So you think it is sepsis: considerations beyond lung and urine in the sick patient without a source

Authors: Marina N. Boushra, MD (EM Resident Physician, Vidant Medical Center) and Susan Miller, MD (EM Attending Physician / Toxicologist, Vidant Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

A 55-year-old woman with a history of diabetes, hypertension, and depression presents to the emergency department with a complaint of altered mental status. Her husband endorses a dry cough for one week that has recently become productive and fevers with a Tmax of 38.9 ºC. He notes that she is not “acting like herself,” and elaborates that she is sleeping more, talking less, and has had multiple episodes of urinary incontinence, which is unusual for her. She started a new medication last week, but he is unsure what it is. Her vitals on arrival are T 38.9º C, HR 110, RR 30, BP 100/70. Her exam is notable for somnolence, increased work of breathing with accessory muscle use, and dry mucus membranes.

Care of the undifferentiated acutely ill patient is a staple in the practice of emergency medicine. Workup and treatment of these patients is typically complicated by multiple co-morbidities and incomplete medical histories. Further muddying the waters are rapidly shifting definitions of disease states that seek to incorporate better understanding of pathophysiology and improve sensitivity and specificity. This is exemplified by sepsis, a syndrome of organ dysfunction resulting from dysregulated host response to an infectious agent. Since the 1992 ACCP/SCCM consensus statement, the definition of sepsis has been hotly (and frequently) debated, resulting in diverse and conflicting consensus statements by multiple societies1-4. Though emergency practitioners see sepsis regularly, several studies have shown that the diagnosis of sepsis–and therefore the treatment of sepsis–is delayed in emergency departments with resulting increase in patient morbidity and mortality5,6,7. Urinary tract infections and lower respiratory tract infections are the most common cause of sepsis in the United States7. Screening for these conditions can be done rapidly by ordering a chest x-ray and urinalysis. Unfortunately, these tests do not always readily yield the cause of the patient’s illness. The cause of this is twofold. First, many practitioners fail to consider sources of infection beyond the respiratory and urinary tracts. Second, multiple non-infectious conditions can present with the fever and tachycardia typical of the septic patient. The following discussion addresses the work-up of the acutely ill-appearing patient without an apparent source, focusing on possible sources of infection as well as alternative diagnoses.

 I. Recognizing sepsis

Studies have shown that between one- and two-thirds of septic patients enter the healthcare system through the emergency department8. As hospital overcrowding continues to plague the healthcare system, optimizing management of sepsis in the emergency department has become a priority. Additionally, since sepsis has increasingly been recognized as a time-critical disease process, emergency department management of septic patients and emergent interventions have the potential to alter patient outcomes9-14. Timely and effective treatment of sepsis necessarily depends on recognition of sepsis. In fact, each hour of delay in administration of appropriate antimicrobials as well as adequate fluid resuscitation results in a 7.6% increase in patient mortality15. Recognition of sepsis is,  however, hampered by the remarkable variability in its presentation and shifting definitions that have increasingly depended on evidence of end organ dysfunction16. Unfortunately, there is no gold standard or clearly outlined clinical criteria to define sepsis, though multiple guidelines have offered their own definitions. Even these definitions fail to achieve anything approaching clinical certainty. For example, the SIRS criteria, the prevailing criteria for sepsis in the last nearly three decades since its inception in 1991,  have been demonstrated to have 72% sensitivity and 61%  specificity for predicting organ dysfunction38. For predicting mortality, the presence ≥2 SIRs criteria was only 77% sensitive and 57% specific38. For comparison, the qSOFA score, the released in 2016 and the most recent guidelines released by the International Consensus for Definitions of Sepsis and Septic Shock, had sensitivities of 30% and 50% and specificities of  96% and 91% for predicting organ dysfunction and mortality, respectively38.  In the setting of such ambiguity, recognition of sepsis depends on maintaining high clinical suspicion for this disease syndrome in the acutely-ill patient.

Current guidelines for the management of sepsis recommend the continuous administration of crystalloid fluids as long as hemodynamic factors continue to improve14. If the administration of fluids fails to achieve a MAP ≥ 65, the use of vasoactive agents is recommended, with norepinephrine being the vasopressor of choice in septic patients14. Source control is of upmost importance. In the septic patient, broad spectrum antibiotic therapy is indicated. The choice of antimicrobial should take into account the pathogen profile of the suspected anatomic site of infection, local pathogen prevalence and resistance patterns, and the presence of immunodeficiencies in the patient. The complexities of this choice are beyond the scope of this post. Cultures should be collected prior to the initiation of antimicrobials if doing so does not significantly delay the administration of antimicrobials14. The spectrum of the antimicrobials can be narrowed appropriately based on culture results after the patient has been admitted. In sepsis, time is key.

