Antipyretic Therapy Research Articles

Effect of metamizol on promyelocytic and terminally differentiated granulocytic cells: Comparative analysis with acetylsalicylic acid and diclofenac

Metamizol is an analgesic and antipyretic agent that can induce agranulocytosis in certain patients. However, its effects on granulocyte viability and differentiation have been poorly evaluated. Here we analysed the effects of metamizol and its active metabolite, 4-methylaminoantipyrine (MAA), on the viability of HL60 promyelocytes and their dimethyl sulphoxide-induced differentiated granulocytes. Metamizol and MAA at 75 μM (above the peak of plasmatic concentration after 2 g intake) did not alter granulocytic differentiation of HL60 cells. Only at concentrations above 100 μM, well over the pharmacological range, metamizol-induced apoptosis in about 30% of the HL60 promyelocytes, while HL60-granulocytic terminally differentiated cells were more resistant to this apoptotic action. When the effects of metamizol were compared with those of acetylsalicylic acid (ASA) and diclofenac on cell viability, at equivalent concentrations used in analgesic and antipyretic therapy (75 μM for metamizol, and ASA and 3 μM for diclofenac) their apoptotic effects were similar. Again, the HL60 promyelocytes were more sensitive to apoptosis than granulocytic differentiated cells, as measured by the percentage of sub-G 1 cells detected by flow cytometry and by determination of caspase activity as a function of poly(ADP-ribose) polymerase cleavage. Furthermore, when human blood-derived granulocytes were treated with metamizol, MAA, and ASA at 75 μM or diclofenac at 3 μM, less than 10% of apoptotic granulocytes were detected, whereas at toxicological/suprapharmacological concentrations (10 mM), about 90% of granulocytes were apoptotic. These results demonstrate that metamizol, MAA, ASA, and diclofenac, at pharmacological concentrations, neither affect the granulocytic differentiation process nor induce relevant apoptosis on terminally differentiated granulocytes.

Pyrexia in head-injured patients admitted to intensive care.

(a) To quantify the occurrence of pyrexia during the first week after head injury; (b) to elucidate the relationships between pyrexia and neurological severity, length of stay in the ICU, intracranial hypertension, and cerebral perfusion pressure (CPP); and (c) to describe the effects of antipyretic therapy on temperature, intracranial pressure (ICP) and CPP. Multicenter retrospective observational study in three ICUs in the Milan area. 110 patients with traumatic brain injury. Eighty patients suffered pyrexia, defined as an external temperature higher than 38 degrees C or internal temperature higher than 38.4 degrees C. Occurrence and duration of pyrexia were associated with the degree of neurological impairment and with prolonged ICU stay. In patients with normal perimesencephalic cisterns the episodes of increased ICP were more frequent in febrile cases. Various antipyretic therapies were used in 66 patients. Pharmacological treatment was slightly effective (mean temperature reduction 0.58+/-0.7 degrees C) but caused a significant drop in CPP (6.5+/-12.5 mmHg). Pyrexia is extremely frequent in the acute phase after head injury. Its incidence is higher in more severe cases and is correlated with a longer ICU stay. It may affect ICP, but its contribution is difficult to assess when other major causes of increased intracranial volume are present. Antipyretic therapy is poorly effective for controlling body temperature and may be deleterious for CPP.

Fever: beneficial and detrimental effects of antipyretics.

Although various forms of therapy have been used, since antiquity, to lower the temperature of febrile patients, it is still not known whether the benefits of antipyretic therapy outweigh its risks. Justifications for the use of antipyretic drugs, and the evidence pertaining to these rationales, are examined. Antipyretic therapy in sepsis, and adverse effects of antipyretic medications, are also reviewed.

