1. Evaluation and Management of Fever in the Critically-Ill Patient. David Oxman MD Assistant Professor of Medicine Division of Pulmonary & Critical Care Medicine Thomas Jefferson University

2. Fever in the ICU Fever very common in the critically ill. Fever very common in the critically ill. Can be symptom of life-threatening illness or relatively harmless process. Can be symptom of life-threatening illness or relatively harmless process. Competing concerns: Competing concerns: Not delaying diagnosis and treatment. Not delaying diagnosis and treatment. Not performing unnecessary tests and procedures Not performing unnecessary tests and procedures

3. Pathophysiology of Fever Fever complex response to many disparate diseases. Fever complex response to many disparate diseases. Febrile response not only includes elevation of body temp. but activation of physiological, endocrinologic and immunologic systems. Febrile response not only includes elevation of body temp. but activation of physiological, endocrinologic and immunologic systems. Neural regulation of body temperature involves several different parts of the brain but preoptic and anterior regions of the hypothalamus have greatest role Neural regulation of body temperature involves several different parts of the brain but preoptic and anterior regions of the hypothalamus have greatest role Pyrogens – either endogenous or exogenous –stimulate cytokines (such IL-1, IL-6, TNF-α, IFN-γ) or act directly on hypothalamic neurons Pyrogens – either endogenous or exogenous –stimulate cytokines (such IL-1, IL-6, TNF-α, IFN-γ) or act directly on hypothalamic neurons decrease their firing rate decrease their firing rate Leads to physiological responses that decrease heat loss and increase heat production. Leads to physiological responses that decrease heat loss and increase heat production.

4. Das Verhalten der Eingenwarme in Krankenheiten “The Behavior of Self-Warmth in Diseases” Wunderlich 1 million observations in 25,000 subjects. Mostly axillary temps and no more than twice/day. Called 98.6 or 37 C normal. 100.4 or 38.0 C as upper limit normal.

5. Definitions of Fever Definition fever somewhat arbitrary. Definition fever somewhat arbitrary. Study of healthy volunteers (Mackowiak, JAMA 1992) Study of healthy volunteers (Mackowiak, JAMA 1992) Temperatures ranged from 35.6 C (96.0F) to 38.5C (100.8) Temperatures ranged from 35.6 C (96.0F) to 38.5C (100.8) Mean of 36.8 + 0.4C (98.2 + 0.7 F) Mean of 36.8 + 0.4C (98.2 + 0.7 F) SCCM defines fever in as temp. > 38.3 (>101F) SCCM defines fever in as temp. > 38.3 (>101F) Reasonable to use lower threshold for immuno- suppressed and elderly. Reasonable to use lower threshold for immuno- suppressed and elderly.

6. Measuring Temperature Conventional means includes intravascular, intravesical, rectal, oral, and tympanic. Conventional means includes intravascular, intravesical, rectal, oral, and tympanic. Axillary and tympanic are inaccurate in critically ill patients and should not be used. Axillary and tympanic are inaccurate in critically ill patients and should not be used. The gold standard is the thermistor on a pulmonary artery catheter. The gold standard is the thermistor on a pulmonary artery catheter. Whichever method is employed should be used consistently and the site of measurement documented. Whichever method is employed should be used consistently and the site of measurement documented.

7. How Common is Fever in ICU? Retrospective cohort study by Laupland Retrospective cohort study by Laupland >24,000 ICU admissions. >24,000 ICU admissions. Incidence of at least one documented fever during ICU course was 44%. Incidence of at least one documented fever during ICU course was 44%. Incidence of “high fever” (>39.5) only 8%. Incidence of “high fever” (>39.5) only 8%. Crit Care Med, 2008

8. Laupland, Critical Care Medicine 2008 Incidence of Fever by ICU Population

9. Fever Evaluation in ICU Main dilemma: infectious vs. non- infectious causes. Main dilemma: infectious vs. non- infectious causes. Fever from infectious cause: Fever from infectious cause: generally treatable generally treatable worse outcomes if diagnosis treatment delayed. worse outcomes if diagnosis treatment delayed. Fever from non-infectious cause: Fever from non-infectious cause: often unmodifiable often unmodifiable not necessarily worse outcomes. not necessarily worse outcomes.