Considering other sources of sepsis

While urinary tract infections and infections of the lower respiratory tract can easily be screened for, other sources of infection abound and may be less readily evident. A thorough physical examination becomes invaluable in these undifferentiated patients, and a source may be revealed through additional imaging and laboratory testing.

Musculoskeletal: Patients with poor vascular circulation, diabetes, and immunocompromise are at the greatest risk for serious musculoskeletal infection. The most common cause of sepsis secondary to skin and soft tissue infections is cellulitis due to Staphylococcus aureus or Streptococcus pyogenes17. Diagnosis of a musculoskeletal cause of sepsis is based on thorough physical examination, especially if the patient is altered or obtunded. Many patients will have decubitus ulcers which may become a source for osteomyelitis or systemic infection. A genitourinary exam may reveal a necrotizing infection such as Fournier’s gangrene. Consider staphylococcal toxic shock syndrome in the ill-appearing patient with a generalized macular rash. An erythematous, hot swollen joint, especially the hip or knee, should raise suspicion for a septic joint. Aspiration is required for diagnosis of septic arthritis.

Cardiac: While a thorough cardiac exam is often difficult in the chaos of the emergency department, the presence of a new murmur in the acutely ill patient should raise suspicion for endocarditis. Risk factors for endocarditis include the presence of a prosthetic valve, intravascular devices, intravenous drug use, and immunocompromise. If the vegetation is large enough, it may be visible on bedside ultrasound, though this is certainly not sensitive18-20. Other physical exam findings consistent with endocarditis include stigmata of peripheral thromboembolism such as Osler nodes, Janeway lesions, or splinter hemorrhages. If endocarditis is a possibility, obtaining transthoracic US with multiple blood cultures is recommended.

Meningitis and encephalitis: The classic triad of meningitis is altered mental status, nuchal rigidity, and fever, though the majority of patients only have one or two of these symptoms. The most common causes of meningitis in adults in the United States are Streptococcus pneumoniae, group B streptococci and Neisseria meningitidis21-22. Listeria monocytogenes is more common in children, older adults, and the immunocompromised. Meningitis and encephalitis may also be caused by viruses such as herpes, enteroviruses, and CMV. Lumbar puncture to obtain cerebrospinal fluid for testing is needed to make a diagnosis of meningitis, but therapy should not be delayed to obtain the lumbar puncture. Empiric therapy includes ceftriaxone to cover streptococcal species and Neisseria, vancomycin to cover ceftriaxone-resistant streptococci, and ampicillin to cover for Listeria if the patient is greater than 50 years or age or immunocompromised. If there is a high suspicion for herpes infection, acyclovir should be added21-22.

Spinal infections: Back pain is an incredibly common chief complaint in the emergency department. While the majority of patients presenting with back pain will have fairly benign pathologies including disc herniation and muscle strain, spinal infection should be considered in all patients presenting with back pain. Risk factors for spinal infection include immunosuppression, recent invasive procedures, spinal implants, and intravenous drug use. Vertebral osteomyelitis, discitis, and epidural abscesses are potential sources of sepsis from a spinal infection. MRI is the imaging study of choice in cases of suspected spinal infection, although CT myelography may also be useful if MRI is unavailable.

Urinary tract pathology: If a patient is more ill-appearing than is explained by a simple urinary tract infection, consider a CT to evaluate for a perinephric abscess, infected nephrolithiasis, or emphysematous pyelonephritis23. A CT will also help evaluate for other causes of pyuria, including appendicitis23-24.

Abdominal sepsis: Recognition of abdominal sepsis is sometimes hampered by the patient’s mental status or body habitus. Conscious patients are able to describe their abdominal pain and may be able to localize their discomfort. In the obtunded patient, an especially thorough abdominal examination is of great diagnostic utility. Absence of bowel sounds, abdominal distention, and rigidity may point to an abdominal cause of sepsis in the acutely ill-patient. While it is difficult to assess pain response in the obtunded or unconscious patient, other markers of discomfort, such as grimacing, guarding, or tachycardia, can be used to localize abdominal pain in a patient with altered mental status. If concern for intra-abdominal source of sepsis, imaging is recommended. Causes of intra-abdominal infection include abscess (perinephric, ovarian abscess), spontaneous bacterial peritonitis, cholecystitis or cholangitis, ruptured hollow viscus, or infection of the gastrointestinal tract (appendicitis, colitis, diverticulitis). Pelvic examination is helpful for the identification of tubo-ovarian abscesses and pelvic inflammatory disease and may help identify the infectious source in toxic shock syndrome. While occult intra-abdominal infections may initially respond to empiric antibiotic treatment, recognition of the presence of these infections is vital as aggressive source control through surgical or vascular interventional means is usually necessary for treatment24-26.

