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17 May 2013 No. 17 ITS GETTING HOT IN HERE!! Is antipyretic therapy necessary in critically ill ICU patients? H Somaroo Commentator: AA Sader Moderator: H Cassimjee Discipline of Anaesthetics CONTENTS INTRODUCTION ................................................................................................... 3 IMPORTANT DEFINITIONS ................................................................................. 4 PATHOPHYSIOLOGY OF FEVER ....................................................................... 5 BENEFICIAL EFFECTS OF FEVER ..................................................................... 8 DETRIMENTAL EFFECTS OF FEVER ................................................................. 9 TREATMENT OF FEVER ................................................................................... 10 Paracetamol .................................................................................................... 11 NSAIDs ............................................................................................................ 12 PHYSICAL COOLING METHODS ...................................................................... 13 TEMPERATURE CURVE COMPLEXITY............................................................ 13 CONCLUSION .................................................................................................... 16 REFERENCES.................................................................................................... 17 APPENDIX .......................................................................................................... 19 Page 2 of 19 Is antipyretic therapy necessary in critically ill ICU patients? INTRODUCTION The practice of treating fever is said to predate 2000BC, when Emperor Shen Nung of China is reported to have first described the antipyretic properties of the antialarial herb ch’ang shan (Dichroa febrifuga). (2) Hipprocrates was quoted more than twenty three thousand years ago as saying “Give me the power to produce fever, and I will cure all disease,” (17), here alluding to his ideas regarding the significance of fever and implications thereof. He was known to have used heat therapy in his routine clinical practice. Fever is a common,non-specific response to various types of infectious or noninfectious stimuli (16) and has been associated with increased mortality in adult patients admitted to adult intensive care units (ICUs).(3) The incidence in ICUs has been reported to range from 23 to 70%, and in half of these cases it was found to be due to an infective cause. (6) The routine control of fever, by pharmacological and physical methods, in critically ill patients has become widespread practice in many ICUs, including our own. However, the use of antipyretic therapy in critically ill patients remains inconsistent. Evidence exists both for and against the treatment of fever. It has also been postulated that the adequate treatment of fever may help reduce excessive investigation, antimicrobial therapy and cost of care in the ICU setting. As compared to with normothermic patients, patients with fever were found to require longer durations of mechanical ventilation and length of ICU stay. (13) The question remains when and who should we treat it? And are there any criteria to highlight this? Arguments against the control of fever view pyrexia as a beneficial, adaptive response to stress, and consider the important adverse effects of of antipyretic therapy. Certain animal studies have also shown an increased mortality in subjects with viral, bacterial and parasitic infections following the treatment of fever with antipyretic drug therapy.(2) Conversely, proponents for the control of fever consider the detrimental effects of fever in increasing oxygen consumption, energy deficit and hypoxic tissue injury; the decreased risk of precipitating multi-system organ failure; and the benefits of increased patient comfort. Fever has also been found to be a predictor of higher mortality in neurological ICU patients. The advantages of antipyretic therapy or induced hypothermia have also been investigated and has been shown to be of benefit in acute respiratory distress syndrome, following cardiac arrest, and in neurological injuries. Page 3 of 19 There are presently no standardised recommendations regarding when and how to approach the treatment of fever in critically ill patients; to understand this it is important to understand the pathogenesis of fever, the specific clinical indications and contraindications to treatment and to consider the risk-vs-benefit of using specific treatment modalities. IMPORTANT DEFINITIONS Fever in ICU patients is defined as a core body temperature ≥ 38.3 degrees celcius (°C) or 101 degrees Fahrenheit (°F), associated with an elevated hypothalamic set point. Fever can have an infectious or non-infectious aetiology. (Refer to appendix – table A). Most abnormal temperature