Brain attack: a new approach to stroke

‘Brain attack’ is a new term to describe the acute presentation of stroke which emphasises the need for urgent action. The article describes the basis for this new approach to acute stroke treatment. Rational treatment requires individual causes of stroke to be identified early and treatment targeted at the mechanism. Acute stroke treatment aims to preserve the ischaemic penumbra, protect neurons against further ischaemia and enhance brain plasticity to maximise recovery. There is a strong evidence base supporting the routine use of aspirin, but not heparin, in acute ischaemic stroke. There is also convincing evidence supporting intravenous thrombolysis using recombinant tissue plasminogen activator in selected patients within 3 hours of stroke onset. Surprisingly, as many as 33% of suspected-stroke patients arrive in Accident & Emergency departments in the UK within 3 hours of onset. New techniques in MR imaging, particularly diffusion weighted imaging, are transforming the approach to diagnosis of acute stroke. Although neuroprotective drugs have proved disappointing, active neuroprotection in acute stroke should include control of blood pressure within certain limits, antipyretic therapy, maintenance of blood glucose, and early feeding and fluid replacement. Surgical hemicraniectomy should be considered in patients with malignant cerebral oedema. There is good evidence that the best way to enhance recovery from stroke is to admit the patient to a stroke unit. To enable patients to benefit from the early active approach outlined in the article, the following are needed: the development of acute stroke units; imaging protocols; and education of patients, general practitioners and the ambulance services. Stroke care has become a specialised field, requiring input from stroke physicians, as well as the multidisciplinary rehabilitation team. The British Association of Stroke Physicians (BASP) has therefore developed a curriculum which is designed to lead to the development of a new sub-specialty of stroke medicine.

Programmable microchip monitoring of post-stroke pyrexia: effects of aspirin and paracetamol on temperature and infarct size in the rat

Background: Recent studies have demonstrated spontaneous and prolonged hyperthermia following stroke in both humans and rodents. However, a full characterization of these pyretic changes and the effects of anti-pyretic drugs on outcome is not available. Methods: The aims of this study were to monitor conscious body temperature ( n=10 per group) using programmable microchips for up to 24 h in rats following either permanent (p) or 90 min transient (t) middle cerebral artery occlusion (MCAO) or sham surgery, and to evaluate the relationship to hypothalamic damage. Also, the effects of anti-pyretic drug therapy on body temperature and infarct volume were evaluated in animals treated with vehicle, optimal doses of either aspirin or paracetamol (250 mg/kg i.p.) following pMCAO ( n=10 per group). Results: At 1 h, body temperature significantly ( P<0.01) increased to 38.6±0.2 °C following tMCAO and 38.9±0.1 °C following pMCAO compared with sham-operated animals (37.1±0.1 °C). Sustained hyperthermia (≥38.1 °C) was observed for up to 24 h following pMCAO but approached baseline within 30 min (37.6±0.2 °C) following tMCAO with reperfusion. The post-stroke pyrexia was related to the degree of ischemia where hypothalamic damage was observed in (80%) of the animals undergoing pMCAO and (0%) in the tMCAO group ( P<0.05). Treatment with paracetamol (250 mg/kg i.p.) significantly attenuated ( P<0.05) but did not normalize core body temperature up to 2 h (38.2±0.4 °C) compared with vehicle treated animals (39.3±0.1 °C). Aspirin had no effect on temperature under these conditions. Hypothalamic damage and lesion volume were not different between animals treated with paracetamol (253.3±8.5 mm 3), aspirin (264.0±11.6 mm 3) or vehicle (274.4±8.2 mm 3). Conclusions: This study is the first to demonstrate the utility of programmable microchips to monitor serial changes in post-stroke hyperthermia. The sustained post-stroke pyrexia and negative effects of antipyretic treatment may be attributed to the extensive hypothalamic injury suggesting that better pharmacologic approaches to reduce body temperature should be identified and evaluated for brain protection in severe experimental stroke.

Can Prophylactic Acetaminophen Prevent Hyperthermia in Acute Stroke?: Results of the Normothermia and Stroke Outcome (NOTHOT) Pilot Clinical Trial