10. Causes of Fever in the ICU Causes of Fever in the ICU Infectious Infectious Catheter infection Catheter infection VAP VAP Sinusitis Sinusitis UTI UTI Wound Infection Wound Infection C. Difficile Colitis C. Difficile Colitis Non-Infectious Non-Infectious Post operative Post operative Transfusions Transfusions Drug fever Drug fever Thromboembolic disease Thromboembolic disease Acalculous cholecystitis Acalculous cholecystitis Cerebral Hemmorrhage ARDS Adrenal insufficiency Thyroid storm Vasculitis Atelectasis (?) Pancreatitis Hematoma Gout ETOH withdrawl Tumor fever Burns Myocardial Infarction..and more !!!

11. The Fever Work-up Menu Blood Cultures Blood Cultures Chest x-ray Chest x-ray Sputum exam Sputum exam Urinanalysis/culture Urinanalysis/culture LE ultrasound/CTA LE ultrasound/CTA CT sinuses CT sinuses CT abdomen CT chest Lumbar puncture Right Upper Quadrant U/S White Blood Cell Scan Procalcitonin/CRP ID Consult

12. The “Fever Workup” Perils & Pitfalls Perils Perils Costly. Costly. Risk in procedures and tests. Risk in procedures and tests. Can lead to unnecessary treatments. Can lead to unnecessary treatments. Goal Goal Clinically appropriate to patient. Clinically appropriate to patient. Know strengths and weakness of tests employed. Know strengths and weakness of tests employed.

13. Issues in Fever Evaluation and Management Common Evaluation Problems Common Evaluation Problems Ventilator-Associated Pneumonia Ventilator-Associated Pneumonia Bacteremia/Intravascular Catheter Infection Bacteremia/Intravascular Catheter Infection Urinary Tract Infection Urinary Tract Infection Sinusitis Sinusitis Meningitis Meningitis DVT/PE DVT/PE Treatment/Outcomes of Fever in Critically-ill Treatment/Outcomes of Fever in Critically-ill

14. Ventilator-Associated Pneumonia Common ICU-acquired infection. Common ICU-acquired infection. Suspected in intubated patient with fever infiltrate, leukocytosis, and purulent secretions. Suspected in intubated patient with fever infiltrate, leukocytosis, and purulent secretions. Difficult to diagnose definitively Difficult to diagnose definitively CXR in ICU patient non-specific. CXR in ICU patient non-specific. Upper respiratory tract colonized with bacteria. Upper respiratory tract colonized with bacteria. Non-infectious reasons for worsened gas exchange Non-infectious reasons for worsened gas exchange Common cause of unnecessary antibiotics Common cause of unnecessary antibiotics

15. Klompas, JAMA Overdiagnosis of VAP

16. Bacteremia/Intravascular Catheter Infection Important to diagnose Important to diagnose Potentially life-threatening condition Potentially life-threatening condition Generally easily treatable Generally easily treatable Difficulties Difficulties Blood cultures not particularly sensitive Blood cultures not particularly sensitive Contamination leads to false positives Contamination leads to false positives Newer technologies (e.g. PCR) may improve sensitivity Newer technologies (e.g. PCR) may improve sensitivity

17. Bacteremia: Perils and Pitfalls Draw before initiation of antibiotics Draw before initiation of antibiotics Don’t draw through peripheral IV: 3x the false positive rate!!! Don’t draw through peripheral IV: 3x the false positive rate!!! Draw proper number - Never draw one set! Draw proper number - Never draw one set! Draw proper volume: minimum 10ml but 20 preferred. Draw proper volume: minimum 10ml but 20 preferred. Try not to draw through intravascular device (unless indicated). Try not to draw through intravascular device (unless indicated). Consider more than two sets of patients with high pretest probability. Consider more than two sets of patients with high pretest probability.

18. Detection of Fungemia Not necessary for routine use. Candida species grow well on routine bacterial culture media. Consider in immunocompromised patients at risk of uncommon fungal (e.g cryptococcus, fusarium) or mycobacterial bloodstream infection. Fungal Isolator

19. Evaluation of Urinary Tract Infection UTIs reported to be common in ICU UTIs reported to be common in ICU But no consistent definition – most studies equate isolation of bacteria/yeast with infection. But no consistent definition – most studies equate isolation of bacteria/yeast with infection. Genuine UTIs in ICU probably uncommon. Genuine UTIs in ICU probably uncommon.

