Tipo de columna
2.6 REHERVIDOR .1 INTRODUCCIÓN
What is fever?
What is the mechanism behind fever?
Why can some people with no obvious illness have fever?
Why do some people with illness have NO fever?
I want to EMPHASIZE strongly that the elderly may not have the ability to develop Fever when ill. Absence of fever does not mean anything
Chee Yong Chuan: Fever is defined as the elevation of core body temperature above normal. In normal adults, the average oral temperature is 37 degrees Celsius.
The febrile response is a complex physiologic reaction to disease involving a
cytokine-‐mediated rise in body temperature and generation of various acute phase reactants. Fever is thus considered a hallmark of IMMUNE SYSTEM ACTIVATION, resulting in a regulated rise in body temperature. So what happens is that
exogenous pyrogens from infectious agents, toxins, tumours induce production of pro-‐inflammatory cytokines, such as interleukins, TNF which subsequently enter the hypothalamic circulation and stimulate release of local prostaglandins(this is where our antipyretics and NSAID exert their effects). The body will then react to rise the temperature to this new thermal set point(manifested by chills and shivering).
Why do some people with illness have no fever? I can observe that response to fever varies with age. Elderly patients especially are unable to regulate their body temperature to the same degree as young adults. Prof Wong had reiterated many times that older patients with serious infections have substantial prevalence of a pyrexia or LOWER febrile responses! Don't be surprised to see hypothermia instead in full blown sepsis in this group of patients. Fever is also considered to be an
important host defence mechanism, hence in those who are immunocompromised i.e HIV, patients receiving steroid therapy, neutropenic patients, due to the inability to mount an adequate immune response, might not give you the textbook febrile response that you would have expected. I can think of a few examples where patients who are well but developing fever.
1) Transfusion associated fever. Again, due to activation of the immune system against antigen on the donor blood
2) Drug induced, probably affects the ability of the body to dissipate heat, or
through immune system activation, serum sickness, allergy 3) Factitious fever
Prof : difference between fever and hyperthermia
Prof : Dear Yin Ling,
I hate all these definitions as my RAM is simply too small to process them. I think of FEVER as a problem but you are sitting for exams and hence stuck in the system.
DEFINITIONS
FUO—>38.3C [>101.8F], duration >3 weeks, diagnosis uncertain after 3 days in hospital or "three outpatient visits"!! This is close to our old definition.
NOSOCOMIAL FUO—hospitalized patients, >38.3C [>101.8F], diagnosis uncertain after 3 days and infection not present or incubating on admission
IMMUNE-‐DEFICIENT (NEUTROPENIC) FUO— >38.3C [>101.8F], >3 days, neutrophil count <500/mm3.
HIV-‐RELATED FUO—HIV patients, >38.3C [>101.8F], duration >3 weeks for outpatients or ">3 days for inpatients"
The era of high technology has changed the goalposts considerably, note inpatients now are THREE days to a diagnosis. With every scan thrown in from PET CT to MRI, 3 days in the IDEAL hospital appears enough.
FEVER, NYD—persistent fever that has not yet met the definition for FUO.
In the HISTORY
-‐the pattern and duration of fever,
-‐the associated symptoms (cough, dyspnea, hemoptysis, chest pain, diarrhea, abdominal pain, dysuria, urethral discharge, hematuria, neck stiffness, headache), -‐any rash (palpable purpura, exanthem),
-‐any exposure (food, water, plants, animals, insects, infected human secretions), -‐weight loss, night sweats,
-‐travel history, sexual history, HIV risk factors, immunizations,
-‐past medical history (rheumatologic disorders, malignancy, alcohol), -‐medications
are ALL CRUCIAL.
PHYSICAL exam—
vitals (tachycardia, tachypnea, hypotension, fever, hypoxemia), oral ulcers, lymphadenopathy,
nuchal rigidity,
respiratory and cardiac examination (murmurs), temporal artery,
abdominal examination (hepatosplenomegaly), prostate examination,
skin lesions (morphology, distribution), insect bite marks, joint examination
Always think of:
INFECTIONS—TB (pulmonary, extrapulmonary, miliary),
abscess (liver, splenic, perinephric, psoas, diverticular, pelvis), osteomyelitis, endocarditis
NEOPLASTIC—hematologic (lymphoma, leukemia, multiple myeloma, myelodysplastic syndrome), solid tumors (renal cell, hepatoma)
COLLAGEN-‐VASCULAR—vasculitis (giant cell arteritis, Still’s disease, polyarteritis nodosa, Takayasu’s arteritis, Wegener’s granulomatosis, mixed cryoglobulinemia), lupus, rheumatoid arthritis
DRUGS—antimicrobials (sulfonamides, penicillins, nitrofurantoin, antimalarials), antihistamines, antiepileptics (barbiturate, phenytoin), NSAIDs/ ASA,
antihypertensives (hydralazine, methyldopa), antiarrhythmics (quinidine, procainamide), antithyroid, iodides, quinine, illicit (cocaine)
UNCOMMON CAUSES OF FUO—
endocrine (hypothalamic dysfunction, hyperthyroidism, pheochromocytoma, adrenal insufficiency),
infections (dental abscess, leptospirosis, psittacosis, melioidosis, syphilis,
gonococcemia, hereditary periodic fever syndromes (familial Mediterranean fever, alcoholic hepatitis, hematoma, factitious fever
Pls do not forget the good old CLASSIC DEFINITION (1961)—>38.3C [>101.8F], duration >3 weeks, diagnosis uncertain after 7 days of investigation in hospital
Prof : Malignancies have now superseded infections as the most common cause of fever of unknown origin (FUO). Did you know this?