P232 Objective: To explore the safety and efficacy of round-the-clock acetaminophen administration to prevent hyperthermia in acute ischemic stroke patients. Background: Fever is a frequent occurrence among stroke patients and large cohort studies have identified early fever as an independent risk factor for poor functional outcome. Conventional management is to use antipyretics only in response to the appearance of fever. A pre-emptive strategy of prophylactic antipyretic therapy has not been previously studied. Methods: Sixteen consecutive patients presenting within 24 hrs of ischemic infarction were given acetaminophen 650mg q 4 hrs for 72 hrs or until discharge. Oral temperatures were recorded q 4 hrs. Cooling blankets were ordered for T &gt;37.6 0 C. These results were contrasted with a historical control cohort of 16 consecutive patients who were admitted within 24 hrs of stroke onset treated with conventional reactive antipyretic therapy. Results: In the acetaminophen group, mean age was 71.4 and 62.5% were male. Mean admission NIHSS score was 8.9. Mean time from stroke onset to first dose of acetaminophen was 12.9 hrs. Mean temperature at presentation was 36.6 0 C for the acetaminophen group vs. 36.4 0 C for controls (p=NS). 44% of the acetaminophen group developed elevated body temperature vs. 40% of controls (p=NS). Mean temperature during the first 24 hrs of treatment with acetaminophen was 36.8 0 C vs. 36.8 0 C for controls. Corresponding numbers for the second and third 24-hour periods were 36.9 0 C for the acetaminophen group vs. 37.1 0 C for controls (p=0.02) and 36.9 0 C for the acetaminophen group vs. 36.9 0 C for controls. Across the 72 hr treatment period, mean temperature was 36.9 0 C for the acetaminophen group vs. 37.0 0 C for controls (p=0.05). Conclusion: This pilot trial demonstrates acetaminophen administered round the clock significantly lowers average body temperature in the first 72 hrs after ischemic stroke. A randomized controlled clinical trial is needed to determine whether acetaminophen mediated body temperature lowering results in smaller infarct volume and improved clinical outcomes.

Antipyretic therapy in patients with sepsis.

Sepsis is a clinical syndrome characterized by a systemic inflammatory response to infection. Mortality rates in sepsis have remained high, despite recent advances in our understanding of the immunological mechanisms that cause sepsis. Fever, a nonspecific acute-phase response, has been associated with improved survival and shortened disease duration in some infections. This article reviews the biological effects of fever and the influence of antipyretic therapy on the outcome in sepsis in experimental models and in humans and offers clinical recommendations for antipyretic therapy in early and late stages of the disorder.

Diagnostic implications and clinical consequences of antipyretic therapy.

It has been suggested that the response to antipyretic therapy might differentiate between fevers due to serious illness and fevers caused by less severe disorders; that neoplastic fevers are more responsive to nonsteroidal anti-inflammatory drugs than are infectious fevers; that the metabolic costs of fever can exceeds its clinical benefits; that antipyretic therapy can prevent or reverse febrile seizures in children and fever-associated mental dysfunction in frail elderly patients. This article examines the data on which these assertions are based.

Brief history of antipyretic therapy.

Both external cooling and pharmacotherapy have been used to treat fever since time immemorial. In the past century such treatments have proliferated at an astonishing rate. The COX-2 inhibitors are the most recent additions to the antipyretic pharmacopoeia. Additional research is needed to determine whether they represent an important new chapter in antipyretic therapy's long history or, for that matter, if the benefits of any currently available treatment for fever outweigh its cost.

Antipyretic Therapy's future.

There is little doubt that clinicians will continue to seek new and, one hopes, more intelligent ways to suppress fever. In the process, new agents will be developed, new uses will be identified for existing antipyretic agents, new measures will be designed to maximize the benefits of antipyretic therapy while minimizing its adverse effects, and a concerted effort will be made to define more clearly and to promote appropriate indications for such therapy.

Hyperthermia in the neurosurgical intensive care unit.

In patients with traumatic or ischemic brain injury, hyperthermia is thought to worsen the neurological injury. We studied fever in the neurosurgical intensive care unit (ICU) population using a definition common to surgical practice (rectal temperature >38.5 degrees C). We sought to determine fever incidence, fever duration, and peak temperature and to quantify the use of antipyretic therapy. We also attempted to determine the patient subgroups that are at highest risk for development of fever. In a retrospective chart review of a 6-month period, all febrile episodes that occurred in a consecutive series of neurosurgical ICU patients in a university hospital setting were studied. A febrile episode was defined as a rectal temperature of at least 38.5 degrees C; an episode lasted until the temperature fell below this threshold. The 428 patients studied had 946 febrile episodes. Fever occurred in 47% of patients, with a mean of 4.7 febrile episodes in each febrile patient. Fevers occurred in more than 50% of patients who were admitted to the ICU for subarachnoid hemorrhage, a central nervous system infection, seizure control, or hemorrhagic stroke, but they occurred in only 27% of patients admitted for spinal disorders. Fevers occurred in 15% of the patients who stayed in the ICU less than 24 hours, but in 93% of those who remained longer than 14 days. Despite the use of antipyretic therapy for 86% of the febrile episodes, 57% lasted longer than 4 hours and 5% lasted longer than 12 hours. Fever is common in critically ill neurosurgical patients, especially those with a prolonged length of stay in the ICU or a cranial disease. If hyperthermia worsens the functional outcome after a primary ischemic or traumatic injury, as has been suggested by several studies of stroke patients, treatment of fever is a clinical issue that requires better management.

