Fever curves are an interesting source of amusement for those that have the ability to collect the data.  This is especially true for those experiencing periodic fever or chills.

Reducing Fevers:  propacetamol (Tylenol) versus  dexibuprofen

Paracetamol, acetominophen, propacetamol are inhibitors of cyclooxygenase  (Cox).  Some references suggest it might interact with the endocannabinoid system.     Dexibuprofen, like its more structurally heterogenous ibuprofen,  is a nonsteroidal anti-inflammatory drug (NSAID).  Cox is part of the pathway that converts arachindonic acid (AA) to the pro-inflammatory cytokine PGE2.

Fevers in kids [1]

This study looked at fevers that accompany upper respiratory track infections (URTI) in children.  The kids were given oral dexibuprofen or intravenous propacetamol.  The rationale was that if a kid is vomiting, oral antipyretics are ineffective.   Auxillary (armpit) temperatures were recorded every 30 minutes.  This was an Equivalence Trial, a trial with the primary objective of showing that the response to intravenous propacetamol differs from oral Ibuprofen by an amount which is clinically unimportant. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of clinically acceptable differences.

Inclusion criteria

• Patients ranging in age from 6 months to 14 years admitted for URTI and presenting with fever (defined as body temperature of the axillar fossa ≥38.0 °C) at the time of admission were included.
• URTI was diagnosed based on disease history and physical examination carried out by the attending pediatricians.

Exclusion criteria

• Patients were excluded under the following circumstances: the patient had been administered antipyretics within 4 h prior to admission,
• a history of febrile crisis within the past 6 months,
• the presence of severe hematological abnormality, currently receiving treated for or was treated within the past 6 months for nephrologic, hepatologic, pulmonary, endocrine, hematologic, or cardiologic illnesses, neurologic or central nervous system abnormality,
• diabetes currently not under control,
• suspected lower respiratory tract infection,
• severe hemolytic anemia,
• under maintenance therapy for bronchial asthma, asthma, urticarial,
• allergic reaction history when using aspirin or NSAIDs, physical or psychological status deemed inappropriate for a clinical trial,
• participation in another clinical trial involving other drug(s) within the past 4 weeks, and failure to receive informed consent from the patient or parent.

This is what a temperature curve looks like.  An attempt has been made to shade the area under the Dexibuprofen  curve (gray) versus the Propanecetamol (blue).  Notethat the X-axis is time and the Y-axis temperature.  The larger the area, the more time the child spends feverish.  Some studies on ClinicalTrials.gov like to use  37.0 °C for calculating area under the curve (AUC).

Outcome measurements

• The primary outcome measurement was the difference in body temperature reduction at 4 h after antipyretic administration between the study and control groups.

The authors failed to demonstrate superiority of intravenous propacetamol oral Dexibuprofen.

• The secondary efficacy variables were range of body temperature reduction at 4 h after antipyretic administration, the Area Under the Curve (AUC) of body temperature change until 6 h after antipyretic administration-and-time relationship,
• the maximum value of body temperature reduction within the 6 h after antipyretic administration,
• the number of patients whose body temperature normalized (< 37.0 °C) at 6 h after antipyretic administration
• the time point when body temperature first reached< 37.0 °C.

In stroke patients [2]

Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to 6 times daily treatments during 5 days after the stroke  with either

• 1000 mg acetaminophen
• 400 mg ibuprofen
• placebo

This study used tympanic temperatures measured every two hours.  Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.  We don’t know how diurnal variations in body temperature came into play.  We can hypothesize that these patients were not getting a lot of natural sunlight to set their circadian rhythms into motion.

Outcome Measures

Clinical trials have primary and secondary measures to see if the tested intervention has the desired effect on the patient’s outcome.
The primary outcome was body temperature measured rectally at 24 hours from start of treatment. Secondary outcomes were change from baseline temperature at 1 and 5 days from start of treatment, and time with elevated body temperature (> 37.0°C) (area under the curve) during the first 24 hours and the first five days.

Patients could be included if they had

• acute ischemic stroke in the anterior circulation
• a body temperature between 36.0°C and 39.0°C,
• computed tomography (CT) scan that was compatible with acute ischemic stroke
• a focal deficit without rapid improvement
• and a possibility to start treatment within 24 h after stroke onset.

Exclusion

• Patients with a posterior circulation stroke were not included because occasional patients could have severe disturbances of temperature regulation through involvement of the hypothalamus.

Results…

Without intervention, the tympanic temperature increases about 0.4 °C  in first 8-10 hours after recording, which places us at 8 to 34 hours after the stroke. After about 24 hours the temperature levels off to about 0.2 °C  above the starting point.

The Barthel Index is a measure of how much a patient needs help with aspects of daily life such as bathing and using the toilet.  A score of 20 is functional independence.  TheModified Rankin Score is also measures the functional impact of a stroke  A score of 2 indicates not back to normal but able to live independently.  A score of 5 indicates bedridden.

1. The antipyretic efficacy and safety of propacetamol compared with dexibuprofen in febrile children: a multicenter, randomized, double-blind, comparative, phase 3 clinical trial
   Seung Jun Choi, Sena Moon, Ui Yoon Choi, Yoon Hong Chun, Jung Hyun Lee, Jung Woo Rhim, Jin Lee, Hwang Min Kim, Dae Chul Jeong BMC Pediatr. 2018; 18: 201. [PMC free article]
2. Dippel, Diederik W J et al. “Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690].” BMC cardiovascular disorders vol. 3 (2003): 2. doi:10.1186/1471-2261-3-2 [PMC free article]