Fever and Hyperthermia DEPARTMENT OF GENERAL MEDICINE

In a neutral temperature environment, the metabolic rate of humans produces more heat than is necessary to maintain the core body temperature in the range of 36.5–37.5°C (97.7–99.5°F) healthy individuals 18–40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 a.m. and higher levels at 4–6 p.m. maximum normal oral temperature is 37.2°C (98.9°F) at 6 a.m. and 37.7°C (99.9°F) at 4 p.m.; an a.m. temperature of >37.2°C (>98.9°F) or a p.m. temperature of >37.7°C (>99.9°F) defines a fever

Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings  Body temperature can be elevated by 0.6°C (1°F) with ovulation and remains at that level until menses occur. in the postprandial state. Pregnancy and endocrinologic dysfunction

warmth/cold receptors from skin through Peripheral nerves blood bathing the region Circum-ventricular organs Pre-optic ant.Hypothalamus Posterior hypothalamus THERMOREGULATORY CENTER Maintain normal temperature

CLINICAL EFECTS AND ITS BASIC PRINCIPLE shift of the hypothalamic set point from "normothermic" to febrile levels (resembles the resetting of the home thermostat to a higher level to raise the ambient temperature in a room)  Individual first notices vasoconstriction in the hands and feet. Shunting of blood away from the periphery to the internal organs essentially decreases heat loss from the skin, and the person feels cold.  Shivering, which increases heat production from the muscles, may begin at this time;  Nonshivering heat production from the liver also contributes to increasing core temperature  Behavioral adjustments (e.g., putting on more clothing or bedding) help raise body temperature by decreasing heat loss.

The processes of heat conservation (vasoconstriction) and heat production (shivering and increased nonshivering thermogenesis) continue until the temperature of the blood bathing the hypothalamic neurons matches the new thermostat setting Once that point is reached, the hypothalamus maintains the temperature at the febrile level by the same mechanisms of heat balance that function in the afebrile state When the hypothalamic set point is again reset downward the processes of heat loss through vasodilation and sweating are initiated. Loss of heat by sweating and vasodilation continues until the blood temperature at the hypothalamic level matches the lower setting. Behavioral changes (e.g., removal of clothing) facilitate heat loss.

Causes of Hyperthermia Syndromes Heat Stroke Exertional: Exercise in higher than normal heat and/or humidity Nonexertional: Anticholinergics, including antihistamines; antiparkinsonian drugs; diuretics; phenothiazines Drug-Induced Hyperthermia Amphetamines, cocaine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA; "ecstasy"), lysergic acid diethylamide (LSD), salicylates, lithium, anticholinergics, sympathomimetics Neuroleptic Malignant Syndrome Phenothiazines; butyrophenones, including haloperidol and bromperidol; fluoxetine; loxapine; tricyclic dibenzodiazepines; metoclopramide; domperidone; thiothixene; molindone; withdrawal of dopaminergic agents

Serotonin Syndrome Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants Malignant Hyperthermia Inhalational anesthetics, succinylcholine Endocrinopathy Thyrotoxicosis, pheochromocytoma Central Nervous System Damage Cerebral hemorrhage, status epilepticus, hypothalamic injury

Autoinflammatory Diseases Adult and juvenile Still's disease Cryopyrin-associated periodic syndromes (CAPS) Familial Mediterranean fever Hyper-IgD syndrome Behçet's syndrome Macrophage activation syndrome Normocomplementemic urticarial vasculitis Antisynthetase myositis PAPA a syndrome Blau syndrome Gouty arthritis

A fever of >41.5°C (>106.7°F) is called hyperpyrexia. Hyperthermia Hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds the body's ability to lose heat. Setting of the hypothalamic thermoregulatory center is unchanged Does not involve pyrogenic molecules Exogenous heat exposure and endogenous heat production Exertional heat stroke typically occurs in individuals exercising at elevated ambient temperatures and/or humidity Nonexertional heat stroke typically occurs in either very young or elderly individuals, particularly during heat waves.

Malignant hyperthermia inherited abnormality of skeletal-muscle sarcoplasmic reticulum that causes a rapid increase in intracellular calcium levels in response to halothane and other inhalational anesthetics or to succinylcholine. Elevated temperature, increased muscle metabolism, muscle rigidity, rhabdomyolysis, acidosis, and cardiovascular instability develop within minutes. This rare condition is often fatal. neuroleptic malignant syndrome the withdrawal of dopaminergic drugs and is characterized by "lead-pipe" muscle rigidity, extrapyramidal side effects, autonomic dysregulation, and hyperthermia. inhibition of central dopamine receptors in the hypothalamus, which results in increased heat generation and decreased heat dissipation

serotonin syndrome Many features that overlap with those of the neuroleptic malignant syndrome (including hyperthermia) but may be distinguished by the presence of diarrhea, tremor, and myoclonus rather than lead-pipe rigidity. distinguish between fever and hyperthermia

Pathogenesis cytokines produced in the CNS can raise the hypothalamic set point, bypassing the circumventricular organs. CNS cytokines probably account for the hyperpyrexia of CNS hemorrhage, trauma, or infection

Approach to the Patient: Fever or Hyperthermia Laboratory Tests complete blood count; a differential count, C-reactive protein level and erythrocyte sedimentation rate, acute-phase reactants

Treatment: Fever or Hyperthermia The Decision to Treat Fever routine treatment of fever and its symptoms with antipyretics does no harm and does not slow the resolution of common viral and bacterial infections with bacterial infections, withholding antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic In newborns, the elderly, patients with chronic hepatic or renal failure, and patients taking glucocorticoids, fever may not be present despite infection. Hypothermia can be observed in patients with septic shock. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate the condition of patients with preexisting impairment of cardiac, pulmonary, or CNS function Children with a history of febrile or nonfebrile seizure should be treated aggressively to reduce fever.

Treating Hyperthermia high core temperature in a patient with an appropriate history dry skin, hallucinations, delirium, pupil dilation, muscle rigidity, and/or elevated levels of creatine phosphokinase) suggests hyperthermia Antipyretics are of no use in treating hyperthermia Physical cooling with sponging, fans, cooling blankets, and even ice baths should be initiated immediately in conjunction with the administration of IV fluids If sufficient cooling is not achieved by external means, internal cooling can be achieved by gastric or peritoneal lavage with iced saline. In extreme circumstances, hemodialysis or even cardiopulmonary bypass with cooling of blood may be performed.

Malignant hyperthermia should be treated immediately with cessation of anesthesia and IV administration of dantrolene sodium. The recommended dose of dantrolene is 1–2.5 mg/kg given intravenously every 6 h for at least 24–48 h—until oral dantrolene can be administered, if needed Dantrolene at similar doses used in serotonin syndrome and thyrotoxicosis. The neuroleptic malignant syndrome also may be treated with bromocriptine, levodopa, amantadine, or nifedipine or by induction of muscle paralysis with curare and pancuronium. Tricyclic antidepressant overdose may be treated with physostigmine.

Mechanisms of Antipyretic Agents reduction of fever by lowering of the elevated hypothalamic set point is a direct function of reducing the level of PGE2 in the thermoregulatory center Oral aspirin and acetaminophen synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase 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 cyclooxygenase are potent antipyretics PGE2 appears to play no role in normal thermoregulation Glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Second, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines.

Regimens for the Treatment of Fever Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. In children, acetaminophen or oral ibuprofen must be used because aspirin increases the risk of Reye's syndrome Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate the condition of patients with preexisting impairment of cardiac, pulmonary, or CNS function

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