20. SCCM Guidelines 2008 “Cultures from catheterized patients showing >10 3 cfu/mL represent true bacteruria or candiuria, but neither higher counts, nor the presence of pyuria alone are of much value in determining if (this) is cause of a patient’s fever; in most cases, it is not the cause of fever (level1).” “Cultures from catheterized patients showing >10 3 cfu/mL represent true bacteruria or candiuria, but neither higher counts, nor the presence of pyuria alone are of much value in determining if (this) is cause of a patient’s fever; in most cases, it is not the cause of fever (level1).”

21. Urinary Tract Infection: Take Home Routine evaluation in febrile ICU patient of questionable benefit. Routine evaluation in febrile ICU patient of questionable benefit. UA/culture hard to interpret in catheterized patient UA/culture hard to interpret in catheterized patient Patients at high risk of complication with UTI (neutropenia, urinary obstruction, pregnancy) should have testing and presumptive treatment. Patients at high risk of complication with UTI (neutropenia, urinary obstruction, pregnancy) should have testing and presumptive treatment. Everyone else: WHO KNOWS? Everyone else: WHO KNOWS?

22. Sinusitis

23. Sinusitis True incidence hard to know True incidence hard to know Many ICU patients have fluid in sinuses Many ICU patients have fluid in sinuses How many ICU patients with fever are DUE TO sinusitis? How many ICU patients with fever are DUE TO sinusitis?

24. Sinusitis Hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients. (Critical Care 2005 R583-R590. ) OR Occult fever in surgical intensive care unit patients is seldom caused by sinusitis. (Am J Surg 1992; 164 (5):412-5)

25. Diagnosis of Sinusitis Difficult to diagnose in ICU patients. Clinical signs symptoms not reliable Fluid in sinuses common Nasal swabs not diagnostic Aspiration of sinuses rarely done

26. Nosocomial Sinusitis in Patients in the Medical Intensive Care Unit: A Prospective Epidemiological Study George, CID 1998 366 intubated patients with fever and/or purulent nasal discharge 366 intubated patients with fever and/or purulent nasal discharge All patients with radiographic signs of sinus fluid had maxillary sinus aspiration. All patients with radiographic signs of sinus fluid had maxillary sinus aspiration. 28 (7.6%) met criteria for sinusitis 28 (7.6%) met criteria for sinusitis RR of nasoenteric feeding with orotracheal intubation 26.7 (3.7-194.5) <.0001 RR of nasoenteric feeding with orotracheal intubation 26.7 (3.7-194.5) <.0001

27. Sinusitis: Take Home Sinusitis is common in critically-ill patients Sinusitis is common in critically-ill patients Common cause of FUO in critically-ill: ??? Common cause of FUO in critically-ill: ??? High risk patients: High risk patients: nasoenteric feeding with oral intubation nasoenteric feeding with oral intubation facial trauma facial trauma immunocompromised (fungal) immunocompromised (fungal) Treatment: Treatment: removal nasoenteric tube removal nasoenteric tube decongestants decongestants brief course antibiotics brief course antibiotics

28. Meningitis in the ICU or “Do I have to LP all my patients with fever.” Dyad of fever and altered mental status very common in ICU. Teaching: “If you think about LP, do one” Tremendous variability in diagnostic practice.

29. What’s the Data Say? Addelson-Mitty 1 : Addelson-Mitty 1 : 70 non-neurosurgical SICU patients 70 non-neurosurgical SICU patients Most LPs performed to evaluate fever and mental status change (“r/o meningitis”) Most LPs performed to evaluate fever and mental status change (“r/o meningitis”) No cases meningitis diagnosed. No cases meningitis diagnosed. Metersky 2 Metersky 2 52 LPs to rule out nosocomial meningitis 52 LPs to rule out nosocomial meningitis None positive None positive 1. Addelson-Mitty, Intensive Care Med 1997 1. Addelson-Mitty, Intensive Care Med 1997 2. Metersky. Clinical Infectious Diseases 1997 2. Metersky. Clinical Infectious Diseases 1997

30. LP for Fever in ICU: Take Home ICU-acquired meningitis very rare. ICU-acquired meningitis very rare. Data does not support routine LP for ICU- acquired fever/altered mental status. Data does not support routine LP for ICU- acquired fever/altered mental status. Exceptions: Exceptions: Neurosurgical patients. Neurosurgical patients. Intracranial device. Intracranial device. Severe immune compromise (including cancer). Severe immune compromise (including cancer). ? Undiagnosed community-acquired ? Undiagnosed community-acquired

31. DVT/PE as Cause of Fever in the ICU DVT common in ICU patients (10- 30%) DVT common in ICU patients (10- 30%) But how common is DVT/PE as But how common is DVT/PE as cause of fever. cause of fever.