Physiological rationale for suppression of fever.

Two critical assumptions are made when prescribing antipyretic therapy. One is that fever is, at least in part, noxious, and the other is that suppression of fever will reduce, if not eliminate, the noxious effects of fever. At present, neither assumption has been validated experimentally.

Diagnosis and treatment of pediatric fever by caretakers

Assessment of pediatric temperature is a multistep task involving both manipulative and cognitive skills. Emergency Physicians typically assume that parents possess these skills, but this assumption has never been fully tested. A prospective survey was conducted of caretakers of children ≤ 36 months of age presenting to an inner city emergency department or pediatric clinic. Participants were asked to read a Fahrenheit scale mercury thermometer and to demonstrate use of that thermometer to “take” the temperature of an infant doll. They were then asked what temperature constituted a “fever” and what temperature would require antipyretic therapy. Caretakers were also asked how they would treat a fever in the child they had brought for treatment. Proportions of correct responses were tabulated and also compared by age and level of education of caretaker. Eighty-two of 92 caretakers (89.1%) possessed working thermometers in their homes. Thirty-six subjects (39.1%) were able to measure temperature appropriately using the mercury thermometer, 52 (56.5%) were able to read the mercury thermometer correctly, and 28 (30.4%) could both measure and read correctly. Sixty-seven subjects (72.8%) described correct treatment of fever. Overall, 27 subjects (29.3%) could measure, read, and treat fever appropriately. There was no statistically significant difference in age or percentage of high school graduates between caretakers who could successfully measure, read and treat and those who could not. In this inner city patient population, caretakers of any pediatric patient whose discharge instructions contain a reference to patient temperature should receive a brief refresher along with written instructions on temperature measurement and treatment.

Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences.

Various treatments have been used to suppress fever since antiquity. Surprisingly, few studies have been performed to ascertain the physiologic consequences of antipyresis and validate the rationale behind such therapy. More importantly, it has not been established conclusively that the benefits of antipyretic therapy outweigh its risks. The present review considers these issues in light of currently available data and formulates guidelines for antipyretic therapy based on these data.

Can Prophylactic Acetaminophen Prevent Hyperthermia in Acute Stroke?: Results of the Normothermia and Stroke Outcome (NOTHOT) Pilot Clinical Trial

P232 Objective: To explore the safety and efficacy of round-the-clock acetaminophen administration to prevent hyperthermia in acute ischemic stroke patients. Background: Fever is a frequent occurrence among stroke patients and large cohort studies have identified early fever as an independent risk factor for poor functional outcome. Conventional management is to use antipyretics only in response to the appearance of fever. A pre-emptive strategy of prophylactic antipyretic therapy has not been previously studied. Methods: Sixteen consecutive patients presenting within 24 hrs of ischemic infarction were given acetaminophen 650mg q 4 hrs for 72 hrs or until discharge. Oral temperatures were recorded q 4 hrs. Cooling blankets were ordered for T >37.6 0 C. These results were contrasted with a historical control cohort of 16 consecutive patients who were admitted within 24 hrs of stroke onset treated with conventional reactive antipyretic therapy. Results: In the acetaminophen group, mean age was 71.4 and 62.5% were male. Mean admission NIHSS score was 8.9. Mean time from stroke onset to first dose of acetaminophen was 12.9 hrs. Mean temperature at presentation was 36.6 0 C for the acetaminophen group vs. 36.4 0 C for controls (p=NS). 44% of the acetaminophen group developed elevated body temperature vs. 40% of controls (p=NS). Mean temperature during the first 24 hrs of treatment with acetaminophen was 36.8 0 C vs. 36.8 0 C for controls. Corresponding numbers for the second and third 24-hour periods were 36.9 0 C for the acetaminophen group vs. 37.1 0 C for controls (p=0.02) and 36.9 0 C for the acetaminophen group vs. 36.9 0 C for controls. Across the 72 hr treatment period, mean temperature was 36.9 0 C for the acetaminophen group vs. 37.0 0 C for controls (p=0.05). Conclusion: This pilot trial demonstrates acetaminophen administered round the clock significantly lowers average body temperature in the first 72 hrs after ischemic stroke. A randomized controlled clinical trial is needed to determine whether acetaminophen mediated body temperature lowering results in smaller infarct volume and improved clinical outcomes.

