Adult Patient with Fever

Adult Patient with Fever - Alterations in Body Alterations...

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Unformatted text preview: Alterations in Body Alterations in Body Temperature: The Adult Patient with a Fever Joe Lex, MD, FAAEM Temple University Hospital March 23, 2006 Objectives Objectives • Differentiate fever from hyperthermia • Explain what causes a fever • Describe an appropriate fever work­up • Recognize life­threatening causes of fever, both infectious and non­infectious Objectives Objectives • Explain reasons to either treat or not treat fever • Describe appropriate methods of treating fever • Explain how acetaminophen and aspirin reduce fever • Describe treatment for NMS Fever Fever • • • • 6% of adult visits 20 – 40% of pediatric visits Benign self­limited diseases 10% to 15% of >65 years old 70 – 90% hospitalized 7 – 9% die within one month Fever Fever Three body systems account for more than 80% of infections • Respiratory tract • Urinary tract • Skin and soft tissue Hypothalamus Hypothalamus Neurons in preoptic anterior and posterior hypothalamus receive signals… ...from peripheral nerves that reflect warmth / cold receptors ...from temperature of blood bathing the region Hypothalamus Hypothalamus • Signals integrated by thermo­ regulatory center to maintain normal temperature • In neutral environment, human metabolism produces more heat than necessary to maintain core body temperature at 37°C Hypothalamus Hypothalamus • Hypothalamus controls temperature by causing heat loss Optic chiasm Pituitary gland Sella turcica Hypothalamus Hypothalamus Hypothalamus • Normal body temperature maintained despite environment • Hypothalamic thermoregulatory center balances heat production from metabolic activity in muscle and liver with heat dissipation from skin and lungs Normal Temperature Normal Temperature • In healthy 18 to 40 year­olds, mean oral temperature 36.8° ± 0.4°C (98.2° ± 0.7°F) • Lowest 6 a.m., highest 4 ­ 6 p.m. • Maximum normal oral: – 37.2°C (98.9°F) at 6 a.m. – 37.7°C (99.9°F) at 4 p.m. Fever Fever • Fever: morning temperature >37.2°C (98.9°F) or evening temperature >37.7°C (99.9°F) • Normal daily variation: 0.5°C (0.9°F) • If recovering from virus, can be 1.0°C Location, Location, Location Location, Location, Location • Rectal temperature higher than oral by about 0.4°C (0.7°F) • Distal esophageal best core temperature • Ear thermometers measure radiant heat energy from tympanic membrane, ear canal, frequently inaccurate Physiologic Elevation Physiologic Elevation • Women: morning temperature lower in 2 weeks before ovulation, then rises about 0.6°C (1°F) with ovulation and stays there until menses • Body temperature also elevated in postprandial state Physiologic Elevation Physiologic Elevation • Daily temperature variation fixed in early childhood • Elderly have reduced ability to develop fever, may have modest fever even in severe infections Fever vs. Hyperthermia Fever vs. Hyperthermia Fever vs. Hyperthermia Fever • Fever: body temperature that exceeds normal daily variation • Occurs in conjunction with in hypothalamic set point • Like resetting home thermostat to a higher level in order to raise ambient room temperature Fever vs. Hyperthermia Fever • Hypothalamic set point raised activates vasomotor center neurons vasoconstriction first noted in hands and feet • Blood shunted from periphery heat loss from skin feels cold Fever vs. Hyperthermia Fever • Shivering heat production from muscles • If heat conservation mechanisms raise blood temperature enough, shivering not required heat production from liver Fever vs. Hyperthermia Fever • In humans, behavioral instinct (e.g., putting on more clothing or bedding) leads to reduction of exposed surfaces helps raise body temperature Fever vs. Hyperthermia Fever • Heat production (shivering, metabolic activity) and heat conservation (vasoconstriction) continue until temperature of blood