32. Clinical Data Fever and DVT RIETE Registry >14,000 patients with DVT 707 (4.9%) with temp >38 C. at presentation ??? % with other signs of DVT AbuRhama (Surgery 1997) 114 Duplexes for FUO DVT considered cause of FUO in 5 (6%) $450 x 144 = $51,300 ; $10,260 per case DVT

33. PIOPED 311 with angiographically proven pulmonary embolism. 311 with angiographically proven pulmonary embolism. 43 (14%) had temp > 100.0 and no other cause. 43 (14%) had temp > 100.0 and no other cause. 19 (6.1 %)) had temp >38.3ºC and no other source. 19 (6.1 %)) had temp >38.3ºC and no other source. 5 (1.6 percent) had a temperature of >38.9ºC. 5 (1.6 percent) had a temperature of >38.9ºC.

34. DVT/PE Bottom Line In ICU patients with FUO and no other sign of thromboembolic disease, DVT/PE examination low yield. In ICU patients with FUO and no other sign of thromboembolic disease, DVT/PE examination low yield. Might be useful to know Might be useful to know Cost-effective ?? Cost-effective ??

35. Does Magnitude of Fever Mean Anything? High fever definition varies, often greater than 39.5 (103F). High fever definition varies, often greater than 39.5 (103F). ? more likely in certain conditions. ? more likely in certain conditions. <102 - ?????? <102 - ?????? 102-106: 102-106: ? more commonly infection ? more commonly infection Laupland: more culture + patients. Laupland: more culture + patients. >106 : >106 : likely non-infectious likely non-infectious Patients do worse Patients do worse

36. Empiric Antibiotics Not every fever needs new antibiotic! Not every fever needs new antibiotic! Those who do: High risk of bad outcome Those who do: High risk of bad outcome Deteriorating condition Deteriorating condition Incipient Shock Incipient Shock Compromised Host Compromised Host neutropenic neutropenic ventricular assist device ventricular assist device Fever ≥102ºF (as most infectious) ???? Fever ≥102ºF (as most infectious) ???? For other patients with new fever  WAIT For other patients with new fever  WAIT

37. In Defense of Fever Fever itself typically seen as harmful to patient. Fever itself typically seen as harmful to patient. Yet questionable evidence if treating fever beneficial. Yet questionable evidence if treating fever beneficial. Could treating fever be bad for patient? Could treating fever be bad for patient?

38. In Defense of Fever Highly preserved evolutionary response. Highly preserved evolutionary response. Number of conditions where fever associated with bad outcomes Number of conditions where fever associated with bad outcomes Other situations could be beneficial Other situations could be beneficial

39. Experimental Data Protective in mouse and sheep models of sepsis. Protective in mouse and sheep models of sepsis. induces heat shock response critical for cellular protection induces heat shock response critical for cellular protection reduces endothelial and organ damage reduces endothelial and organ damage downregulates activity of NF-κB, modulating the immune response downregulates activity of NF-κB, modulating the immune response In vitro effect on antibiotics. In vitro effect on antibiotics. growth time bacteria prolonged growth time bacteria prolonged MIC reduced MIC reduced Ozveri et al Intensive Care Med 1999, 25:1155-1159. Mackowiak, et al J Infect Dis 1982, 145:550-553.

40. Clinical Data Uncontrolled and Retrospective Uncontrolled and Retrospective Higher survival from gram-negative bacteremia in patients with fever 1. Higher survival from gram-negative bacteremia in patients with fever 1. elderly patients with CAP > mortality rate with no fever (29% vs. 4%) 2. elderly patients with CAP > mortality rate with no fever (29% vs. 4%) 2. Prospective and Controlled Prospective and Controlled 44 Trauma ICU patients 3. 44 Trauma ICU patients 3. Randomized to treatment vs permissive fever. Randomized to treatment vs permissive fever. 7 deaths in treatment vs 1 death permissive 7 deaths in treatment vs 1 death permissive 1. Bryant et al Arch Intern Med 1971, 127:120-128 2. Ahkee et al SouthMed J 1997, 90:296-298. 3. Schulman et al. Surg Infect (Larchmt) 2005, 6:369-375.

