Sepsis Mimics

Many conditions mimic sepsis by meeting criteria for SIRS. If these conditions are not considered, there is potential for increased mortality and morbidity.

The next two patients are roomed and the charge nurse asks you to look at them before you head to grab a quick meal. The first patient is a 63 year-old male with several episodes of emesis and a fever of 100.5. He has been feeling worse over two days and has not been able to eat, so he called EMS for transport. He has a past history of COPD, HTN, and DM with several recent hospitalizations for COPD exacerbations. His initial vital signs reveal tachycardia, fever, and tachypnea. He meets SIRS criteria. You begin treatment for pneumonia and COPD exacerbation. Your second patient is a 38-year-old female with dyspnea and low grade temperature of 100.6. She is tachypneic and has some slight chest pain worse with deep breaths. Her pulse oximeter reads 92% on room air. Chest X-ray reveals a right-sided consolidation, and ECG shows sinus tachycardia. You provide 1 L of NS and some antibiotics for what you think is pneumonia. You then head to the cafeteria, comfortable with your diagnoses.

Background
Systemic inflammatory response syndrome (SIRS) and sepsis are common clinical entities, consisting of a continuum of clinical syndromes. The definition of SIRS includes: HR > 90 bpm, RR > 20 or PaCO2 < 32, temperature < 36oC or > 38oC, and a WBC count < 4 x 109 cells/L or > than 12 x 109 cells/L or > 10% bands. Two or more of these equals SIRS, and two or more with a source of infection equals sepsis.1,2 Severe sepsis is sepsis with organ dysfunction, and septic shock is sepsis with hypotension, defined by systolic blood pressure less than 90 mm Hg, unresponsive to fluid rehydration. Unfortunately, these criteria are non-specific, and the criteria alone do not provide a diagnosis or predict outcome. However, associated organ dysfunction does predict worse outcome. The definition of SIRS includes: HR > 90 bpm, RR > 20 or PaCO2 < 32, temperature < 36oC or > 38oC, and a WBC count < 4 x 109 cells/L or > than 12 x 109 cells/L or > 10% bands. Two or more of these equals SIRS, and two or more with a source of infection equals sepsis, according to the “old” definition [1,2].

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Prevalence
A wide range of estimates for prevalence exists, with 300 to 1000 cases per 100,000 persons per year. Once a septic patient is admitted, more than half will re- quire at least step down unit care or greater. Mortality rates vary from 20% to 50%. Not only is the mortality severe, but studies have demonstrated increasing costs of care for these patients [1-4].

Clinical Importance
A great deal of literature exists on sepsis and providing state of the art care in the ED. As emergency providers, we pride ourselves on resuscitating the sick patient, and septic patients can rapidly decline clinically. Resuscitation includes source evaluation, antibiotics, ensuring adequate preload with intravenous (IV) fluids, and vasopressors if necessary as key components. The SIRS criteria were established as a safety net to catch patients as quickly as possible and begin treatment. However, as discussed later, SIRS is prevalent in a wide variety of clinical conditions. Many have questioned the use of SIRS and the old definition of sepsis. According to the SIRS naysayers, one of the major issues with SIRS is that it misses 1 out of 8 patients with diagnosed severe sepsis (notice this is not sepsis, but severe sepsis), reported in a recent study from the NEJM [3]. However, another way of thinking about this is it catches 7 out of 8 patients with severe sepsis, for a sensitivity of 88%.

Why does SIRS occur in sepsis? Sepsis ultimately results from a complex interaction of pro-inflammatory, anti-inflammatory, activated complement system, and coagulation mediators that trigger a host response. If the initiators are not controlled locally, they lead to dysfunction in multiple organ systems [4,5]. Other important aspects of sepsis include vascular tone instability through depletion of vasopressin, adrenal insufficiency, and nitric oxide enhancement of vasodilation. The range of organ system derangements is demonstrated in Table 1 below (click to enlarge).

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Signs of Sepsis
Fever is a cardinal sign of inflammation and infection; however, fever does not equal infection. Cytokines induce a febrile response, mediated by the hypothalamus. Most diseases causing true sepsis are associated with temperatures greater than 102 [5]. This is excluding elderly and immunosuppressed patients, where a temperature of 99/100oF is often a true fever [6]. Per an older review by Cunha, a normal host (i.e. not elderly, uremic, immunosuppressed), with a temperature of less than 102 or greater than 106 is usually noninfectious. On the other hand, hypothermia is a clue to bacteremia and true sepsis [5].

Hemodynamic effects of septic shock include decreased peripheral resistance with increased cardiac output and tachycardia in the early stages, or distributive shock (also with anaphylaxis, pancreatitis, etc.). Later stages demonstrate findings of hypovolemic shock with increased vascular resistance, lower cardiac output, and cooler peripheral extremities with poor capillary refill. These findings are not specific for sepsis unfortunately [3-5].

Laboratory data are also not specific for sepsis, similar to the hemodynamic effects. Stress causes an increased WBC count with left shift. Coagulopathic derangements occur in this systemic inflammatory state as well. Fibrin split products, fibrinogen, coagulation panel will not help in differentiating mimics from true sepsis. Leukopenia and thrombocytopenia are more suggestive of sepsis, but they are not definitive. C-reactive protein (CRP) and procalcitonin (PCT) have been studied for use in sepsis, but again, they are not specific for sepsis. Lactic acid elevation and base excess/deficit are commonly used for resuscitation, but they will not pinpoint the cause of shock [4,5].

