* Corresponding author.

E-mail addresses: [email protected] (J. Fang), [email protected] (C. Chen), [email protected] (H. Cheng), [email protected] (R. Wang), [email protected] (L. Ma).

http://dx.doi.org/10.1016/j.ajem.2017.03.039

0735-6757/(C) 2017

Results 1532

Description of studies and quality assessment 1532

The change in body temperature at 24 h from the start of treatment 1532

Effect on functional outcome (mRS <= 2) 1533

Competing interests statement 1534

Funding 1534

References 1534

Introduction

Many patients with acute stroke have fever or subfebrile body tempera- tures, and it has some association with case fatality and poor functional out- come [1-4]. Every degree increase of body temperature within 12 h of stroke onset indicates that the odds of poor outcome can be doubled [5]. Clinical outcome is associated with body temperatures measured in the first 12- 24 h of stroke onset, but has no connection with initial Stroke severity, Lesion volume, age, sex, and stroke type [6-8]. And this relation may be mediated by the increased metabolic demands, an increased release of neurotransmit- ters, increased free-radical production, breakdown of the blood-brain barri- er, and increased proteolysis caused by high body temperature [9].

Previous studies revealed that mitigation of even mild spontaneous hyperthermia had a favorable influence on neuroprotection in animal models of stroke, and was beneficial to have reduced infarct volume and improved functional outcome [10]. Reduction of body temperature and prevention of fever may have important potential in improving functional outcome after stroke onset. Indeed, guidelines for the treat- ment of acute ischaemic stroke and intracerebral haemorrhage have recommended antipyretic drugs to reduce body temperature in patients with fever or body temperature above 37.5 ?C [11,12].

It is widely accepted that paracetamol (acetaminophen) is one of the most commonly used antipyretic drugs and is featured by potent inhibition of prostaglandin production in the CNS for reduction of body temperature [13-15]. In addition, paracetamol almost has no side-effects in doses up to 6 g per day [16]. One study reported that patients with acute ischaemic stroke obtained paracetamol at a daily dose of 6 g within 4 h, and the body temperature was reduced 0.3 ?C within 4 h from start of treatment [17].

Clinically, several trials have focused on paracetamol (acetamino- phen) for body temperature reduction in acute stroke. However, the ev- idence base for acetaminophen’s reputation is not entirely obvious. The aim of this paper was to investigate the efficacy of acetaminophen in pa- tients with acute stroke through a systematic review and meta-analysis.

Methods

Study eligibility criteria (PICOS)

Participants (P)

Patients with ischaemic stroke or intracerebral haemorrhage and body temperature N 36 ?C.

Intervention (I)

Intervention: paracetamol (acetaminophen).

Control (comparison) (C)

Control: placebo.

Outcome (O)

Primary outcomes:

? body temperature reduction at 24 h from the start of treatment

? body temperature at 24 h from the start of treatment

? body temperature reduction after 5 days from the start of treatment

Secondary outcomes:

? functional outcome (Modified Rankin scale, mRS <= 2)

? adverse events

Study design (S)

The studies selected for analysis were either randomized controlled trials (RCT) or controlled clinical trials (CCT). We did not use these terms as a restriction when searching the database, but filtered the arti- cles by reading the abstract (and when necessary, the full-length article, or by contacting the authors) in order to classify the studies.

Fig. 1. Flow diagram of study searching and Selection process.

Search strategy

Ischaemic or intracerebral haemorrhage stroke

Ischemic or hemorrhagic stroke

Ischemic stroke

Medline, SCOPUS, Google Scholar, EMBASE, Springer, and Science Di- rect were searched till April 2016 using keywords of paracetamol/acet- aminophen, acute ischemic stroke/intracerebral haemorrhage without limitation of language, and the references of eligible studies were also searched. When the full length article was not available from the data- bases, we contacted the author asking for it.

Stroke type

Ischemic stroke

Ischemic stroke

Quality assessment in individual studies

Methods and dosage

Matched placebo

Matched placebo Matched placebo Matched placebo Matched placebo

Two reviewers independently performed data extraction and quality assessment. Four items were used to assess the quality of included stud- ies based on Cochrane Collaboration recommended criteria: Adequate sequence generation, Allocation concealment, Blinding, and addressing the problem of incomplete outcome data.

Body temperature at start of treatment (?C)

36.9 +- 0.6

(mean +- SD)

37.0 +- 0.5

(mean +- SD)

36.95 +- 0.45

(mean +- SD)

36.6 (36.0-37.4)

(mean/range)

37.2 +- 0.51

(mean +- SD)

Risk of bias across studies

The selective reporting within studies was assessed by answering whether the results were fully reported as the study was prespecified.

