a b s t r a c t

Objective: Fever is one of the frequent reasons for admission to the emergency department. Studies comparing oral forms of Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol with intravenous (IV) forms for fever are common in the literature. Our study is the first emergency department study comparing IV forms of ibuprofen and paracetamol in the treatment of febrile patients.

Methods: A randomized, double-blind study was conducted in a tertiary university emergency department for a six-month period. Patients aged 18-65 years who had a fever of >=38.0 ?C were included. Patients were adminis- tered 400 mg of IV ibuprofen and 1000 mg of IV paracetamol. The primary aim of the study was to determine whether there was a difference in the effect of the two drugs on fever. The secondary aim was to investigate whether there was a difference in terms of Numeric rating scale (NRS) measurements and the need for additional antipyretic therapy.

Results: A total of 200 people, 100 of whom were female, were included in the study. The mean age was 30.77 +-

10.61 years. The mean initial temperature for ibuprofen and paracetamol was 38.79 +- 0.470 ?C and 38.70 +-

0.520 ?C, respectively, with no difference noted between the groups (p = 0.380). It was found that both drugs significantly provided fever control in the first 30 min (p < 0.001), with no difference between them in terms of fever reduction (p = 0.980). Both drugs significantly improved in accompanying symptoms, although both drugs did not show superiority to each other (p = 0.0226). When evaluated in terms of a need for rescue med- ication, no significant difference was found between the two drugs (p = 0.404). No side effects were encountered during the study.

Conclusion: In adult age group patients admitted to the emergency department with high fever, the IV forms of 1000 mg paracetamol and 400 mg ibuprofen effectively and equally reduce complaints, such as fever and accom- panying pain. They can be effectively used as each other’s rescue medicine and as an alternative to each other in patients with comorbid diseases.

(C) 2021

1. Introduction
   1. Background

Fever is among the common reasons for pediatrics and adults pres- ent to the emergency department [1]. The American College of Critical Care Medicine and Infectious Disease Society of America defined fever as 38.3 ?C [1,2]. In other studies in the literature, fever is considered to be 38.0 ?C, 38.1 ?C, and 38.5 ?C [3-6]. Salicylates (e.g., sodium salicylate and acetylsalicylic acid), ibuprofen, and other non-steroidal anti-

* Corresponding author at: Ege University, Faculty of Medicine, Emergency Department, 35100 Izmir, Turkey.

E-mail addresses: [email protected] (O. Can), [email protected] (G.S. Kiyan), [email protected] (S. Yalcinli).

inflammatory drugs (NSAIDs) and para-aminophenol derivative acetominophen (paracetamol) are used to treat high fever [3,6-8].

Studies on fever have been conducted more frequently because of the more typical observation of fever in childhood, anxiety of the par- ents, and decrease in the seizure threshold. Moreover, the effectiveness of alternative oral therapy as well as paracetamol and ibuprofen and their combinations were compared to reduce fever. It has been observed that both drugs are effective and safe in fever response, and success in- creases with combined therapies [9-11].

Oral antipyretics are widely used in pediatric patients treated in hos- pitals. However, patients who visit the emergency department for sur- gery or admission to the hospital are not able to tolerate Oral medications and absorption is difficult. The desired therapeutic level cannot be achieved with rectal forms of some drugs, such as acetominophen [10].

It has been shown in previous studies that the 400 mg IV form of ibu- profen is effective in reducing fever [12,13]. In the treatment of fever,

https://doi.org/10.1016/j.ajem.2021.02.057

0735-6757/(C) 2021

the intravenous form of ibuprofen has been comparatively studied with placebo in intensive care patients (critical and noncritical patients), burn patients, and patients with acute malaria [3,13,14].

In studies comparing the intravenous and/or oral forms of paraceta- mol with placebo, the IV form was found to be effective and safe and could be preferred in patients who could not take orally and required rapid effect [15-17].

However, no studies were found comparing the efficacy of IV forms of ibuprofen and paracetamol in fever treatment in the emergency department.

• 1. Study protocol

Fig. 1. Numeric rating scale.

