Fever in the ICU

1. Paul Jones PYG2 Family Medicine Fever in the ICU

2. So what? • Fever in critically ill patients may be of infectious, noninfectious, or mixed origin and the confirmation of the source is often difficult, which leads to a diagnostic dilemma (i.e. a difficult decision: ‘‘to treat or not to treat’’)

3. Objectives • What is Fever? • What is the difference between fever and hyperthermia? • What are common causes of fever in ICU patients? • How to approach to fever in ICU patients? • What about antipyretic treatments?

4. Definition • Fever |ˈfēvər| • Noun - an abnormally high body temperature, usually accompanied by shivering, headache, and in severe instances, delirium • Body temperature of 38.3ºC (101ºF) or higher

5. Fever & Hyperthermia Fever Hyperthermia In contradistinction to fever, the setting of the thermoregulatory center during hyperthermia remains unchanged at normothermic levels, while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. Hyperthermiacan be rapidly fatal, and its treatment differs from that of fever. Porat, R and Dinarello, CA . Pathophysiology and treatment of fever in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012. • Fever is regulated at the level of the hypothalamus. • The thermostat setting in the hypothalamic thermoregulatory center shifts upwards during a fever • The vasoconstriction produces a noticeable cold sensation in the hands and feet. Blood is shunted away from the periphery to the internal organs, essentially decreasing heat loss from the skin, and the patient feels cold. For most fevers, this is sufficient to raise core body temperature 1 or even 2ºC. • Thermogenesis in either the fat or muscle takes place by uncoupling proteins, which release ATP and heat. The combination of heat conservation and thermogenesis accounts for the majority of fever. There is also increased heat production from the liver.

6. Physiology Pyrogenic Cytokines Interleukin 1 (IL-1) Interleukin 6 (IL-6) Tumor Necrosis Factor (TNF) Interferon (IFN)-alpha Porat, R and Dinarello, CA . Pathophysiology and treatment of fever in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012. • Elevated levels of PGE2 in the hypothalamus appear to be the trigger for raising the set-point. • Once the hypothalamic set-point is raised, this activates neurons in the vasomotor center to commence vasoconstriction and warm-sensing neurons to slow their firing rate and increase heat production in the periphery.

7. Fever Porat, R and Dinarello, CA . Pathophysiology and treatment of fever in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012.

8. Hyperpyrexia Hyperpyrexia is the term for an extraordinarily high fever (>41.5 ºC), which can be observed in patients with severe infections but most commonly occurs in patients with central nervous system (CNS) hemorrhages.

9. Approach • …a previously afebrile, critically ill patient in whom the source of the fever is not obvious merits a detailed evaluation of the patient’s medical history and a careful physical examination before the order of any laboratory or imaging procedure or before the administration of any drug…

10. Approach • The initial approach to the febrile patient includes: (a) the overview of the medical record; (b) the physical examination; and (c) the evaluation of characteristics of the fever (magnitude, duration, relationship to patient’s pulse rate, and temporal relationship to diagnostic and therapeutic interventions).

11. Culture before Empiric therapy • In all febrile patients before the initiation of any antimicrobial treatment, at least two blood cultures by separate needles from different sites as well as other appropriate cultures must be obtained

12. Source of Fever • Fevers between 38.3ºC (101ºF) and 38.8ºC (101.8ºF) may be infectious or noninfectious. The differential diagnosis is longest in this range; fortunately, most noninfectious sources of fever can be excluded by a detailed history and physical examination. • Fevers between 38.9 (102ºF) and 41ºC (105.8ºF) can be assumed to be infectious. • Fevers ≥41.1ºC (106ºF) are usually noninfectious. Examples include drug fever, transfusion reactions, adrenal insufficiency, thyroid storm, neuroleptic malignant syndrome, heat stroke, and malignant hyperthermia.

13. Algorithm

14. Non-Infectious “[Up to] Half of fever episodes in the ICU are of noninfectious origin…” 3

15. Non-Infectious • Acalculouscholecystitis* • Adrenal insufficiency • Benign post-operative fever • Drug fever • Acute pancreatitis • Thyroid storm • Acute respiratory distress syndrome (late) • Burns • Drug overdose • Drug withdrawal • Gout • Heat stroke • Intracranial hemorrhage • Ischemic colitis • Malignancy • Malignant hyperthermia • Myocardial infarction • Neuroleptic malignant syndrome • Pheochromocytoma • Seizures • Serotonin syndrome • Thromboembolic disease • Vasculitis • Acute hemolytic transfusion reaction • Non-hemolytic transfusion reaction • Mesenteric ischemia • Gastrointestinal bleed • Cirrhosis • IV constrast reaction

16. Infectious “The ICU-acquired infections show a prevalence of between 10% (NNIS) and 20.6% (EPIC study)…” 3

17. Infectious • Cellulitis • Cholangitis • Diverticulitis • Empyema • Endocarditis • Intra-abdominal abscess • Meningitis • Myonecrosis • Necrotizing fasciitis • Pseudomembranous colitis • Septic arthritis • Sinusitis • Suppurativethrombophlebitis • Urinary tract infection • Viral infections (CMV, HIV etc) • Fungal infections

18. Nosocomial “The prevelance of nosocomial infection in ICUs has been reported to vary from 3-31%.” 5

19. Nosocomial • VAP • Line Infection • Catheter related UTI • Surgical Site/Wound Infection • Sinusitis • MRSA • C. Diff • Bacteremia

20. Central “Fever in the absence of documented infections occurs commonly in the [Neuro}ICU, especially among patients with subarachnoid haemorrhage and vasospasm.” 6

21. Antipyrexia • The synthesis of PGE2 depends upon the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate limiting step in the synthesis of PGE2. • Inhibitors of cyclooxygenases (either COX-1 or COX-2) are potent antipyretics • Corticosteroids are also effective antipyretics, which act at two levels: • Similar to the cyclooxygenase inhibitors, corticosteroids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2 which is needed to release arachidonic acid from the membrane. • Corticosteroids block the transcription of the mRNA for the pyrogenic cytokines.

22. Caution Approximately 10 % of septic patients are hypothermic and 35% are normothermic at presentation. Septic patients who fail to develop a temperature of a significantly higher mortality than febrile septic patients.

23. Photography All photos are Creative Commons Licensed from the US Library of Congress’ photostream on Flickr.

24. References • Porat, R and Dinarello, CA . Pathophysiology and treatment of fever in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012. • MacLaren, G and Spelman, D. Fever in the intensive care unit. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012. • Dimopoulos, G & Falagas, ME. Approach to the Febrile Patient in the ICU. Infect Dis Clin N Am 23 (2009) 471–484. • Egi, M and Morita, K. Fever in non-neurological critically ill patients: A systematic review of observational studies.Journal of Critical Care - 09 January 2012. • Marik, PE. Fever in the ICU. CHEST 117:3 (2000) 855-869. • Rabinstein, AA and Sandhu, K. Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J NeurolNeurosurgPsychiatry 78 (2007) 1278–1280. • Hyperthermia in the Neurosurgical Intensive Care Unit. Neurosurgery, 47: 4(2000) 850-855.