmol/L) can be a manifestation of organ hypoperfusion in the presence or absence of hypotension and is an important component of the initial evaluation, since elevated lactate is associated with poor prognosis

• Plasma procalcitonin more than two standard deviations above the normal value – Elevated serum procalcitonin levels are associated with bacterial infection and sepsis.

• Despite this, a meta-analysis of 18 studies found that procalcitonin did not readily distinguish sepsis from nonseptic systemic inflammation (sensitivity of 71 percent and specificity of 71 percent).

• Mid-regional pro-Adrenomedullin (MR-proADM) has been used to predict occurrence and worsening of organ failure in critically ill patients.

• Yet controversial, monitoring of MR-proADM levels may improve the diagnosis of bacterial infection and contribute to prognosis and antibiotic therapy effectiveness

Imaging — There are no radiologic signs that are specific to the identification of sepsis other than those associated with infection in a specific site (eg, pneumonia on chest radiography, fluid collection on computed tomography of the abdomen).

Microbiology — The identification of an organism in culture in a patient who fulfills the definition of sepsis is highly supportive of the diagnosis of sepsis but is not necessary.

• The rationale behind its lack of inclusion in the diagnostic criteria for sepsis is that a culprit organism is frequently not identified in up to 50 percent of patients who present with sepsis nor is a positive culture required to make a decision regarding treatment with empiric antibiotics.

DIAGNOSIS • A limitation of the definitions is that they cannot identify patients whose organ dysfunction is

truly secondary to an underlying infection.

• Thus, a constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock.

• The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when followup data returns (eg, positive blood cultures in a patient with endocarditis) or a response to antibiotics is evident.

• Importantly, the identification of a culprit organism, although preferred, is not always feasible since in many patients no organism is ever identified.

• In some patients this may be because they have been partially treated with antibiotics before cultures are obtained.

• Although septic shock has a specific hemodynamic profile on pulmonary artery catheterization (PAC), PACs are difficult to interpret and rarely placed in patients with suspected sepsis.

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

Stabilize respiration

• Supplemental oxygen should be supplied to all patients with sepsis, who have indications for oxygenation, and oxygenation should be monitored continuously with pulse oximetry.

• Ideal target values for peripheral saturation are unknown but we typically target values between 90 and 96 percent.

• 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

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.

Initial investigations — An initial brief history and examination, as well as laboratory, microbiologic (including blood cultures), 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

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), started by one hour and completed 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.

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.

• However, additional diagnostic testing or interventions may be required to identify the anatomic site(s) of infection.

• In particular, in addition to antibiotics, closed space infections should be promptly drained or debrided (eg, empyema, abscess) for effective source control.

• Timing — Once a presumed diagnosis of sepsis or septic shock has been made, optimal doses of appropriate intravenous antibiotic therapy should be initiated, preferably within one hour of presentation and after cultures have been obtained

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

• 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).

Choosing a regimen

• Many patients with septic shock, particularly those suspected to have gram negative sepsis, 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.

Choosing a regimen

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.

• 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) should be considered for patients with refractory or virulent MRSA, or with a contraindication to vancomycin.

Choosing a regimen

• if Pseudomonas is an unlikely pathogen, we favor combining vancomycin with one of the following:

• •A 3rd generation (eg, ceftriaxone or cefotaxime) or 4th generation cephalosporin (cefepime), or

• •A beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate [limited supply]), or

• •A carbapenem (eg, imipenem or meropenem)

Choosing a regimen

Pseudomonas – Alternatively, if Pseudomonas is a likely pathogen, we favor combining vancomycin with two of the following, depending on local antibiotic susceptibility patterns:

• Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or

• Antipseudomonal carbapenem (eg, imipenem, meropenem), or

• Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or

• Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or

• Aminoglycoside (eg, gentamicin, amikacin), or

• Monobactam (eg, aztreonam)

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:

Location of admission • Whether patients should be admitted to an intensive care unit (ICU) or

ward is unclear and likely varies with the individual presenting characteristics as well as available institutional services and policy, which also may vary from state to state and country to country.

• For example, patients with septic shock who require mechanical ventilation and vasopressors clearly require ICU admission while those without shock who quickly respond to fluid and antibiotics may be safely transferred to the floor.

• For those in between these extremes, close observation and a low threshold to admit to the ICU is prudent.