increases are due to fever, however abnormally elevated body temperatures may also occur in association with a normal hypothalamic set point, in which case it is defined as hyperthermia. This can be due to: 1. environmental causes (eg. heatstroke) 2. drug induced (eg. malignant hyperthermia 3. endocrine causes (eg. thyrotoxicosis) I will not go into more detail regarding hyperthermia, as this is not in the scope of this talk. Page 4 of 19 PATHOPHYSIOLOGY OF FEVER Fever is an evolutionary response to various kinds of infectious and non-infectious stimuli, which, via different mechanisms induce an up-regulation of the thermostatic setpoint in the preoptic area of the hypothalamus, resulting in fever. Activation of the hypothalamus can occur via three ways (refer to figure 3): 1. The classical method, whereby exogenous pyrogens (such as exotoxins and viruses) timulate leucocytes, to produce cytokines (or endogenous pyrogens), mainly IL-1β, TNFα, and IL-6. These act on the central nervous system at the level of the organum vasculosum of the laminae terminalis (OVLT) to induce the production of prostaglandin E2 (PGE2). The OVLT is located below the preoptic area of the hypothalamus, and forms part of the circumventricular system of the brain ie. sites which do not possess a blood-brain barrier, at which endogenous pyrogens act. PGE2 acts directly on the cells of the preoptic nucleus, to induce a febrile response.(18) Figure 1: Midsagittal view of the brain, demonstrating hormonal pathways through the circumventricular organs (18) Page 5 of 19 The febrile response is thus controlled by neurons in or near the OVLT, which monitor circulating cytokines and and input to areas in the hypothalamus and brainstem, to elicit autonomic, endocrine and behavioural responses which are involved in fever. (illustrated in figure 2) Figure 2: Mechanism for the action of cytokines on the brain that induce Fever (18) 2. The second mechanism is also mediated by IL-1β, which induces ceramide production by the enzymatic shingomelinase pathway. Ceramide acts as a 2nd messenger, inducing an early increase in core temperature.(16) 3. The third method is a neuronal mechanism, whereby Kuppfer cells in the liver are stimulated by lipopolysaccharide to produce prostaglandin E2, which stimulates a neural pathway involving the vagus nerve and nucleus tractus solitarius, which then in turn elicits a hypothalamic febrile response. (16) Page 6 of 19 Figure 3: Mechanism of activation of the hypothalamus (16) The Immune Response to Fever Fever is known to induce changes in effector cells of the immune system, as well as induce the heat shock response, which is a complex reaction ultimately resulting in the production of heat shock proteins (HSPs), which are a class of proteins crucial to cellular survival.(6) Hyperthermic preconditioning has been investigated in animal models, and it was found that pre-treated subjects showed a significantly lower mortality and decreased organ damage following subsequent endotoxin infection. This was also associated with increased levels of HSPs measured in these subjects. Severe sepsis is thought to be associated with a decreased heat shock response. The septic response in re-infection may however be modulated by heat shock response, and is associated with higher levels of HSPs.(6) HSPs have an anti-inflammatory effect, resulting in reduced levels of TNFα, IL-1, IL-6 and IL-10 in vitro. Recent studies have also shown that the heat shock response decreases the activity of NF-κβ, which is a potent modulator of the proinflammatory response. NF-κβ activity has been found to be associated with increased mortality in septic shock patients. .(6) Page 7 of 19 Hyperthermia has been found to induce the heat shock response, thus it plays a role in modulating the immune response to sepsis. The heat shock response leads to the eventual inhibition of NF-κβ activation, and to a decreased cytokine production. (6) This demonstrates a protective role of fever in sepsis, and brings challenges the routine practice of using antipyretic therapy in critically ill patients. BENEFICIAL EFFECTS OF FEVER How fever could influence the outcome in septic patients is critical. However, it is an issue which remains debated because of the limited value of studies that include a heterogeneous population of patients with different levels of severity of sepsis (16). Several observations have been made regarding the beneficial effects of fever, which include effects on: 1. the invading microorganism 2. accelerating the immune response and 3. attenuating the immune response, thus preventing collateral tissue damage. Effects on the invading microorganism Fever impacts on invading microorganisms by reducing their growth or prolonging their growth time. Human infectious pathogens usually grow optimally between temperatures of 35-37 °C. In studies of meningitis it was found that an increased body temperature resulted in an increased pneumococci