In the past infectious diseases were the most common etiology of FUO, and
neoplasms constituted the second most frequent category. This shift from infectious to malignant etiology as the most frequent cause of FUO is related to several
factors.
Firstly, due to the widespread introduction of computed tomography (CT) and magnetic resonance imaging (MRI), many intra-‐abdominal causes of infection are diagnosed early and therefore do not meet the definition of FUO. Sub phrenic abscesses, pelvic pathologies and even sinus infections well hidden from the clinician Is not exposed clearly.
Secondly, radionucleotide imaging studies, that is, indium scans, gallium scans, and bone scans, have been useful in identifying occult malignancies undetectable by other means.
Now PET CT has made detection of both well hidden infections and malignancies much easier.
Prof : lymphoma is the most common etiology of neoplastic fever of
underdetermined origin. The pathophysiology of tumor-‐induced fever may be due to several mechanisms of which release of cytokines from tumor cells or tumor necrosis factor and interleukin-‐1; necrosis of tumoral tissue; all contribute.
I cannot resist asking you, What is the Naproxen challenge in FUO? ?
THE NSAID naproxen Is very effective in suppressing tumor fever and this property may be useful in elucidating suspicion of cancer in patients with prolonged,
undiagnosed fever.
Naproxen IS THE classically touted agent for suppressing tumor fever due to its unique ability to suppress tumoral cytokines in preference over infectious cytokines.
While the “naproxen challenge” may be useful in evaluating prolonged fever
suspected to be of neoplastic origin, it must be utilized in the context of a thorough, clinically-‐driven assessment.
14) NMS
A 66-‐year-‐old male was hospitalized for increasingly aggressive behavior. He had no prior psychiatric admissions. On the day of admission after he sustained a fall, a CT scan of the brain revealed a subarachnoid hemorrhage at the right superior sulcus and a possible hemorrhagic contusion at the left frontal lobe.
Over the course of hospitalization, the patient had a series of CT scans showing resolution of the hemorrhage.
He was started on olanzapine for intermittent agitation. Olanzapine was titrated to 7.5 mg daily.Ten days later the patient became abruptly somnolent with body temperature reaching 39.7 º C and severe muscle rigidity in both upper and lower extremities. He had severe diaphoresis and fluctuation of blood pressure and pulse.
Laboratory data revealed elevation of white blood cells to 14800 K/L, creatine
phosphokinase to 2800 U/L (normal < 174 U/L), and mild elevation of serum alanine and aspartate aminotransferase. MRI of the brain, CSF studies, and chest radiograph were unremarkable.
What is the diagnosis?
What will you do now?
Pathophysiology fr Medscape
'' The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. In this widely accepted model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways.
Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-‐dissipating mechanisms. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.
Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While this has not been proven in controlled studies, several such states have been proposed as risk factors for neuroleptic malignant syndrome.''
Diagnostic features of NMS:
Neuroleptics within 1 to 4 weeks.
Hyperthermia (above 38°).
Muscle rigidity lead pipe.
Five of the following:
Changed mental status.Tachycardia.Hypotension or
hypertension.Tremor.Incontinence.Diaphoresis (excessive sweating) or sialorrhoea.
Increased creatine phosphokinase (CPK) or urinary myoglobin.
Metabolic acidosis.Leukocytosis.
Exclusion of other illnesses (neuropsychiatric, drug-‐induced, systemic).
Prof : Have you heard of 'an extreme Parkinson's crisis' ?
It may be possible that NMS is as an extreme parkinsonian crisis resulting from overwhelming blockade of dopamine pathways in the brain.
In this view, NMS resembles the parkinsonian-‐hyperthermia syndrome that can occur in Parkinson’s disease patients following abrupt discontinuation
or loss of efficacy of dopaminergic therapy, which can be treated by reinstituting dopaminergic agents.
Evidence to support this view includes:
• Parkinsonian signs are a cardinal feature of NMS
.• Withdrawal of dopamine agonists precipitates the syndrome.
• All triggering drugs are dopamine receptor antagonists.
