1. Anas Naeem 8 May 2013 AN UNDERSTANDING & APPROACH TO FEVER IN THE ICU

2. DEFINITION Normal body temperature is approximately 37.0ºC Fever defined as a body temperature of 38.3ºC or higher It is reasonable to use a lower temperature to define fever in immunocompromised patients.

3. TEMPERATURE MEASUREMENT Intravascular, intravesicular (e.g. bladder), rectal, and oral The gold standard is the thermistor on a pulmonary artery catheter, although these are used infrequently Regardless of which method is chosen, the same method and site of measurement should be used repeatedly to facilitate the trending of serial measurements Alternative methods, such as axillary, temporal artery, tympanic, and chemical dot monitors, should not be used because they are inaccurate during critical illness

4. EPIDEMIOLOGY

5. Fever complicates up to 70% of all ICU admissions Increased length of stay, increased cost of care, and poorer outcomes May prompt unnecessary investigations and lead to inappropriate antibiotic use.

7. Significance of Fever

8. Julius Wagner-Jauregg (in black jacket) watching the transfusion of blood from a patient with malaria to a patient with neurosyphilis, to trigger fever. This approach won Wagner –Jauregg the 1927 Nobel Prize in Medicine

9. Significance of Fever The beneficial effects… An adaptive response that has evolved to help rid the host of invading pathogens Enhance several parameters of immune function Some pathogens such as strep pneumoniae are inhibited by febrile temperatures

10. Significance of Fever The harmful effects… Increase in cardiac output, oxygen consumption, carbon dioxide production and energy expenditure. Poorly tolerated in patients with limited cardiorespiratory reserve In traumatic head injury moderate elevation of brain temperature may markedly worsen the resulting injury

11. Fever Patterns May provide some diagnostic clues > 48 h after mechanical ventilation secondary to a developing pneumonia 5 to 7 days postoperatively may be related to abscess formation 10 to 14 days post antibiotics for intra-abdominal abscess may be due to fungal infections

12. DIFFERENTIAL DIAGNOSIS Infectious or non infectious Distinguishing between infectious and noninfectious fevers is challenging The magnitude of the fever may be helpful Fevers between 38.3ºC and 38.8ºC may be infectious or non infectious. The differential diagnosis is longest in this range; fortunately, most non infectious sources of fever can be excluded by a detailed history and physical examination

13. DIFFERENTIAL DIAGNOSIS Fevers between 38.9 and 41ºC can be assumed to be infectious Fevers ≥41.1ºC (106ºF) are usually non infectious  Drug fever  Transfusion reactions  Adrenal insufficiency  Thyroid storm  Neuroleptic malignant syndrome  Heat stroke  Malignant hyperthermia

14. Infectious Causes Ventilator-associated pneumonia Intravascular catheter-related infections Surgical site infections Catheter-related urinary tract infections Bacteremia from these and other sources Sinusitis

15. Infectious Causes Ventilator-associated pneumonia (VAP) Patient who has been receiving mechanical ventilation for more than 48 hours Decreased oxygenation Decreased tidal volume Increased minute volume Increased respiratory rate Purulent tracheobronchial secretions New or progressive pulmonary infiltrate, leukocytosis

16. Infectious Causes Intravascular catheter-related infection Commonly present as a fever without localizing symptoms or signs. A cellulitis at the insertion site Purulent drainage from the insertion site Incidentally detected bacteremia Rarely, a patient may present with suppurative thrombophlebitis, endocarditis, or septic abscesses.

17. Infectious Causes Surgical site infection Should be considered in any post-operative patient Most surgical site infections occur one to four weeks after surgery, although they may occasionally occur during the first postoperative week or more than a month after surgery. The clinical manifestations and likely pathogen depend upon the surgical site

18. Infectious Causes Catheter-related urinary tract infections The incidence of catheter-related urinary tract infections has probably been overestimated because many studies did not distinguish asymptomatic bacteriuria from a genuine urinary tract infection May present as a fever without localizing symptoms or signs. They may also present with symptoms and signs of cystitis (fever, suprapubic pain, hematuria, pyuria), pyelonephritis (fever, chills, flank pain, costovertebral angle tenderness, nausea, and vomiting), or urosepsis