growth time in cerebrospinal fluid, as opposed to when the febrile response was blunted. In vitro studies on Plasmodium falciparum also demonstrated inhibited parasite growth at febrile temperatures. Febrile temperatures have also shown to be associated with increased antibiotic sensitivity and a reduced minimum inhibitory concentration. Effects on accelerating the immune response Fever also results in an increased immune response, by modulating the cellular immune response and inducing the heat shock response. Hyperthermic preconditioning has been demonstrated to reduce the severity of infection, inhibit lymphocyte cell reduction (CD4 lymphocytes and B cells) and also resulted in reduced serum levels of TNFα. Febrile temperatures have also been shown to induce an increase in: - the mobility of polymorphonuclear cells - the speed of phagocytosis - the adherence of T-helper lymphocytes - immunoglobulin levels - TNFα cytotoxicity Page 8 of 19 Effects on attenuating the immune response Fever also proves beneficial by attenuating the immune response and thus preventing collateral tissue damage. This accomplished by an increase in heat shock proteins, which are vital for reducing endothelial and end organ damage during various stressors, including fever (16). Heat shock proteins also cause a decrease of NF-κβ, which in turn reduces cytokine production (TNFα and INFγ ) and thus reduces the immune response. Animal studies have shown a decreased mortality and reduced organ injury following hyperthermic preconditioning.(16) Human clinical studies have also shown similar results. A significantly higher survival rate has been demonstrated in patients with Gram-negative bacilli infections, who mounted a febrile response on the day of bacteraemia, as opposed to those who did not. .(16) A fever > 38.2°C was also shown to be protective against invasive Candida species infections in ICU patients. The benefits of fever have also been demonstrated indirectly in clinical trials which show the benefits of not treating fever eg. in children infected with P.falciparum malaria, treatment with the antipyretic agent paracetamol was shown to prolong the parasite clearance time, as compared with those children who were not treated.(6) DETRIMENTAL EFFECTS OF FEVER Though the febrile response does confer many advantages, it does also have numerous harmful effects on clinical outcome as well. These include: 1. increased metabolic demand and oxygen consumption 2. patient discomfort 3. seizures in children 4. harmful collateral tissue damage The febrile process causes an increased metabolic demand and oxygen consumption on organ systems, particularly of note in the brain and heart, which worsens pre-existing disease. In neurological pathology, fever is a recognised cause of secondary cerebral insult, and is associated with a worsening clinical outcome. (16, 18) This is discussed further below. Myocardial injuries are another pathological state in which fever is associated with a deterioration in clinical outcome. Patients with pre-existing cardiac conditions, especially those with coronary artery disease and ischaemic cardiomyopathy, are more at risk to the systemic effects of fever, as a result of the increased oxygen consumption it induces. An increase in temperature up to 39°C has been shown to increase infarct size in an acute myocardial infarction model.(18) Page 9 of 19 Conversely, a reduction in fever from 39 to 37°C has been shown to decrease oxygen consumption, lessening the stress on the cardiorespiratory system, and improving oxygen delivery in febrile, critically ill patients with impaired oxygen delivery.(6,16,18) Studies have also shown that the treatment and resolution of fever without antipyretic therapy increased the left ventricular stroke volume index, and that left ventricular performance was improved with the abatement of the fever.(18) Another negative effect is patient discomfort from fever, which can either stem from the febrile process itself, or due to neuro-endocrine or metabolic pathways, triggered in response to infection.(16) Patient discomfort is often the justification clinicians use when opting to treat for fever. Febrile seizures in children is another recognised undesired complication of fever. Preventative treatment for this, however, remains a contentious issue, as antipyretic therapy has never been shown to prevent febrile seizures (11). Randomised controlled studies investigating ibuprofen compared with a placebo, and similar studies with acetaminophen, showed no reduction in the recurrence rate of febrile seizures with prophylactic antipyretic treatment.(9,16) At high fever level (> 40 to 41°C), the beneficial immunomodulatory effect may be outweighed by the harmful metabolic/inflammatory effect of fever(16). By inducing enhanced microbicidal mechanisms, fever can result in inadvertent collateral tissue damage. In an animal model of Gram negative bacterial pneumonia, fever was found to decrease survival, even in the face of improved innate host response mechanisms and pathogen elimination.