Confort thermique et fièvre où la recherche du mieux être

Thermic comfort is the affective perception of temperature (to be or not comfortable). It depends on the difference between thermoregulatory central set point and body temperature. Any measures which help to reduce this difference is felt as pleasant, and vice-versa. This must be taken into consideration in the prescriptions and advices for feverish children. Thus antipyretic therapy, and face fanning are always felt as pleasant, while undressing and tepid baths may be felt as unpleasant.

Benefits and risks of antipyretic therapy.

Physicians have used various forms of antipyretic therapy since antiquity to lower the temperature of febrile patients. Nevertheless, it has yet to be determined whether the benefits of antipyretic therapy outweigh its risks. It is not known, for example, if core temperatures encountered during the febrile state ever reach levels that are intrinsically noxious (and therefore merit antipyretic intervention) or when, if ever, fever's metabolic costs exceed its physiologic benefits, or if the benefits of symptomatic relief afforded by antipyretic drugs consistently exceed their toxicologic cost. Whereas preliminary experimental and clinical observations suggest that antipyretic therapy has the potential to increase the duration and/or severity of certain infections, such data are as yet too fragmentary to draw firm conclusions regarding their validity. Finally, although clinicians have long suspected that bacteremia and other severe infections might induce fevers that are less responsive to antipyretic therapy than are those associated with self-limited infections, this concept has not held up under scientific scrutiny. Thus, despite over 2.5 millennia of clinical experience, important questions regarding the risks and benefits of antipyretic therapy remain to be answered.

Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria

Routine antipyretic therapy in children with infectious diseases has long been the source of controversy. Each year, in addition to antimalarial medication, millions of children with Plasmodium falciparum malaria receive paracetamol to reduce fever. However, the usefulness of this practice has not been proven. In a randomised trial in Lambaréné, Gabon, 50 children with P falciparum malaria were treated with intravenous quinine, and received either mechanical antipyresis alone, or in combination with paracetamol. Rectal body temperature and parasitaemia were recorded every 6 h for 4 days. Plasma concentrations and inducible concentrations of tumour necrosis factor (TNF) and interleukin-6 were measured every 24 h. In addition, production of oxygen radicals was measured in both groups. The mean fever clearance time was 32 h for children treated with paracetamol and 43 h for those who received mechanical antipyresis alone; however, this 11 h difference was not significant (95% CI -2 to 24 h; p = 0.176). Parasite clearance time was significantly prolonged in patients who received paracetamol with a difference of 16 h (8-24 h; p = 0.004). Plasma concentrations of TNF and interleukin-6 were similar in both groups during the study. However, the induced concentrations of TNF, and the production of oxygen radicals, were significantly lower in children treated with paracetamol than those who received mechanical antipyresis alone. These data suggest that paracetamol has no antipyretic benefits over mechanical antipyresis alone in P falciparum malaria. Moreover, paracetamol prolongs parasite clearance time, possibly by decreased production of TNF and oxygen radicals.

A difference of 5°C between ear and rectal temperatures in a febrile patient

A 4-year-old boy with a history of seizures triggered by fever presented at an emergency department (ED) with tachycardia, skin vasoconstriction, and a rectal temperature of 42.2°C. However, his ear temperature (as repeatedly measured in two ears, by two experienced nurses, and with two infrared thermometers) was between 36.4°C and 37.6°C. Antipyretic therapy resulted in skin vasodilation, a rapid decrease of rectal temperature, restoration of heart rate, and disappearance of the difference between the two temperatures. Seizures did not occur. This case shows that infrared ear thermometry cannot be recommended in EDs as the procedure of choice for detecting fever in small children, especially when they are vasoconstricted.

TREATMENT OF FEVER

Fever is an important indicator of disease and should not be routinely suppressed by antipyretics. There is considerable evidence that fever may actually benefit the host defense mechanism. In most patients, fever is short-lived and causes only minor discomfort. Antipyretic agents are effective in lowering temperature, but have significant side effects. Routine antipyretic therapy should be avoided but may be necessary in individual patients with underlying cardiovascular or neurologic disorders.