Indwelling devices: Indwelling devices such as central venous catheters, ports, and dialysis access may be a nidus for infection. Physical examination of the septic patient with invasive devices should include examination of the site of the device, taking particular note of any erythema or purulent drainage. Though specific, signs of exit-site infection are not sensitive for the presence of line-associated bacteremia. One study found that only 4.6% of catheter-associated bacteremia was associated with purulent drainage at the exit site39. In the absence of clear physical exam findings for line-associated bacteremia, clinical suspicion must remain high for line infection in patients with indwelling devices. If possible, the device should be promptly removed and cultured.

III.   Broadening the differential

While it is tempting to pigeonhole the hyperthermic, tachycardic, ill-appearing patient into a diagnosis of sepsis, multiple conditions can cause what appears to be a septic picture. If a seemingly septic patient does not appear to have an obvious source or is not improving with antibiotics and fluids, it is important to broaden the differential. Outlined below are several processes which may present similarly to sepsis and in which prompt recognition and intervention may be life-saving. A review of the patient’s home medications is vital and laboratory testing to help broaden the differential includes TSH, salicylate levels, and urine or serum drug screens.

Neuroleptic malignant syndrome (NMS): NMS is a clinical syndrome of altered mental status, dysautonomia, hyperthermia, and rigidity associated with the use of neuroleptic agents. Risk factors include higher doses of neuroleptic agents, recent or rapid dose escalation, a switch from one agent to another, and parenteral administration27. While NMS typically develops in the first two weeks of therapy, this syndrome can occur after a single dose or after years of treatment with the agent28. A review of the patient’s medication list will help stratify their risk for this syndrome. Management is prompt discontinuation of the offending agent as well as aggressive support of the cardiopulmonary system, maintenance of normothermia and euvolemia, and prevention of complications including deep venous thrombosis, acute renal failure, and cardiac dysrhythmias27-28.

Serotonin syndrome (SS): SS is clinical syndrome of altered mental status, neuromuscular abnormalities, and autonomic hyperactivity caused by excess serotonin, typically due to therapeutic medication or interactions between medications. Common medications that may lead to SS include linezolid, fentanyl, and any selective serotonin reuptake inhibitor. SS is rapidly progressive and can manifest with a wide range of clinical symptoms that range from mild to life-threatening. There is no laboratory test to confirm a diagnosis of SS. The Hunter criteria for serotonin syndrome are fulfilled if the patient has taken a serotonergic agent and has one of the following symptoms: spontaneous clonus, inducible clonus and agitation or diaphoresis, ocular clonus and agitation or diaphoresis, tremor and hyperreflexia, hypertonia, temperature > 38C, and ocular or inducible clonus29. Supportive management for the normalization of vital signs and benzodiazepines for agitation is the initial treatment. If supportive management is insufficient or ineffective, use of cyproheptadine (under the guidance of a toxicologist) should be considered29.

Malignant hyperthermia (MH): MH is a genetic disorder that results in hypermetabolic response to volatile anesthetics and depolarizing muscle relaxants such as succinylcholine. MH is characterized by hyperthermia, tachycardia, tachypnea, hypercarbia as demonstrated by a rising end-tidal carbon dioxide, increased oxygen consumption, muscle rigidity, hyperkalemia, and rhabdomyolysis. In the ED setting, this is most likely to present following an intubation using succinylcholine; this diagnosis should be considered if an intubated patient is deteriorating post-intubation. In the inpatient setting, MH should be considered in patients who recently received volatile anesthetics or succinylcholine. Dantrolene sodium is the antidote to MH and should be loaded at a dose of 2.5mg/kg intravenously followed by bolus doses of 1mg/kg until symptoms abate. Treatment of hyperkalemia may also be required.  Cooling measures should be instituted to prevent end-organ effects of hyperthermia.  Patients and families should be counseled after recovery to prevent future reactions in the patient as well as the family; genetic testing is available.

Salicylate overdose: The presentation of toxicity from salicylates such as aspirin can easily be confused for a septic picture. Patients with salicylate toxicity will have tachycardia and elevated temperature, much like patients with infection. Tachypnea is also present (common in sepsis, especially for older patients). This is due interference with aerobic metabolism, which also leads to lactic acidosis30. The classic triad of salicylate toxicity is hyperpnea, gastrointestinal irritation, and tinnitus30. Tinnitus may be difficult to illicit if the patient is altered. Patients with salicylate toxicity will have a classic “triple acid-base disorder” on laboratory testing, which will show a respiratory alkalosis (from hyperventilation), a compensatory non-anion gap metabolic acidosis, and an anion-gap metabolic acidosis (from lactic acid build up)30. Prompt recognition of salicylate toxicity is important for the initiation of appropriate management through systemic alkalinization with sodium bicarbonate.