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Sepsis – A New Definition
A task force consisting of the European Society of Intensive Care Medicine and the Society of Critical Care Medicine recently proposed a new definition for sepsis and septic shock. These definitions are based on the use of two scores, qSOFA and SOFA, which are validated in the ICU, not ED. According to the new definition, Sepsis is defined as life-threatening organ dysfunction due to dysregulated host response in the setting of infection. Organ dysfunction can be identified based on total SOFA score > 2 points (a score > 2 points is associated with a mortality of 10%). The SOFA score is based on blood pressure, vasopressor use, platelet count, bilirubin, GCS, creatinine, PaO2/FiO2 ratio, and presence of mechanical ventilation. The qSOFA score does not require laboratory tests and can be used quickly at the bedside. This consists of hypotension (SBP < 100 mm Hg), altered mental status (or a GCS of 13 or less), and tachypnea with RR > 22/min. Greater than or equal to 2 suggests poor outcome. Septic shock is defined by persisting hypotension that requires vasopressor use to keep MAP > 65 mmHg with a lactate > 2mmol/L, despite adequate volume resuscitation. (Mortality for this group exceeds 40%.)

Back to our patients. Your two patients have not improved, and in fact, have worsened despite your treatments. The 63-year-old male is now hypotensive despite 1 L NS and antibiotics. His wife finally arrives and mentions that he has been unable to take his oral medications due to his vomiting, one of them being his oral steroid that he has been taking for over one month. His labs demonstrate a slight hyperkalemia and hypoglycemia. The female patient has desaturated to 88%. You start oxygen and take a closer look at the X-ray. She mentions that she just got off a 12 hour flight from overseas. You order a contrasted computed tomography of the pulmonary vasculature for pulmonary embolism.

Many conditions mimic sepsis by meeting criteria for SIRS. If these conditions are not considered, there is potential for increased mortality and morbidity. A diagram below demonstrates the overlap of SIRS, sepsis, and conditions that may result in positive SIRS criteria.

Mimics of sepsis are a common cause of misdiagnosis in the ED. All of these clinical conditions produce symptoms and signs that meet SIRS, clouding the clinical picture. These conditions are demonstrated in Table 2.

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Approach: Several keys are important in the management of patients who meet SIRS. Due to the morbidity and mortality associated with sepsis, rapid resuscitation is vital.

1. The first key is to resuscitate first. As the patient with a sepsis mimic will look just like a true septic patient with fever, tachycardia, tachypnea, and change in WBC, initial efforts should focus on resuscitation. The standard approach of Airway, Breathing, Circulation, Disability/D-stick, exposure, FAST exam/fetus is required. Obtain IV access, attach monitors, and be prepared to provide supplemental O2.
2. A focused history and exam from head to toe is essential, evaluating for other conditions and sources. This can allow the provider to target resuscitation and management to the clinical condition. Always think sepsis first, especially in the immunocompromised and elderly patient.
3. Once the primary and secondary examinations are completed, the next task is to search for a potential source in the setting of SIRS. The LUCCAASS mnemonic will assist the search for source: lung (pneumonia), urine (cystitis/pyelonephritis), cardiac (endocarditis), CNS (meningitis, encephalitis), abdominal (abscess, cholecystitis), arthritis (septic arthritis), spine (osteomyelitis, abscess), and skin (cellulitis, IV line/PICC infection). Fortunately, history, physical exam, laboratory data, and imaging can usually pinpoint the source of sepsis. Utilizing chest Xray, urinalysis/urine dipstick, physical exam (HEENT, cardiac, lung, abdomen, GU, and skin), and history will likely provide a diagnosis, but a systematic approach should be followed [2-4].
4. If no source is found, carefully evaluate the patient again while continuing resuscitation, using history and physical exam to evaluate for the above clinical entities that meet SIRS criteria. Using a systematic approach will provide the best avenue for diagnosis and treatment, with focused testing. If another entity is discovered, treat that condition as indicated. For example, the patient with UTI may also have DKA, requiring further fluid rehydration, electrolyte management, and insulin.
5. Frequent evaluation of the patient to response to treatment is necessary. Use laboratory tests such as lactate clearance and patient hemodynamic response to resuscitation to ensure the patient is improving [46-48]. A combination of mental status, capillary refill, urine output, blood pressure, heart rate, and laboratory markers are better than one one single marker.

Case Conclusions
The clinical condition of the 63 year-old male is suggestive of adrenal insufficiency. You provide hydrocortisone 100 mg IV, which results in improved vital signs. You admit the patient to the hospital for further management. The CT of the 38 year-old female returns with a large right-sided segmental PE. You begin anticoagulation and speak with the hospitalist for admission.

Lessons Learned
SIRS and sepsis exist along a continuum, resulting from uncontrolled systemic response. There are many mimics for sepsis. The most important aspect of managing these patients is resuscitation first. Obtain a safety net of IV access, monitor placement, and supplemental oxygen while evaluating the ABCDEs. The history and exam are keys to finding the culprit, but always consider infection first. Sepsis requires a source of infection. If no source is found, reassess the differential and consider anaphylaxis, aspiration, bowel obstruction, colitis, hypovolemia, pancreatitis, PE, GI bleeding, toxic overdose, medication effect, and vasculitis, among others. Always evaluate the patient for response to treatment by using a combination of clinical markers.

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