• 1. Objectives

The primary aim of this study was to investigate whether there was a difference in the rate of fever reduction between the drugs at 15, 30, 45, and 60 min. The secondary aim was to investigate whether there was a difference in terms of Numeric rating scale between the drugs at 15, 30, 45, and 60 min and the need for additional antipyretic treatment.

1. Material and method
   1. Study design

This was a prospective, randomized, double-blind study. The study was held in the university emergency department of the tertiary level, where approximately 200,000 patients were admitted annually. It was conducted within the guidelines of the 1975 Helsinki Declaration after the approval of a local ethics committee and the Ministry of Health.

• 1. Study population and exclusion criteria

Determination of the population: patients aged 18-65 years were included in the study because drug use was indicated for adults aged

>=18 years, and the etiology and management of fever in patients aged

>65 years were different. The exclusion criteria were as follows: pa- tients with conditions contraindicated for both drugs, such as end- stage chronic renal failure, congestive heart disease, Liver failure, history of gastrointestinal bleeding, presence of malignancy, asthma, chronic obstructive pulmonary disease, presence of bleeding diathesis, preg- nancy, history of analgesic or antipyretic drug use 6 h before admission, history of ibuprofen or paracetamol allergy, shock or resuscitation re- quiring procedure, as well as patients who could not give consent.

• 1. Sample size

The sample size was calculated for the statistical significance of the fever variable, which is the primary purpose of the study, between groups (paracetamol and ibuprofen) and its interaction with time (0, 15, 30, 45, and 60 min).Under the repeated measures ANOVA test using G*Power 3.1.9.2 software and the correlation among ? = 0.05, f = 0.10 (small effect size), and repeated measures with 95% power was taken as 0.5, a total of 188 individuals, 94 individuals in each group, was found to be sufficient. However, considering the possibility of missing observations, 200 individuals were determined as the sample size.

• 1. blindness“>Randomization and blindness

A randomization scheme was created by the study coordinator to equal the number of drug groups using a simple random method. Case report forms were numbered. Patients included in the study were shown, the number of the case report form filled by the assistant re- searcher to the other researcher, and the corresponding drug was pre- pared in the randomization scheme. In this way, double blindness of both the patient and the assistant researcher who measured the drug ef- fect was achieved.

Patients with fever of >38 ?C by tympanic route who presented to the emergency department were reported to the emergency physician. Our clinical experiments and also other studies in the literature [3] sug- gest the definition of fever as a temperature of >=38 ?C. Both drugs were administered in double-blind randomized conditions via a 30-min infu- sion. The patients were followed up for fever at 0, 15, 30, 45, and 60 min, and the accompanying pain levels were evaluated with NRS Fig. 1.

Rescue therapy was applied when the 60th min temperature mea- surements of the patients were >=38 ?C. Since it was known by the assis- tant researcher as to which drug was initially, IV paracetamol was administered as a Rescue drug if IV ibuprofen was initially administered. To ensure patient safety during and after drug infusion, vital signs mon- itoring (blood pressure, pulse, respiration, temperature) of all patients was performed at the beginning, and at 30 and 60 min. The vital signs of the patients were checked at the end of the rescue treatments. Pa- tients were observed for possible drug side effects. The exit treatment of the patient from the emergency department was left to the physician responsible for the follow-up of the patient.

• 1. Outcomes

A decrease in fever response of the patients below 38.0 ?C was con- sidered as sufficient antipyretic, and a decrease in the NRS of three units or more was considered as sufficient analgesic efficiency. It was defined as the need for Rescue medication to stay below 38.0 ?C.

• 1. Statistical method

In this study, numerical data, such as the mean, standard deviation, median, minimum and maximum values, and categorical data using fre- quency and ratio values, were calculated using IBM SPSS Statistics 25.0 software (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp). The level of significance was set at 0.05 in all analysis. The suitability of variables to normal distribution was analyzed using the Shapiro-Wilk test.

Since fever measurement and NRS scores do not show normal distri- bution, the time-dependent change in drug groups was calculated using non-parametric methods, such as the Brunner-Langer model (F1-LD-F1 design) and R 3.5.2 software (R software, version 3.5.2, package: nparLD, R. Foundation for Statistical Computing, Vienna, Austria; http://r-project.org). Categorical data was analyzed using chi-square test. A paired sample t-test was conducted to compare systolic blood pressure decreases over time.