Anticholinergic overdose: Many prescription medications, over-the counter treatments, and environmental exposures can cause an anticholinergic syndrome. Common substances that result in anticholinergic effects include antihistamines, tricyclic antidepressants, tainted illicit drugs, and jimson weed. Like sepsis, anticholinergic toxicity may present with high temperature, agitation or altered mental status, and tachycardia. Clues to the anticholinergic toxicity include dilated nonreactive pupils, urinary retention, and anhidrotic hyperthermia (whereas the typical septic patient is diaphoretic)31.

Sympathomimetic intoxication or overdose: Sympathomimetic medications or illicit drugs can cause hyperthermia through a variety of different mechanisms, including directly through alpha-receptor agonism and indirectly through heat production from psychomotor agitation. Illicit drugs that cause sympathomimetic toxicity include cocaine, MDMA, PCP, and amphetamines and their derivatives. Symptoms of sympathomimetic toxicity include altered mental status, hypertension, tachycardia, hyperthermia, and dilated but reactive pupils. It is important to note that withdrawal from alcohol presents symptomatically similarly to intoxication with sympathomimetics. History is key to these diagnoses. Benzodiazepines titrated to level of psychomotor agitation are the cornerstone of management.

Thyroid storm: Thyroid storm is a rare condition with substantial mortality which is characterized by severe manifestations of thyrotoxicosis. It can be caused by overdose of therapeutic thyroid hormone or may present in patients with underlying thyrotoxicosis, in whom it may be precipitated by an acute event such as trauma, infection, or parturition or may be unprovoked31-33. Presenting symptoms include tachycardia, hyperthermia, diarrhea, and agitation. Cardiovascular collapse and liver failure may also occur. Laboratory abnormalities will include a severely low or undetectable TSH. Clues to the presence of thyroid storm include physical exam findings such as Graves ophthalmopathy, hand tremor, goiter, and lid lag. Acute management of thyroid storm includes immediate treatment with a beta blocker (typically propranolol), a thionamide (typically propylthiouracil), and glucocorticoids (hydrocortisone)31-33.

Nonexertional heat stroke: Heat stroke typically affects older individuals with underlying chronic medical conditions that impair thermoregulation, prevent removal from a hot environment, or decrease access to adequate hydration. The diagnosis of non-exertional heat stroke is a diagnosis of exclusion made clinically based upon an elevated core body temperature (generally >40°C), central nervous system dysfunction, and exposure to severe environmental heat. Liver function testing often reveals elevated liver enzymes. Early and aggressive evaporative and convective cooling are the treatments of choice and result in decreased morbidity and mortality35-37.


In the acutely ill patient without an apparent source, consider musculoskeletal, cardiac, nervous system, and abdominal sources of sepsis. A thorough physical examination, abdominal CT scan, and lumbar puncture may help reveal the source of sepsis. Keep the differential broad when treating the hyperthermic, tachycardic patient, as many conditions can mimic sepsis. A review of the patient’s medical history and medications may be invaluable in pinpointing the source of the patient’s fever and tachycardia. Summarized below are features of sepsis mimics and their treatment.

References/Further Reading:

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  4. Knaus WA, Sun X, Nystrom O, Wagner DP. Evaluation of definitions for sepsis. Chest 1992; 101:1656.
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  25. Leligdowicz A, Dodek PM, Norena M, et al. Association between source of infection and hospital mortality in patients who have septic shock. Am J Respir Crit Care Med 2014; 189:1204.
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  31. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 2006; 35:663.
  32. Chiha M, Samarasinghe S, Kabaker AS. Thyroid storm: an updated review. J Intensive Care Med 2015; 30:131.
  33. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016; 26:1343.
  34. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium – theory, evidence and practice. Br J Clin Pharmacol 2016; 81:516.
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  37. Yeo TP. Heat stroke: a comprehensive review. AACN Clin Issues 2004; 15:280.
  38. Williams JM et al. SIRS, qSOFA and organ dysfunction: Insights from a prospective database of emergency department patients with infection. Chest 2016 Nov 19.
  39. Sychev D, Maya ID, Allon M. Clinical management of dialysis catheter-related bacteremia with concurrent exit-site infection. Semin Dial 2011; 24:239.

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