19. Infectious Causes Bacteremia  May be secondary to any of the above infections, as well as many others.  Fever may be the only sign of bacteremia  It can rapidly progress to sepsis, severe sepsis, or septic shock  Transfusion-transmitted bacterial infection is a rare, but life- threatening, complication of hospital care that does not always occur during transfusion

20. Infectious Causes Sinusitis  Occurs in 8% of all ICU patients  More common among mechanically ventilated patients who have sinus opacification on imaging  It most typically manifests as fever without localizing symptoms and signs, since most patients are mechanically ventilated and unable to communicate the presence of a headache and sinus tenderness.  Purulent nasal drainage is occasionally present

21. Infectious Causes Candida infections  7% of all nosocomial infections  Should be considered in febrile patients who have been in ICU > 10 days with multiple courses of antibiotics  Most ICU patients colonized with candida species  Isolation of Candida from urine/pulmonary samples usually represents colonization rather than infection

22. Infectious Causes Other causes  Cellulitis  Cholangitis  Diverticulitis  Empyema  Endocarditis  Intra-abdominal abscess  Meningitis  Myonecrosis  Necrotizing fasciitis  Pseudomembranous colitis  Septic arthritis  Suppurative thrombophlebitis

23. Noninfectious Causes  In most cases the fever is not the only sign  The cause can usually be identified with a detailed history and physical examination  The role of atelectasis as a cause of fever is unclear; however, atelectasis probably does not cause fever in the absence of pulmonary infection  The non infectious causes of fever may be conceptualized as those that are accompanied by distributive shock and those that are not

24. Non infectious Causes Non-hemolytic transfusion reaction  Fever is the most common sign  It generally occurs within one to six hours after the initiation of a transfusion of red blood cells or platelets and may be accompanied by chills and mild dyspnea  Non-hemolytic reactions are benign with no lasting sequelae, but can be uncomfortable

25. Noninfectious Causes Drug fever  Drug fever is a diagnostic challenge  It can occur several days after the initiation of the drug, can take several days to subside after cessation of the drug, and can produce high fevers (>38.9ºC) without other signs.  The true incidence is unknown  It is essentially a diagnosis of exclusion unless other signs of hypersensitivity (eg, rash) are present

26. Noninfectious Causes Acalculous cholecystitis  Generally presents with fever, leukocytosis, and vague abdominal discomfort  A right upper quadrant mass may be palpable  An insidious presentation is associated with gallbladder gangrene and perforation  Acalculous cholecystitis may have a mortality rate as high as 30 to 40 percent, even with treatment

27. Noninfectious Causes Mesenteric ischemia  Fever is a late sign in both arterial and venous mesenteric ischemia  It usually signifies bowel infarction, by which time other signs have usually developed such as abdominal tenderness, hematochezia, or lactic acidosis ARDS Fever and leukocutosis may result from the inflmmatory-fibrotic process present in the airspace of patients with ARDS

28. Non infectious Causes Acute pancreatitis  Abdominal pain, distension, nausea and vomiting Deep vein thrombosis (DVT)  DVT is common among ICU patients, with an incidence that has been estimated to be 12 to 33 % depending upon the patient populations studied and type of prophylaxis  DVT is a rare cause of fever. More common manifestations of DVT include asymmetric extremity edema, pain, or erythema

29. Non infectious Causes Pulmonary embolism (PE) The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study about PE in hospitalized patients (not necessarily ICU patients) detected fever with the following frequency:  14% when defined as >37.8ºC (>100ºF)  6% when defined as >38.3ºC (>101ºF)  1.5% when defined as >38.9ºC (>102ºF)

30. Noninfectious Fever with Shock  Adrenal crisis (ie, acute adrenal insufficiency)  Thyroid storm  Acute haemolytic transfusion reaction.  The fever is often >38.9ºC and the shock is distributive, which is characterized by hypotension, warm extremities, oliguria, altered mental status, and metabolic acidosis