(16) This decreased survival was found to be associated with increased pulmonary vasculature injury, increased aggregation of neutrophils, and increased levels of cytokines found in the broncho-alveolar lavage(19). Thus this enhanced response is also capable of causing injury to collateral host tissue, illustrating that the ultimate effect of fever is in fact determined by the balance between the accelerated clearance of pathogens and the damage to collateral tissue. TREATMENT OF FEVER Treatment modalities for fever in our ICUs involves either pharmacological interventions or physical cooling methods. The assumption made by most clinical workers is that fever is noxious (11) and that the suppression of fever will reduce or eliminate the detrimental effects. However, these interventions are by no means innocuous, and the benefit vs the risk of treatment needs to be considered. Page 10 of 19 PHARMACOGICAL TREATMEANT In our practice, the common pharmacological agents used are paracetamol and NSAIDs, so these will be discussed further, with emphasis on paracetamol, as it forms the mainstay of our antipyretic pharmacological practice. Indications for their use include a decrease in morbidity and mortality in febrile patients, the relief of patient discomfort, the contentious notion that they play a role in the preventing febrile seizures, reducing cognitive impairment, preventing secondary injury, and improving outcome in patients with neurological injuries. Paracetamol Pharmacodynamics Paracetamol acts centrally, and two mechanisms are responsible for it’s antipyretic and analgesic properties: 1. selective inhibition of cyclo-oxygenase (COX) in the central nervous system, via a tissue-specific inhibitory effect on the COX enzyme, in the presence of low peroxide levels, as is encountered in intact neuronal cells. This peroxidedependent specificity accounts for the relatively poor anti-inflammatory and antiplatelet properties, and also the better side-effect profile, as compared to the NSAIDS. 2. an indirect effect on cannabinoid and vanilloid receptors in the thermoregulatory and nociceptive pathways in the central nervous system. Paracetamol is a prodrug of the fatty acid amide N-arachidonoylphenolamine (AM404). AM404 has been demonstrated to: - inhibit in-vitro COX activity and PGE2 formation, resulting in a resetting of the thermoregulatory set-point. - increase levels of the endogenous cannabinoid neurotransmitter, anandamide, which act to lower temperature and modify nociceptive signals (4) . There is also evidence for a synergistic relationship existing between paracetamol and endogenous opioid analgesic pathways at a spinal and supraspinal level. Pharmacokinetics The pharmacokinetics of paracetamol in critically ill patients is variable, due to different pathological processes(4). Nasogastric administration leads to delayed absorption, however absorption following post-pyloric administration results is rapid; rectal absorption is poor. The volume of distribution is also found to be increased in ICU patients. The clinical significance of these differences is not clear. Page 11 of 19 Adverse effects - Hepatic necrosis following paracetamol overdose is the most serious, lifethreatening side effect. This leads to hepatocellular injury related to accumulation of its toxic metabolite N-aceto-þ-benzo-quinone imine, when glutathione reserves are exceeded. In normal patients paracetamol is considered safe, however acute hepatitis may occur in ICU patients who have a diminished glutathione reserve eg. malnourished patients and alcoholics. - Evidence also suggests the same pathway implicated in the kidney, causing paracetamol-associated nephropathy. - Serum increases in ALT of > three times has also been demonstrated; the clinical significance of this requires further investigation (16). - Paracetamol does not usually affect platelet function, however intravenous paracetamol has been demonstrated to inhibit platelet COX-1 enzyme in a dose dependent manner. - Intravenous paracetamol has been shown to induce increases in skin blood flow, due to its antipyretic action, with a consequent drop in systemic vascular resistance, which may be associated with significant hypovolaemia in critically ill patients, in whom baroreceptor reflexes may be dysfunctional or cardiac reserve limited. (21) The fall in blood pressure observed may be severe enough to warrant treatment in some critically ill patients. NSAIDs Non steroidal anti-inflammatory drugs are also sometimes used to treat pyrexia in ICU patients. They work by inhibiting COX enzymes, with those with a higher affinity for COX-1 being ten times more likely to induce gastrointestinal (GIT) toxicity.(16) Selective COX-2 inhibitors have fewer GIT side effects, but they lack the cardio-protective effect shared by non-selective and COX-1 inhibitors.