41. Laupland CCM 2008 ICU FEVER AND MORTALITY

42. Bad Effects of Fever in ICU Patient Appears to worsen outcomes in traumatic brain injuries. Appears to worsen outcomes in traumatic brain injuries. Increases cardiac output, O2 consumption and CO2 production. Increases cardiac output, O2 consumption and CO2 production. Poorly tolerated in patients with low cardio- respiratory reserve. Poorly tolerated in patients with low cardio- respiratory reserve. Specific hyperthermias (e.g. NMS, malignant hyperthermia, heat stroke) need treatment. Specific hyperthermias (e.g. NMS, malignant hyperthermia, heat stroke) need treatment.

43. Treatment of Fever: Take Home Effect of fever on outcomes unclear Effect of fever on outcomes unclear Evidence that in infections may be beneficial Evidence that in infections may be beneficial Several specific conditions where fever detrimental. Several specific conditions where fever detrimental.

44. Overall Conclusions Fever, especially low grade, is very common in ICU patients. Fever, especially low grade, is very common in ICU patients. Unexplained fever merits some clinical assessment. Unexplained fever merits some clinical assessment. Blood cultures perhaps only mandatory investigation. Blood cultures perhaps only mandatory investigation. Other tests should be appropriate to patient Other tests should be appropriate to patient Important to know something about performance of test. Important to know something about performance of test. Interpret with entire clinical picture Interpret with entire clinical picture Many non-infectious causes have benign course Many non-infectious causes have benign course Not every fever needs an antibiotic Not every fever needs an antibiotic Treatment of fever only proven benefit in specific populations. Treatment of fever only proven benefit in specific populations.

45. References 1. Circiumaru, et. al. Prospective study of fever in the intensive care unit. Intensive Care Med 1999: 25(7):668-73. 2. Mackowiak, et. al. Critical appraisal of 98.6F, the upper limit of normal body temperature, and other legacies of Carl Reinhold August Wunderlich; JAMA 1992:268 (12): 1578-80. 3. Kane, et. Al The detection of microbial DNA in the blood: a sensitive method for diagnosing bacteremia and/or bacterial translocation in surgical patients. Ann Surg 1998 Jan;227(1):1-9 4. Galicier and Richet. Prospective study of postoperative fever in a general surgery department. Infect Control 1985: 6:487-90 5. Engeron M. Lack of association between atelectasis and fever. Chest 1995: 107 (1): 81-4. 6. Kisala JM Am J Physiol Regul Integr Comp Physiol 264: R610-164 1993. 7. Marik et. al. Incidence of deep venous thrombosis in ICU patients. Chest 1997: 111 (3): 661-4. 8. Fagon et. al. Evaluation of clinical judgement in identification and treatment nosocomial pneumonia in ventilated patients. Chest 1993; 102 (2):547-53 9. Fabregas, et. al. Clinical diagnosis of ventilator associated pneumonia revisited. Thorax 1999; 54 (10):867-73 10. Marik PE, Fever in the ICU. Chest 2000; 117;855-869. 11. Peres BD; Melot C, et al. Crit Care Med 2003 Nov;31(11):2579-84.

47. Infectious causes fever in ICU Prevalence of nosocomial infection in ICU quoted as from 3-31%. 8 Prevalence of nosocomial infection in ICU quoted as from 3-31%. 8 True numbers difficult because of varying definitions. True numbers difficult because of varying definitions. Strong correlation between ICU length of stay and likelihood infection. Strong correlation between ICU length of stay and likelihood infection.

48. Post-operative Fever Well-recognized but poorly defined syndrome. Well-recognized but poorly defined syndrome. Magnitude of trauma correlated with degree fever response. Magnitude of trauma correlated with degree fever response. Cytokine release from tissue trauma. Cytokine release from tissue trauma. ? Elevated levels bacterial endotoxins and exotoxins. ? Elevated levels bacterial endotoxins and exotoxins.

49. Post-operative Fever Prospective study 800 surgical patients, 81 (9%) developed fever with no cause. Prospective study 800 surgical patients, 81 (9%) developed fever with no cause. Those with fever within 48 hours much less likely to be infectious. Those with fever within 48 hours much less likely to be infectious. > 96 hours post-op infection much more likely. > 96 hours post-op infection much more likely. Practice of deferring workup 48 hours probably sound. Practice of deferring workup 48 hours probably sound. Galicier and Richet. Infect Control 1985