• Risk of NMS correlates with drugs’ dopamine receptor affinity.
• Dopaminergic agonists may be an effective treatment.
• Lesions in dopaminergic pathways produce a similar syndrome.
• Patients with NMS have demonstrated low cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid.
Yin ling: this patient is likely having what we know as a Neuroleptic Malignant Syndrome due to the Olanzapine that was just started ten days ago.
Neuroleptic malignant sydrome is caused by drugs causing Dopamine receptor antagonists (commonly antipsychotics) and also withdrawal of Dopamine agonists (commonly anti Parkinsonian drugs). temperature regulation became haywire and patient presents with classic tetrad of hyperthermia which is unable to be brought down by antipyrogens, RIGIDITY, mental confusion/somnolence/coma, and
autonomic dysfunction (perfused sweating, tachycardia, labile BP and etc). it can occur after a few days of taking the drugs up to years after that. classically it occurs within a few weeks.
Labs wise: increase total white and v high CK, deranged transaminases and decrease in se iron is classical for NMS.
Stopping the culprit drug is first and foremost. Secondly bring down the patients temperature with methods like cooling blanket, hydration, and medical therapy with dopamine agonists like bromocriptine can help. Dantrolene a muscle relaxant is used too but not available in many hospitals. Supporting patient's ABC is of course vital
NMS has been claimed to have some similar genetic profile as Malignant Hyperthermia that occurs when anaest drugs classically succinylcholine is administered. MH is autosomal dominant and a drug history will help us with diagnosis.
It is often difficult to differentiate Serotonin syndrome and NMS. even more so when serotonin containing drugs will also have dopamine antagonist effect.
Serotonin syndrome is due to a high level of serotonin in the body caused by giving two serotonin containing drugs concurrently, giving these drugs tgt with CYP 2D6/
3A4 inhibitors OR giving a Long Acting drugs which increase serotonin eg
Prozac(fluoxetine). classical drugs that causes SS are antidepressants like SSRI, SNRI, MAOi-‐A (MAOi-‐B that we are giving to our parkinsons disease patients won't cause that effect. i don't know why). other common drugs are PAIN CONTROL drugs eg Tramadol, fentanyl, meperidine; ANTIEMETRICS eg Maxolon, granisetron(Kytril), ondansetron; TRIPTANS, LITHIUM.
Pathophysiology of NMS and SS is different because SS does not cause
hyperthermia by altering the hypothalamus setpoint. it is due to the overall hyperexcitability.
The few ways to differentiate:
1) Serotonin syndrome causes neuromuscular excitation : hyperreflexia, myclonus, clonus, increase in bowel sounds, pupils dilatation, as opposed to LEAD PIPE
RIGIDITY in NMS.
2) Lab reuslts of increase total white and CK and transminases and decrease se iron will point to NMS. SS less likely
3) SS can occur immediately after serotonin containing drugs is given while NMS
might occur after a few weeks.
Mx of SS : diazepam for the hyperexcitability, intubation and sedation may be needed. anti serotonergic drug like cyproheptadine can be given.
Dr Hu : Neuroleptic malignant–like syndrome (NMLS) ……
Withdrawal or dose reduction of levodopa in patients with Parkinson’s disease (PD) has been reported to precipitate a potentially fatal syndrome closely resembling neuroleptic malignant syndrome (NMS). This syndrome is referred to as neuroleptic malignant–like syndrome (NMLS) and parkinsonism-‐hyperpyrexia syndrome by some authors.
Clinical features of NMS and NMLS are very similar and include high fever, marked rigidity, altered consciousness, leukocytosis, autonomic dysfunction, rhabdomyolysis with elevated serum creatine kinase (CK) levels, and renal failure. NMS and NMLS share a similar pathophysiologic mechanism consisting of an acute reduction in nigrostriatal and hypothalamic cerebral dopaminergic transmission. In the case of NMS, the primary mechanism occurs when neuroleptics block D2 dopamine
receptors, while the cause of NMLS is the withdrawal of exogenous dopamine. This usually occurs in the form of its precursor, levodopa. Clinical conditions that may contribute to the occurrence of NMLS include disturbance in the gastrointestinal tract resulting in poor absorption of levodopa, intercurrent infection, dehydration due to heat, and poor adherence to medications.
It is well recognized that “high dietary protein” intake can impair the absorption of levodopa, leading to loss of efficacy and PD symptom fluctuations. The amino acids of the protein may compete with levodopa for absorption in the gut and for
transport through the blood-‐brain barrier. (Health-‐care professionals should be aware of the interaction between levodopa and protein content of enteral nutrition to avoid the occurrence of NMLS in patients with PD.)
The treatment of NMLS due to levodopa withdrawal consists of supportive measures, hydration, and Levodopa reintroduction or increase in dose can be effective.
(The Annals of Pharmacotherapy 2010 September, Volume 44)
15) on Cardiac Tamponade