(16) Adverse effects of this group include: - GIT toxicity, which may be divided into three categories, viz. mucosal lesions, GIT discomfort (eg dyspepsia) and severe GIT complications (including GIT bleeding and perforated ulceration). Patients at risk for these include those on high doses of NSAIDs, advanced age, a prior history of peptic ulcer disease or GIT bleeding, concomitant use of steroids or anticoagulants, and a short duration of therapy. - NSAIDs are also known to have nephrotoxic adverse effects, which can manifest as fluid and electrolyte disturbances, acute renal failure, acute interstitial nephritis and analgesic drug-associated nephropathy.(11) Studies have shown a markedly decreased creatinine clearance in patients taking NSAID therapy, more especially in those on diuretic or angiotensin-converting enzyme inhibitors. - These drugs have also been known to cause vasospasm in patients with preexisting coronary artery disease. (16) Page 12 of 19 PHYSICAL COOLING METHODS Physical cooling is also utilised as an antipyretic modality in critically ill pyrexial patients. Methods employed include external air and water blanket techniques, internal cold gastric lavage and cold fluid infusions.(1) However, its practice is controversial, due to certain adverse effects, viz: - its ability to induce sympathetic system activation, thus opposing attempts to lower core temperature, by thermoregulatory mechanisms; - cutaneous vasodilation and - shivering, which results in increased oxygen consumption, up to 40%.of normal (16) These also contribute to worsening levels of patient discomfort. Hypothermia blankets have also been used in febrile ICU patients, but have been found to induce large temperature fluctuations and rebound hypothermia. TEMPERATURE CURVE COMPLEXITY The measurement of body temperature is a long used, reliable clinical tool, and fever is considered to be a reliable index of illness in patients. However fever provides little in the way of diagnostic or prognostic information. In theory, temperature is a quantitative variable used, but in practice it behaves as a dichotomous variable, with poorly a delineated cutoff point. (21) It is however, the culmination of an intricate, complex system, and may provide useful physiological information in both patients with and without a fever. Using nonlinear dynamics and complexity analysis, with approximate entropy used as a measure of complexity, disturbances in the thermoregulatory system can be represented by the temperature curve, in patients with or without fever. The clinical status of critically ill patients with multiorgan failure has been found to have an inverse association to the complexity of the temperature curve, expressed as approximate entropy. (21) Thus a reduced complexity is associated with a poor prognosis. Complexity of the temperature curve was also found to decrease significantly with age. The advantages of this assessment is it is non-invasive, cost effective and it allows for the real-time, continuous monitoring of clinical status (21), which is useful especially in critically ill patients. Page 13 of 19 Figure 4: Receiver operating characteristic (ROC) curves of complexity measures and SOFA scores to predict death. (23) ...IS ANTIPYRETIC THERAPY NECESSARY? Despite the magnitude of evidence demonstrating the the beneficial effects of fever as part of the host response to fever, antipyretic therapy is still commonly utilised in febrile critically ill patients. This somewhat contradictory practice has triggered various studies reviewing fever in intensive care unit patients, what levels of fever should warrant antipyretic therapy, the morbidity and mortality related to various forms of antipyretic therapy and the differences encountered in critically ill patients with infectious and non-infectious pathologies. However there are as yet no established guidelines for fever in the critically ill demographic. For critically ill patients with sepsis, a temperature ≥39.5°C is also associated with increased mortality. Considering the mechanisms of fever as a normal and an adaptive physiological process (18, 2), and that the febrile response to infection is beneficial, as discussed before, at a cellular level with the direct inhibition of micro-organisms, as well as the enhancement of the protective cellular and immune responses; fevers less than this value should not be treated (1,18,16,4). Page 14 of 19 Figure 5: Forest plot of odds ratio for death by antipyretic versus placebo treatment, in septic patients (2) Differences exist in the septic and non-septic patients. In non-septic patients it is found that fever ≥39.5°C is independently associated with an increased mortality, without the association of antipyretic therapy administration with mortality. However, in septic patients the administration of antipyretic therapy is independently associated increased mortality, without the association of fever with mortality. (1) This indicates that fever