1. Results

Of the 796 patients who were admitted to the emergency depart- ment with high fever during the study period, 596 were excluded owing to reasons, such as additional illness, critical intervention, addi- tional drug requirement that may affect the study, voluntary with- drawal from the study, and missing data (Fig. 2: Patient Flow Chart). Information regarding age, gender, admission to the emergency depart- ment, fever, requirements are presented in Table 1.

Both drugs significantly decreased fever (p = 0.001). However, no difference was observed between the fever reduction efficiency of the

Table 1

Demographic characteristics of the patients

	IV Ibuprofen	IV Paracetamol
Age	30.69 +- 11.15	30.85 +- 10.09
Sex Female	46	54
Male	54	46
Complaint Fever	55	57
Sore Throat	20	27
Myalgia	7	9
Others	18	7

two drugs (p = 0.980) and the time to reach the desired fever response (p = 0.152). Both drugs reduced the patient’s temperature to below

38.0 ?C in the 30th min (Fig. 3).

No statistically significant difference was found between the means of fever and pain levels of drugs (Table 2). Both drugs provided a signif-

1. Discussion

Fig. 3. Fever response over time.

icant and similar reduction in pain scores (p = 0.226). No difference was noted between the drugs in terms of reduction in pain scores and evaluation of pain reduction in terms of time (p = 0.323).

Both drugs yielded a statistically significant reduction in pain (p = 0.001). In the comparison of pain reduction rates of both drugs (3-point difference in the NRS levels), no significant difference was ob- served between the drugs (p = 0.149) (Table 3).

Twenty-one and 26 patients in the groups receiving ibuprofen and paracetamol, respectively, needed rescue medication. When evaluated in terms of the need for rescue medication, no significant difference was noted between the two drugs (p = 0.404). Rescue medication, which was administered as a 30-min infusion in accordance with the study drug procedure, was given to seven patients in the ibuprofen group and four in the paracetamol group. The fever of the patients who took rescue medication (n = 11) decreased to below 38.0 ?C at the 90th min according to the starting time. An additional treatment was not required.

There was a significant difference in the decrease of systolic blood pressure with paracetamol and ibuprofen (p = 0.000). Table 4 presents the measurements of systolic blood pressure differences in time.

No side effects were observed in any of the patients during the study.

In our study, fever response was evaluated in adult patients admit- ted to the emergency department with fever. We found that 400 mg of IV ibuprofen and 1000 mg of IV paracetamol effectively reduced the fever in a short period of 30 min, and no difference was observed be- tween them in terms of fever efficiency. We found that both drugs sig- nificantly reduced pain, and no difference was noted between them in terms of pain reduction effectiveness. After the administration of both drugs, we found that although less in ibuprofen, there is a little need for rescue with each drug, and both drugs can be used effectively as each other’s rescue medication.

Our study is the first study comparing the IV forms of ibuprofen and paracetamol in adult patients admitted to emergency department with fever. In the literature, there are studies comparing the IV forms of para- cetamol with placebo, ketorolac, and metamizole [4,6,15,16,18]. In the studies of Gozzolli and Oborilova et al., an alternative to paracetamol, which has been used for a long time in patients who preferred IV treat- ment, sought for a more effective and rapid response. However, consid- ering the side effects of IV metamizole, IV paracetamol stands out in treatment [4,6]. In our study, it seems that the IV forms of paracetamol and ibuprofen are effective in both fever and pain control as well as both drugs do not cause side effects. The fact that IV use relieves complaints

Evaluated by fever:796

Need additional treatment:60

Without consent:90

Measured below 38 degrees ate at the start of the study:46

Excuded by additional illnes:400

Iv Paracetamol:100

Iv Ibuprofen:100

Included in the study:200

Fig. 2. Patient flow chart.