bathing hypothalamic neurons matches new thermostat setting Fever vs. Hyperthermia Fever • Hypothalamus maintains febrile level by same mechanisms operative in afebrile state • When reset downward heat lost through vasodilation and sweating Fever vs. Hyperthermia Fever • Fever >41.5°C (106.7°F) hyperpyrexia • Can develop in severe infections • Most common in patients with CNS hemorrhages • Preantibiotic era: fever due to infection rarely >106°F Fever vs. Hyperthermia Fever • “Hypothalamic fever” caused by abnormal hypothalamic function • Most patients with hypothalamic damage have subnormal body temperature Fever vs. Hyperthermia Fever vs. Hyperthermia is characterized by a normothermic setting of thermoregulatory center in conjunction with uncontrolled increase in body temperature that exceeds the body's ability to lose heat Fever vs. Hyperthermia Fever vs. Hyperthermia • Exogenous heat exposure or endogenous heat production • Over­insulating clothing core temperature • Work or exercise in hot environment heat production > peripheral heat loss Fever vs. Hyperthermia Fever vs. Hyperthermia • Thermoregulatory failure with warm environment exertional or nonexertional (classic) heat stroke Fever vs. Hyperthermia Fever vs. Hyperthermia • Classic heat stroke: elderly during heat waves – Chicago: July 1995, 465 deaths certified as heat related – Europe: Summer 2003, estimated 17,000 additional deaths Some Causes of Some Causes of Nonexertional Hyperthermia Nonexertional Hyperthermia • Anticholinergics, • including antihistamines • Antiparkinsonian • drugs • • Diuretics • • Phenothiazines • Amphetamines • Monoamine oxidase (MAO) inhibitors Cocaine Phencyclidine Tricyclic antidepressants LSD Some Causes of Some Causes of Nonexertional Hyperthermia Nonexertional Hyperthermia • Malignant hyperthermia: – Genetically unstable sarcoplasmic reticulum – Massive calcium release after inhalational anesthetic or succinylcholine • Endocrinopathy – Thyrotoxicosis – Pheochromo­ cytoma Neuroleptic Malignant Neuroleptic Malignant Syndrome • Muscle rigidity, autonomic dysregulation, hyperthermia • Inhibition of central dopamine receptors in hypothalamus heat generation and heat dissipation Neuroleptic Malignant Neuroleptic Malignant Syndrome • Phenothiazines (Thorazine®, Compazine®, Mellaril®) • Butyrophenones (Haldol®) • Thiothixene (Navane®) • Dibenzoxazepines (Loxitane®) • Dibenzodiazepines (Clozaril®) • Indoles (Moban®) • Metoclopramide (Reglan®) …and many others Drug­Induced Hyperthermia Drug­Induced • Prescription psychotropic drugs – monoamine oxidase inhibitors, – tricyclic antidepressants – amphetamines • Illicit drugs – phencyclidine – lysergic acid diethylamide (LSD) – cocaine Malignant Hyperthermia Malignant • Inherited abnormality of skeletal­ muscle sarcoplasmic reticulum • Halothane or succinylcholine ++ causes rapid intracellular Ca++ temperature, muscle metabolism, rigidity, acidosis, rhabdomyolysis, cardiovascular instability Fever vs. Hyperthermia Fever vs. Hyperthermia can be rapidly fatal No rapid way to differentiate from fever • Physical aspects may be a clue • • – History of drug that blocks sweat – Skin hot and dry – No response to antipyretics Pyrogen Pyrogen • • Any substance that causes fever Exogenous: microbial products or toxins, whole microorganisms – Classic: lipopolysaccharide endotoxin from all Gram­negatives – Enterotoxin from Staphylococcus aureus and group A and B strep toxins (superantigens) Pyrogenic Cytokines Pyrogenic Cytokines • Cytokines: small proteins that regulate immune, inflammatory, and hematopoietic processes • Endogenous pyrogens IL­1, IL­6, tumor necrosis factor (TNF), ciliary neurotropic factor (CNTF), and interferon (IFN) all known to cause fever Pyrogenic Cytokines Pyrogenic Cytokines • Induced exogenous pyrogens, mostly from bacterial or fungal sources • Viruses induce pyrogenic cytokines by infecting cells Pyrogenic Cytokines Pyrogenic Cytokines • Inflammation, trauma, tissue necrosis, and antigen­antibody complexes cause production of IL­1, TNF, and IL­6, which trigger hypothalamus to raise set point to febrile levels • Cellular sources: monocytes, neutrophils, lymphocytes How to Make a Fever How to Make a Fever • IL­1, IL­6, and TNF released into systemic circulation • Induce central and peripheral synthesis of PGE2 – Peripheral PGE2 causes nonspecific myalgias, arthralgias – Central PGE2 raises hypothalamic set point How to Make a Fever How to Make a Fever PGE2 not a neurotransmitter Triggers receptor on glial cells rapid release of cyclic adenosine 5'­monophosphate (cAMP, which is neurotransmitter) • Activates neuronal endings from the thermoregulatory center • • Working Up a Febrile Patient Working Up a Febrile Patient Taking a History Taking a History “It is in the diagnosis of a febrile illness that the science and art of medicine come together. In no other clinical situation is a meticulous history more important…” William Osler? Osler? Harvey Cushing? th 18th edition Harrison’s Taking a History Taking a History “Painstaking attention must be paid to the chronology of symptoms in relation to the use of prescription drugs (including drugs or herbs taken without a physician's supervision) or treatments such as surgical or dental procedures…” Taking a History Taking a History • Occupational history: exposure to... ...animals? ...toxic fumes? ...potential infectious agents? • Other febrile individuals at home, work, or school? • Prosthetic materials? • Implanted devices? Taking a History Taking a History • Travel history, • Dietary including military – raw or poorly cooked meat service – raw fish • Unusual hobbies – unpasteurized Sexual • milk or cheese orientation • Household pets Practices – – Precautions Taking a History Taking a History • Tobacco, marijuana, intravenous drugs, alcohol • Trauma • Animal bites • Tick or other insect bites • • • Prior transfusion Immunizations Drug allergies or hypersensitivity Taking a History Taking a History Family history • Tuberculosis, • Other febrile or infectious diseases • Arthritis / collagen vascular disease Unusual familial symptomatology: • Deafness • Urticaria • Fevers and polyserositis • Bone pain • Anemia Taking a History Taking a History Ethnic origin • Hemoglobinopathies: more common in African­American • Familial Mediterranean fever: more common in Turks, Arabs, Armenians, Sephardic Jews Fever Pattern Fever Pattern • Usual times of peak and trough may be reversed in typhoid fever and disseminated tuberculosis • Temperature­pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug­induced fevers, and factitious fever Fever Pattern Fever Pattern • Normothermia, hypothermia despite infection: newborns, elderly, patients with chronic renal failure, and patients taking glucocorticoids • Hypothermia observed in septic shock Fever Pattern Fever Pattern • Relapsing fevers: separated by intervals of normal temperature st • Tertian fever: paroxysms on 1st rd and 3rd days (e.g. Plasmodium vivax) st th • Quartan fever: on 1st and 4th (Plasmodium malariae) Fever Pattern Fever Pattern • Borrelia infections and rat­bite fever: several days of fever followed by a several afebrile days, then relapse of fever days • Pel­Ebstein fever: 3 to 10 days fever followed by afebrile 3 to 10 days – Hodgkin's disease, lymphomas Fever Pattern Fever Pattern • Cyclic neutropenia: fevers every 21 days accompany neutropenia • Familial Mediterranean fever: no periodicity Physical Examination Physical Examination • • All vital signs are relevant Temperature may be oral or rectal, but consistent site used – Axillary temperatures unreliable • Daily physical examination until diagnosis certain and anticipated response achieved Physical Examination Physical Examination • Special attention to skin, lymph nodes, eyes, nail beds, cardiovascular system, chest, abdomen, musculoskeletal system, and nervous system. • Rectal examination