and anti-pyretic therapy have different clinical implications for patients with and without sepsis. Page 15 of 19 4: Mean peak temperature observed in ICU patients with and without sepsis However patient discomfort and the metabolic demands of fever, especially in patients with a decreased cardiopulmonary reserve, also needs to be taken into consideration here; and in certain cases the adaptive advantage of the febrile response may need to be forfeited. At high grade fevers > 40°C, central nervous system and other collateral tissue injury may actually warrant antipyretic treatment. Treatment here needs to be individualised. In critically ill patients with neurological injuries (including traumatic brain injury and stroke) fever is associated with increased mortality, and in this demographic temperature control with antipyretic therapy is essential. Fever in this setting results in unacceptable pathophysiological changes, both locally (including increased proteolysis and free radical production (4), and systemically, resulting in decreased cerebral perfusion pressure. In these patients antipyretic therapy is therefore warranted. CONCLUSION Fever, triggered by infectious and non-infectious processes, is frequently encountered in critically ill ICU patients. The balance of its benefit to harm is a complex issue, and many factors including the presence and severity of infection, the intensity of the cellular and immune response, the extent of collateral tissue damage, and the pre-existing physiological reserve of the patient need to be considered before deciding whether or not to institute antipyretic therapy. The adequate treatment of fever may also help reduce excessive investigation, antimicrobial therapy and cost of care in the ICU setting, and therefore further investigation into this is certainly needed, to establish evidence based consensus regarding its management. Page 16 of 19 REFERENCES 1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, et al. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16:R33. 2. Jefferies S. The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis. Critical care and resuscitation. 2011-06;13:125-31. 3. Niven D. Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. Journal of critical care. 2013-06;28:303-10. 4. Jefferies S. Paracetamol in critical illness: a review. Critical care and resuscitation. 2012-03;14:74-80. 5. Kiekkas B. Physical antipyresis in critically ill adults. The American journal of nursing. 2008-07;108:40-9; quiz 50. 6. Ryan M. Clinical review: fever in intensive care unit patients. Critical care (London, England). 2003-06;7:221-5. 7. Gozzoli V. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive care medicine. 2004-03;30:401-7. 8. Young P. Early peak temperature and mortality in critically ill patients with or without infection. Intensive care medicine. 2012-01-31;38:437-444. 9. Arons M. Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Critical care medicine. 199904;27:699-707. 10.Rizoli S. Saturday night fever: finding and controlling the source of sepsis in critical illness. The Lancet infectious diseases. 2002-03;2:137-44. 11.Greisman L. Fever: beneficial and detrimental effects of antipyretics. Current opinion in infectious diseases. 2002-06;15:241-5. 12.Young P. Fever and fever management among intensive care patients with known or suspected infection: a multicentre prospective cohort study. Critical care and resuscitation. 2011-06;13:97-102. 13.Laupland K.B. Fever in the critically ill medical patient. Critical care medicine. 2009; 7:S273-278. 14.Launey Y. Clinical review: fever in septic ICU patients--friend or foe?. Critical care (London, England). 2011;15:222. 15.Dinarello C. Cytokines as endogenous pyrogens. The Journal of infectious diseases. 1999-03;179 Suppl 2:S294-304. Page 17 of 19 16. Launey Y. Clinical review: fever in septic ICU patients--friend or foe?. Critical care (London, England). 2011;15:222. 17. Bierman W. The History of Fever Therapy in the Treatment of Disease. Bulletin of the New York Academy of Medicine (1925). 1942-01;18:65-75. 18. Saper C. The neurologic basis of fever. The New England journal of medicine. 1994-06-30;330:1880-6. 19. Miller’s Anaesthesia, Neurosurgical anesthesia. 7th edition, Churchill, Livingstone 20. Krajčová A. Mechanism of paracetamol-induced hypotension in critically ill patients: A prospective observational cross-over study. Australian critical care. 2012-03-14;null. 21. Varela M. Clinical implications of temperature curve complexity in critically ill patients. Critical care medicine. 2005-12;33:2764-71. 22. Boyle M. Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study. Australian critical care. 2010-11;23:208-14. 23. Varela, Manuel;Churruca, et al. Temperature Curve Complexity Predicts Survival in Critically Ill Patients. American Journal of Respiratory and Critical Care Medicine. Aug 1, 2006; 174:290-298. Page 18 of 19 APPENDIX Table 1 – causes of fever - Page 19 of 19