Table 2

Comparison of fever and NRS levels averages over time

p	Group: 0.980 Time: <0.001 Interaction: 0.529
	Ibuprofen n:100	Paracetamol n:100

Ibuprofen n:100 Paracetamol n:100

Mean	S.D.	Median	Min.	Max.		Mean	S.D.	Median	Min.	Max.
0. th 38.79	0.48	38.80	38.00	40.50		38.73	0.53	38.60	38.00	40.00
15. th 38.46	0.68	38.50	36.30	40.00		38.45	0.76	38.45	36.60	40.50
30. th 38.10	0.70	38.10	35.60	39.40		38.12	0.75	38.05	36.00	40.20
45. th 37.81	0.66	37.80	35.50	39.40		37.87	0.72	37.85	35.60	39.70
60. th 37.54	0.59	37.50	35.90	39.20		37.56	0.69	37.50	35.80	39.40

	Mean	S.D.	Median	Min.	Max.		Mean	S.D.	Median	Min.	Max.
0. th	7.28	1.86	7.50	2.00	10.0		7.61	1.94	8.00	3.00	10.0
15. th	6.16	1.94	6.00	2.00	10.0		6.30	1.99	6.00	1.00	10.0
30. th	5.04	2.04	5.00	1.00	10.0		5.40	2.20	5.00	0.00	10.0
45. th	4.19	2.09	4.00	0.00	10.0		4.44	2.30	4.00	0.00	10.0
60. th	3.33	2.16	3.00	0.00	10.0		3.90	2.39	4.00	0.00	10.0

p Group:0.261 Time:<0.001

Interaction:0.332

Table 3

Comparison of the 3-point decrease in the NRS levels and Need for Rescue Medicine

Three-point decrease in the NRS level Drug

IV Ibuprofen IV Paracetamol

Positive 78 69

Negative 22 31

Pearson Chi-Square p = 0.149 Rescue medicine

Need	21	26
Applied	7	4

in at least 30 min, offers a very significant advantage, especially for crowded emergency department. We believe that the drugs used in our study are fast, effective, and have no side effects. This makes a seri- ous contribution to the literature.

Only one study comparing fever responses of the IV forms of ibupro- fen and paracetamol in children on emergency department admission could be found. In contrast to our study, IV ibuprofen was observed to provide a more pronounced fever reduction in children. This difference may be due to the oral route of paracetamol administration [10].

When evaluated in terms of the time to reach a fever response, it was seen that the 6 and 24-h efficacy was compared rather than the acute period in the literature. In studies investigating the IV forms of ibupro- fen with placebo and oral with iv paracetamol in which an effective fever response was achieved, it was observed that the Duration of action of both drugs began at the 30th min [10,15]. In our study, the time for fever to drop below 38.0 ?C was 30 min as in those studies. Considering

the emergency department crowd, the use of a drug that provides an ef- fective treatment as soon as possible is a relevant goal. In our study, it was found that both drugs were effective in reducing fever over time, al- though were not superior to each other. In a randomized controlled study comparing the effects of oral paracetamol, IV paracetamol, and in- tramuscular ketorolac in emergency department patients, it was re- ported that a significant fever response was yielded for IV drugs at 60 min. It has been reported that those who received additional antibi- otic and fluid therapy in addition to antipyretic therapy and those who received fluid therapy had better fever responses [18]. In our study, al- though the patients were not given additional treatments, the duration of fever reduction was found to be 30 min. Our study sheds light on a significant finding proving that the use of the IV forms of paracetamol or ibuprofen may be more appropriate in a rapid and effective treatment.

Ibuprofen has been known for years and its oral form is a commonly used drug in the treatment of fever and pain in both adult and pediatric patients. There are rare studies on pain and fever, and the IV form of which has just entered the literature [12]. In the treatment of Plasmo- dium flaciparum-related fever associated with fever response, IV ibu- profen was found to be effective in reducing fever compared with placebo in terms of efficacy and safety [3]. In a study comparing fever re- sponse with IV ibuprofen and placebo in burn patients, ibuprofen was found to be effective, although the duration of fever response was eval- uated according to the first 4-h response within the first 24 h [14]. In a study conducted by Morris et al. comparing IV ibuprofen with placebo in a group of critical and noncritical patients, its effectiveness in reduc- ing fever was determined as 400 mg of IV ibuprofen [13]. Our study is the first to compare the IV forms of ibuprofen and paracetamol in terms of fever response in adult emergency department patients. Both drugs are effective and have no superiority to each other. This means that in cases where one drug is contraindicated, the other can easily be used as an alternative. Considering the variety of patients admitted to the emergency department and the high incidence of additional dis- eases, our study provides a proven chance to use these drugs as alterna- tives to each other. This is a significant advantage for emergency department.