imperative Physical Examination Physical Examination • Penis, prostate, scrotum, and testes; retract foreskin • Pelvic examination: pelvic inflammatory disease, tubo­ ovarian abscess Generating a Differential Generating a Differential Organ system Respiratory Critical Diagnosis Pneumonia with respiratory failure Gastrointestinal Peritonitis Neurologic Meningitis Systemic Cavernous sinus thrombosis Sepsis Meningococcus Generating a Differential Generating a Differential Organ system Respiratory Emergent Diagnosis Bacterial pneumonia Peritonsillar abscess Retropharyngeal abscess Epiglottitis Cardiovascular Endocarditis Pericarditis Generating a Differential Generating a Differential Organ system Emergent Diagnosis Gastrointestinal Appendicitis Cholecystitis Diverticulitis Genitourinary Intraabdominal abscess Pyelonephritis Tuboovarian abscess Pelvic inflammatory disease Generating a Differential Generating a Differential Organ system Neurologic Soft tissue Emergent Diagnosis Encephalitis Brain Abscess Cellulitis Infected decubitus ulcer Soft tissue abscess Generating a Differential Generating a Differential Organ system Nonemergent Diagnosis Respiratory Otitis media Sinusitis Pharyngitis Bronchitis Influenza Tuberculosis Gastrointestinal Colitis / enteritis Generating a Differential Generating a Differential Organ system Nonemergent Diagnosis Genitourinary Cystitis Epididymitis Prostatitis Noninfectious – Critical Noninfectious – Critical Acute myocardial infarction Pulmonary embolus or infarct Intracranial hemorrhage Cerebrovascular accident Neuroleptic­ malignant syndrome Thyroid storm Acute adrenal insufficiency Transfusion reaction Pulmonary edema Noninfectious – Emergent Noninfectious – Emergent Congestive heart failure Dehydration Recent seizure Sickle­cell disease Transplant rejection Pancreatitis Deep venous thrombosis Noninfectious – Nonemergent Noninfectious – Nonemergent Drug fever Malignancy Gout Sarcoidosis Crohn's disease Postmyocardiotom y syndrome Algorithm: Young and Healthy Algorithm: Young and Healthy Algorithm: Elderly or Algorithm: Elderly or Chronically Ill Laboratory Studies Laboratory Studies • • Many diagnostic possibilities If history, epidemiology, or physical examination suggests more than simple viral illness or streptococcal pharyngitis, then laboratory testing is indicated Laboratory Studies Laboratory Studies • Tempo and complexity of work­ up depends on pace of illness, diagnostic considerations, immune status of host • If findings focal, laboratory examination can be focused • If fever undifferentiated, more studies warranted Complete Blood Count Complete Blood Count • • • Highly insensitive Highly nonspecific Most valuable use: ensure adequate immune response (polymorphonuclear neutrophil leukocyte count) in elderly or those with immune compromise Complete Blood Count Complete Blood Count • Manual or automatic differential sensitive to identification of eosinophils, band forms, toxic granulations, and Döhle bodies • Last three associated with bacterial infections Other CBC Clues Other CBC Clues • If febrile illness prolonged, examine smear for malarial or babesial pathogens (where appropriate) as well as classic morphologic features • Erythrocyte sedimentation rate • C­reactive protein Fever and Neutropenia Fever and Neutropenia • Viral infection, particularly parvovirus B19 • Drug reaction • Systemic lupus erythematosus • Typhoid • Brucellosis • Infiltrative diseases of bone marrow: – Lymphoma – Leukemia – Tuberculosis – Histoplasmosis Fever and Lymphocytosis Fever and Lymphocytosis • • • • Typhoid Brucellosis Tuberculosis Viral disease Atypical lymphs • EBV, CMV, HIV • Dengue • Rubella • Varicella • Measles • Viral hepatitis. • Serum sickness Fever and Other WBCs Fever and Other WBCs Monocytosis • Typhoid • Tuberculosis • Brucellosis • Lymphoma Eosinophilia • Hypersensitivity drug reactions • Hodgkin's • Adrenal insufficiency • Metazoan infections Other Labs – Possible Other Labs – Possible • Urinalysis with examination of urine sediment • Any abnormal fluid accumulation (pleural, peritoneal, joint) needs exam in undiagnosed fever • Stool for fecal leukocytes, ova, or parasites may be indicated Other Labs – Possible Other Labs – Possible BMP recommended Liver function tests if other organ cause not obvious • Blood, urine, and abnormal fluid collections culture • Additional labs added as work­up progresses • • Other Labs – Possible Other Labs – Possible • Smears and cultures of throat, urethra, anus, cervix, and vagina • Sputum for Gram's stain, acid­ fast bacillus staining, culture • CSF if meningismus, severe headache, mental status change Radiography Radiography • Chest x­ray part of evaluation for significant febrile illness Resolution Resolution • Most patients recover without treatment or history, physical examination, and initial studies lead to diagnosis • Fever 2 to 3 weeks, examination and laboratory tests unrevealing provisional diagnosis FUO Treating a Fever Treating a Fever Antipyretics Antipyretics Antipyretics Antipyretics • By reducing fever with antipyretic, assume no diagnostic benefit gained by allowing fever to persist • Daily highs and lows of normal temperature exaggerated in most fevers Antipyretics Antipyretics • PGE2 synthesis depends on enzyme cyclooxygenase (COX) • COX substrate is arachidonic acid released from cell membrane • Release of arachidonic acid is rate­limiting step • COX inhibitors: antipyretics Antipyretics Antipyretics • Potency correlated with inhibition of brain COX • Acetaminophen – Poor peripheral COX inhibition – Poor anti­inflammatory – Oxidized in brain by cytochrome p450 potent COX inhibitor Acetaminophen Acetaminophen • Discovered 1889 by Karl Morner (8 years before aspirin) • Principal active metabolite of phenacetin and acetanilid • As effective as phenacetin, but less toxic • APC=aspirin/phenacetin/caffeine • Widespread use after 1949 Acetaminophen Acetaminophen • McNeil Laboratories first sold in 1955 (Tylenol Children's Elixir) • Package looked like fire truck! Acetaminophen Acetaminophen • • • • • • • • • • Abenol Aceta Actamin Aminofen Anacin­3 Apacet APAP Atasol Banesin Dapa Datril Exdol Feverall Genapap Genebs Halenol Liquiprin Meda Cap • Neopap • • • • • • • • Panadol Phenaphen Redutemp Ridenol Robigesic Rounox Snaplets­ FR • Suppap • Tapanol • Tempra • • • • • • • Acetaminophen Acetaminophen • APAP = N­acetyl­para­aminophenol • Britain: Paracetamol Aspirin Aspirin Aspirin Aspirin • Hippocrates: willow tree leaves for eye diseases and childbirth • Leviticus: “boughs of goodly trees, ... willows of the brook” • Dioscorides (AD1): “…leaves of willow...excellent formentation for ye Gout…” Aspirin Aspirin • AD 60 Caius Plinius Secundus: poplar bark for sciatica • 1763 Reverend Edward Stone: willow bark as remedy for agues • Standard treatments until 1800s – Pain: opium – Fever: Peruvian cinchona bark Aspirin Aspirin 1828 Johann Büchner: salicin 1838 Raffaele Piria derived salicylaldehyde from salicin, then converted to salicylic acid • 1874 Heyden Chemical Company produced commercial salicylic acid • • Aspirin Aspirin • August, 1897: Felix Hoffman, working for Frederick Bayer, synthesized acetylsalicylic acid (ASA) Aspirin Aspirin • A few weeks later, Hoffman synthesized diacetylmorphine • Initial subjects felt “heroic” • Bayer sold commercially: “Heroin” • Aspirin required prescription, heroin sold over the counter Antipyretics Antipyretics • Oral aspirin and acetaminophen equally effective in reducing fever in humans • Nonsteroidal anti­inflammatory agents (NSAIDs) also excellent antipyretics Antipyretics Antipyretics • Chronic high­dose aspirin or NSAID therapy in arthritis does not reduce normal core body temperature • Thus, PGE2 appears to play no role in normal thermoregulation Antipyretics Antipyretics • Glucocorticoids act at two levels – Reduce PGE2 synthesis by inhibiting activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane – Block transcription of mRNA for the pyrogenic cytokines Antipyretics Antipyretics • Drugs that interfere with vasoconstriction (phenothiazines) or block muscle contractions can also lower fever • Not true antipyretics: reduce core temperature independent of hypothalamic control Comparing Antipyretics Ketorolac Indomethacin Diclofenac Naproxen Ibuprofen Piroxicam Tenoxicam Aspirin Analgesia Analgesia 0.7 3 8 13 45 100 100 228 Anti­Inflammatory 2 4 7 56 10 3 5 162 Antipyretic 0.9 21 0.4 0.5 7 1.7 1.7 18 Reasons to Treat Reasons to Treat • • Fever increases oxygen demand Every of 1°C over 37°C 13% in O2 consumption 2 • Fever can aggravate preexisting cardiac, cerebrovascular, or pulmonary insufficiency Reasons to Treat Reasons to Treat • Fever mental changes in patients with organic brain disease • Fever oxygen consumption • Fever metabolic demands • Fever protein breakdown • Fever gluconeogenesis Reasons to Treat Reasons to Treat • Peripheral PGE2 production is potent immunosuppressant • Treating fever does not slow resolution of common viral and bacterial infections • Reducing fever with antipyretics reduces headache, myalgias, arthralgias Reasons to Not Treat Reasons to • Moderate elevations of body temperature may increase chemotaxis, decrease microbial replication, and improve lymphocyte function • Fever directly inhibits growth of certain bacteria and viruses Reasons to Not Treat Reasons to • No proof that treating fever with antipyretics has beneficial effect on outcome or prevents complications …but no evidence that fever facilitates recovery from infection Treating Fever Treating Fever • Objectives: reduce elevated hypothalamic set point and facilitate heat loss Treating Fever Treating Fever • Acetaminophen is preferred antipyretic • Oral aspirin and NSAIDs reduce fever, but can affect platelets and gastrointestinal tract • Children: aspirin increases risk of Reye's syndrome Treating Fever Treating Fever If patient unable to take oral: • Parenteral preparation of NSAID • Rectal suppository preparations of antipyretics • Rectal dose: 30­45 mg/kg Rectal Acetaminophen Rectal Acetaminophen • Antipyretic plasma concentration range: 10 – 20 µg/ml • 45 mg/kg rectal APAP mean peak concentration <15 µg/ml more than 3 hours after insertion • Rectal absorption unpredictable • 2 to 4 hours to peak concentrations • Bioavailability 30 – 50% oral Treating Fever Treating Fever • In hyperpyrexia, cooling blankets facilitate temperature reduction • Don’t use without oral antipyretic • When your house is too hot, do you turn down the thermostat, or hose down the roof with cold water? Special Cases Special Cases Malignant Hyperthermia Malignant Hyperthermia Stop anesthesia, succinylcholine Cool externallly Dantrolene sodium: 1 – 2.5 mg/kg of body weight • Procainamide to prevent ventricular fibrillation • • • Treating NMS Treating NMS Supportive care Discontinue offending medication Treat agitation, hyperactivity, rigidity with IV benzodiazepines • If refractory, RSI and neuromuscular blockade with nondepolarizing agent (e.g., pancuronium, atracurium) • • • Treating NMS Treating NMS • Manage hyperthermia: IV fluids, active external cooling • Treat rhabdomyolysis • Dopamine antagonists (bromocriptine, amantadine): no consistent benefit, response requires at least 24 hours, linked to stroke, seizure, MI, etc Treating NMS Treating NMS • Dantrolene inhibits calcium release from sarcoplasmic reticulum • No proven benefit • Muscular rigidity of NMS due to brain abnormality, not muscle • No advantage over neuro­ muscular blockade, benzos Conclusion Conclusion • • • • • Fever is symptom, not a disease Careful history and physical will reveal source of most fevers Recognize life­threats early Make decision about benefits of treating fever before doing so Acetaminophen is drug of choice Questions? Questions? ...
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