31. Noninfectious Fever with Shock Adrenal crisis  In patients with previously undiagnosed adrenal insufficiency who are subjected to a serious infection or other major stress  Patients with known adrenal insufficiency who do not take more glucocorticoid during a serious infection or other major stress,  Patients with acute bilateral adrenal infarction or hemorrhage  Patients whose chronic glucocorticoid therapy is abruptly withdrawn  Distributive shock is the predominant manifestation of an adrenal crisis, but fever, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, hypoglycemia, confusion, or coma may also be present

32. Noninfectious Fever with Shock Thyroid storm  Severe, life-threatening thyrotoxicosis  It is often precipitated by an acute stressor, such as surgery, infection, trauma, or an acute iodine load  Clinical manifestations may include severe fever (>40ºC), distributive shock, severe tachycardia (>140 beat/min), congestive heart failure, nausea, vomiting, diarrhea, agitation, delirium, psychosis, stupor, and coma

33. Noninfectious Fever with Shock Acute haemolytic transfusion reaction Is a medical emergency that results from the rapid destruction of donor red blood cells by recipient antibodies. It is usually due to ABO incompatibility Common clinical manifestations include fever, chills, distributive shock, disseminated intravascular coagulation, and acute kidney injury. Flank pain, red or brown urine, and bleeding occur less often

34. DIAGNOSTIC APPROACH Medical history and a full physical examination Blood cultures are the only mandatory diagnostic tests in patients with a new fever The rationale is that clinical findings cannot reliably exclude bacteremia and mortality is high without appropriate treatment

35. DIAGNOSTIC APPROACH Laboratory studies  Transaminase, bilirubin, alkaline phosphatase,lipase, and lactate measurements are indicated for patients with abdominal pain or whose abdominal exam cannot be reliably assessed due to sedation or coma.  Serum sodium, potassium, glucose, and cortisol levels should be drawn if adrenal insufficiency is possible  Thyroid stimulating hormone (TSH), T3, and T4 levels if thyroid storm is possible.  Direct antiglobulin test, plasma free hemoglobin, and haptoglobin, as well as a repeat blood type and cross-match if an acute haemolytic transfusion reaction is suspected.

36. DIAGNOSTIC APPROACH  Procalcitonin (PCT) is adjunctive diagnostic tools for distinguishing fever due to infection from noninfectious fever  C-reactive protein (CRP) it lacks specificity, rises later than PCT, doesn’t correlate as well with severity of disease, and tends to be lower among patients with liver disease  Both PCT and CRP predict mortality in ICU patients

37. DIAGNOSTIC APPROACH  Urinalysis and urine culture  Chest imaging  Abdominal imaging  Sinus evaluation:  Mechanically ventilated patients who have purulent nasal drainage or whose evaluation has otherwise been completely negative  Radiographic evaluation looking for sinus opacification, CT is the preferred modality  Culture of sinus fluid obtained by endoscopic-guided middle meatal aspiration is indicated for patients with sinus opacification and no other cause for fever

38. MANAGEMENT Whether or not empiric antibiotic therapy is warranted  Patients who are deteriorating, in shock, neutropenic, or have a ventricular assist device  Patients who have a temperature ≥38.9ºC because most fevers in this range will be infectious

39. MANAGEMENT Whether or not to routinely remove an intravascular catheter  Controversial and evolving issue  Considerations in the decision include:  The severity of illness  Age of the catheter  Probability that the catheter is the source of fever

40. MANAGEMENT  Fever itself does not generally require treatment with antipyretics (eg, acetaminophen) or external cooling  Some evidence suggests that the use of antipyretics may worsen outcomes in sepsis  Exceptions to this are when the fever may be detrimental to the outcome (eg, increased intracranial pressure), limited cardiorespiratory reserve or temperature ≥41ºC  If body temperature exceeds the “critical thermal maximum”, which is thought to be between 41.6ºC and 42ºC, life-threatening complications can ensue (eg, rhabdomyolysis)

41. Things to keep in Mind 1.Critically ill patients often have more than one infection. 2.Evidence of infection and inflammation (eg, leukocytosis, pus) may be altered if the patient is immunosuppressed. 3. Medical technologies (eg, continuous renal replacement therapy, extracorporeal membrane oxygenation [ECMO]) can modify or mask a fever.