Diseases with fever are known to have accompanying symptoms, such as myalgia, sore throat, and headache, and the treatment of these symptoms is done with antipyretic agents. Contrary to the belief that the analgesic properties of NSAID agents are more dominant, the reduc- tion of symptoms was found to be similar in studies comparing oral NSAIDs with paracetamol [5,19]. Eccles reported in his review that oral paracetamol and ibuprofen provided symptom relief [7]. Further- more, our study is relevant because it is the first study confirming that these two drugs equally and significantly reduce symptoms.

In our study, it was determined that both drugs caused a statistically significant decrease in the follow-up blood pressure compared with the initial systolic blood pressure. Although it was statistically significant, there may be situations where there might be no clinical significance. In these cases, minimal clinically important difference is used. For min- imal clinically important difference in the drop in systolic blood

Table 4

Systolic blood pressure change over time

	Paracetamol						Ibuprofen
	Mean +- SD	Mean of diff	SD	95% CI of the	Difference	p	Mean +- SD	Mean of diff	SD	95% CI of the	Difference	p
SBP				Lower	Upper					Lower	Upper
0.th	119.24 +- 13.46						120.13 +- 15.83
15. th	113.53 +- 11.88	5.71	10.35	3.54	7.87	0.00	115.94 +- 14.18	4.18	12.46	1.66	6.71	0.00
30. th	111.08 +- 12.79	8.15	13.49	5.32	10.98	0.00	113.84 +- 14.35	6.29	14.16	3.42	9.16	0.00
45. th	109.66 +- 15.96	9.57	16.45	6.13	13.02	0.00	113.95 +- 14.02	6.17	13.07	3.52	8.82	0.00
60. th	110.9 +- 16.30	8.34	16.26	4.93	11.75	0.00	114.37 +- 13.52	5.76	13.29	3.06	8.45	0.00

pressure, it should be 20 mmHg [20]. However, because the mean de- crease was below the clinical significance value and it did not cause any symptoms in patients, it was not considered significant. These find- ings suggest that hypotensive patients might be monitored during infusion.

1. Limitations

In our study, patients with uncomplicated fever and upper respira- tory tract infection were included. However, the results could be differ- ent if it was performed in more Serious diseases, such as pneumonia, sepsis, severe soft tissue infection, complicated urinary tract infections, and etc. Therefore, drug studies are needed for more serious diseases.

The infusion rate is stated to be 30 min in the ibuprofen prospectus. Although there are studies demonstrating no side effects in 15 min, our study complied with the proprietary information. Paracetamol is ad- ministered at a 15-min infusion. Both drugs were infused for 30 min to ensure blindness. If paracetamol was administered in 15 min, a differ- ence between the fever effectiveness and duration of the drugs may have been observed. Sociocultural level and disease severity are signifi- cant factors in pain assessment. This may have affected the assessment of pain in our study. Although similar complaints were received in our study, there are limitations in terms of pain levels because cryptic tonsil- litis and acute rhinopharyngitis pain are not similar.

1. Conclusion

In adult age group patients admitted to the emergency department with high fever, 1000 mg of IV paracetamol and 400 mg of IV ibuprofen effectively and equally reduce complaints, such as fever and accompa- nying pain. The need for rescue medication is very low for both drugs. Moreover, both can be used effectively as each other’s rescue medicine and as an alternative to each other in patients with comorbid diseases. No side effects were observed owing to the use of either drug.

Funding

This article was supported by Ege University Scientific Research Pro- jects Coordination.

Declaration of Competing Interest

None declared.

Acknowledgements

We thank all of our patients who agreed to participate in our re- search, and also Timur Kose and Semiha Ozgul for their contributions to the statistical analysis. We also express our gratitude to the emer- gency medicine residents; Ece Yilmaz, Emre Ustsoy, Cemile Yurtseven, Gulten Kara, Mevlut Ozden, Eylul Destina Firat, Zisan Andizoglu for their support during the data collection. We are grateful to Ege University Planning and Monitoring Coordination of Organizational Development

and Directorate of Library and Documantaion for their support in editing and proofreading service of this study.

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