Sepsis

Septic
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Diagnosis and reasoning

This middle aged man has presented with fever and progressive leg swelling, in a background of poorly controlled diabetes mellitus. Examination reveals the left lower limb to be erythematous and tender, with ipsilateral inguinal lymphadenopathy; this appears to be acute cellulitis. Note also the presence of altered mentation and a blood pressure ≤100 mmHg; his qSOFA score is 2 points, indicating that he is likely to be septic. Given his comorbidities, this is highly concerning; sepsis may instigate acute kidney injury (AKI), give rise to acid-base disturbances, and precipitate diabetic emergencies, such as a hyperglycemic hyperosmolar state (HHS). His renal functions turn out to be only mildly deranged, with the disproportionately elevated blood urea nitrogen (BUN) being most likely secondary to dehydration. However, his random plasma glucose is markedly elevated to 465 mg/dL, raising concern for HHS. That said, calculation of the serum osmolality via the formula (2*Na) + (glucose/18) + (BUN/2.8) gives a result of 317 mOsm/kg. Note that an osmolality >320mOsm/kg is required for the diagnosis of HHS. His arterial blood gas (ABG) are also within normal limits, although it could be argued that they are close to becoming acidotic. Given the likelihood of sepsis, this patient is ideally managed in an intensive care unit (ICU); following admission, his Sequential Organ Failure Assessment (SOFA) score should be calculated, so as to confirm the clinical diagnosis. Furthermore, empirical intravenous (IV) antibiotics should be commenced as soon as possible; this is the single most important step in controlling the infection. IV fluid therapy is also a must; this will correct the dehydration and restore perfusion. Vasopressor therapy is not indicated immediately, but may become necessary down the line. Note also that the surviving sepsis campaign recommends deep venous thrombosis (DVT) prophylaxis in these patients, due to the increased risk secondary to immobility while receiving intensive care.


Discussion

For over two decades, sepsis has been defined as infection accompanied by the systemic inflammatory response syndrome (SIRS). In 2015, this definition was updated by the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3); sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, organ dysfunction is defined as an acute change in the total Sequential Organ Failure Assessment (SOFA) score of ≥2 points, consequent to the infection. This scoring system is described in more detail later in this monograph. Note that in the old nomenclature, severe sepsis was defined as sepsis in the presence of organ dysfunction; as might be appreciated, this is superfluous under the Sepsis-3 classification. The definition of septic shock has also changed; this is now considered a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Septic shock is clinically identified by the presence of severe hypotension necessitating vasopressors to maintain a mean arterial pressure (MAP) of ≥65 mmHg AND a serum lactate level >2 mmol/L, in the absence of hypovolemia. These definitions are of more than just theoretical importance; in North America alone, there are over 750,000 hospital admissions for sepsis each year, with in-hospital mortality rates ranging from 15% to 30%; early recognition and treatment is key to improving the prognosis of these patients. When dealing with sepsis, a couple of clinical points are of relevance. First of all, it is more common at extremes of age (i.e. the very elderly, and the very young), and in immunocompromised individuals. In addition, over half of cases are secondary to pneumonia and other lung infections; intra-abdominal and urinary tract infections are the next most common etiologies. Gram-positive bacteria are most often implicated, although gram-negative and anaerobic organisms can also cause sepsis. Investigations should be aimed at confirming that sepsis is present, identifying the source of infection, and determining the causative organism. As mentioned at the beginning of this monograph, the SOFA score is key in confirming the presence of sepsis; this objectively assesses the quantity and severity of dysfunction of six organ systems, via the following parameters: - Respiratory: Partial pressure of oxygen (PaO2) / fraction of inhaled oxygen (FIO2) - Coagulation: Platelet count - Liver: Serum bilirubin level - Cardiovascular: Mean arterial pressure - Central nervous system: Glasgow coma scale (GCS) - Renal system: Serum creatinine level OR Urine output Each of the above parameters is assigned a value from 0 to 4, based on pre-defined criteria; these are then totaled. By default, the baseline score should be assumed to be zero, unless the patient was known to have preexisting (acute or chronic) organ dysfunction before the onset of infection. Unfortunately, the SOFA score is often impracticable outside a critical care unit; in a general medical ward, or in a primary care setting the 'quickSOFA' (qSOFA) bedside clinical score is an alternative means of identifying individuals more likely to have a prolonged ICU stay or to die in hospital. This score is based on three criteria: alteration in mental status, systolic blood pressure ≤100 mmHg, or respiratory rate ≥22/min; the presence of two or more of these indicates a high risk for sepsis. With respect to determining the likely site of infection, the patient's signs and symptoms are often helpful. However, in the elderly, atypical presentations are common, and a full septic screen may prove necessary. An important clinical point is that two sets of blood cultures on both anaerobic and aerobic media should always be obtained before starting antimicrobial therapy. This should consist of one sample drawn from a percutaneous site, and one sample per vascular access device. The initial management of these patients is aimed at providing cardiorespiratory resuscitation and mitigating the immediate threat of uncontrolled infection. The former includes restoring perfusion with intravenous (IV) fluids and restoring cardiac preload, afterload, and contractility via the use of vasopressors such as norepinephrine or dopamine. In addition, oxygen delivery should be balanced with demand, via oxygen therapy and/or mechanical ventilation. Urgent empirical antimicrobial therapy is key to controlling the infection, with broad-spectrum antibiotics preferred. The choice of the exact agent depends on the site of infection, setting in which the infection developed (i.e. home vs. hospital), medical history, and local or regional guidelines. Ongoing care is best provided in a critical care or high-dependency unit; after the first six hours, the focus should be on fluid management, supporting organ functions, and avoiding complications. Once cultures and sensitivity test results are available, conversion to a more specific antibiotic should be considered; this will prevent the emergence of resistant organisms, minimize the risk of drug toxicity, and reduce healthcare costs. Overall, antibiotic therapy should last between 7-10 days; a longer duration is indicated in individuals with a poor response to therapy, immunodeficiency, or where the source of infection has not been removed. These patients should also receive deep venous thrombosis (DVT) prophylaxis, as they are at an increased risk for venous thromboembolism. Note that the complications of sepsis are numerous; some of the most important are ischemic stroke, acute kidney injury, heart failure (leading to septic shock), and disseminated intravascular coagulation. Unfortunately, the morbidity and mortality of these patients is still high, despite advances in diagnosis and management. Early detection and treatment is associated with markedly better outcomes.


Take home messages

  1. As per the 2015 Sepsis-3 definition, sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
  2. The qSOFA score is a simple and rapid way to identify patients who are at risk of sepsis.
  3. Fluid resuscitation, vasopressors, and empirical IV antibiotic therapy are key elements in the acute management of these patients.
  4. Prompt diagnosis and treatment is key to decreasing mortality; the first six hours are especially crucial.

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