NIHSS scores

7 (0-30)

(median/range)

14 +- 11

(mean +- SD) 11/9

(mean/median)

5.5 (2-24)

(mean/range)

6.8 +- 5.4

(mean +- SD)

Statistical analysis

Statistical analysis was carried out using RevMan 5.3 software. The het- erogeneity test for the included studies was applied and p values of b 0.05 were considered as statistical significance. The fixed effect model was ap- plied. G +- 1.96S_G (G-Geometric mean, S_G-standard error of geometric mean) was used to describe continuous variables and Risk Ratios (RR) and their 95% confidence interval (95%CI) were used for binary variable.

placebo group

Number

Age

70.1 +- 13.0

(mean +- SD)

65 +- 10

(mean +- SD) 67 +- 18

(mean +- SD) 71 (55-88)

(median/range) 68 +- 15

(mean +- SD)

Results

703

25

19

22

24

Description of studies and quality assessment

Methods and dosage

Daily dose of six times 1 g for 3 days

1 g 6 times daily

during 5 days

650 mg every 4 h for

24 h

1 g 4 times daily for

5 days

1 g 6 times daily

during 5 days

Fig. 1 shows the diagram of meta-analysis search strategy and selection process. In all, 937 studies in the first search seemed to be potentially rel- evant. 302 duplicates were removed. A total of 627 studies were excluded (irrelevant subjects) on the basis of initial screening of the titles and/or ab- stracts. And 2 protocols and 1 brief communication were removed. The re- maining 5 articles were included in the meta-analysis [16,18-21].

Body temperature at start of treatment (?C)

36.9 +- 0.6

(mean +- SD)

Table 1 showed the characteristics of the included studies. Five trials were conducted and they were all RCT [16,18-21]. National Institutes of Health Stroke Scale scores were used to indicate the stroke severity, and its mean (or median) ranged from 5 to 18. In two trials, acetaminophen group patients obtained 1 g 6 times daily during 5 days [16,19], and one study re- vealed that acetaminophen group patients obtained 1 g 4 times daily for 5 days [21]. While one trial reported that acetaminophen group patients got 1g6 times daily for 3 days [18]. In another trial, acetaminophen group patients obtained 650 mg every 4 h for 24h [20]. All of their placebo group patients re- ceived matched placebo for comparison. Two included studies reported pa- tients with ischaemic or intracerebral haemorrhage stroke [18,21], and three included studies reported patients with ischaemic stroke [16,19,20].

Acetaminophen group

NIHSS scores

69.6 +- 13.0

(mean +- SD)

6 (0-28)

(median/range)

69 +- 16

(mean +- SD) 70 +- 13

(mean +- SD)

69.5 (48-82)

(median/range) 69 +- 13

(mean +- SD)

18 +- 16

(mean +- SD) 14/15.5

(mean/median) 5 (2-14)

(mean/range)

8.8 +- 5.6

(mean +- SD)

37.3 +- 0.5

(mean +- SD)

36.96 +- 0.64

(mean +- SD)

36.6 (36.0-37.2)

(mean/range)

37.1 +- 0.47

(mean +- SD)

Table 2 showed the quality assessment of the included studies. After contacting the author, all articles got “yes” in “Adequate sequence gen- eration”, “Allocation concealment” and “Blinding” [16,18-21].

Table 1

Characteristics of included studies.

Age

Primary outcomes of the effects of intervention

Number

697

26

20

20

26

The change in body temperature at 24 h from the start of treatment Two of the five included studies reported the body temperature reduc- tion at 24 h from the start of treatment [16,19]. Fig. 2 showed the change of body temperature in experimental (acetaminophen) group compared with the control groups receiving matched placebo. The difference in re- duction in body temperature at 24 h after start of treatment between

No.

Author

1

den Hertog 2009

Dippel 2003

Kasner 2002

Koennecke 2001

Dippel 2001

2

3

4

5

Table 2

Quality assessment of included studies.

RCT: randomized controlled trial, CCT: controlled clinical trial, Y: yes, N: no, U: unclear.

acetaminophen and placebo was -0.3 (95% CI: -0.52 to -0.08), with statistical significance (P = 0.007).

In another trial, the data of body temperature at 24 h from the start

of treatment were provided [20]. Fig. 3 demonstrated body temperature of patients in experimental (acetaminophen) group compared to the control (placebo) group at 24 h. In the results, the fixed effect model was applied, the pooled RR and its 95% CI were – 0.22 (- 0.29,

-0.15), with statistical significance (P b 0.00001).

The change in body temperature after 5 days from the start of treatment

In the five included studies, only two trials reported the body temperature reduction after 5 days from the start of treatment [16,19]. Fig. 4 showed the change of body temperature in experimental (acetaminophen) group compared with the control (placebo) group after 5 days. In the results, the fixed effect model was applied, and the difference in reduction in body tem- perature at 24 h after start of treatment between acetaminophen and placebo was 0.04 (95% CI: -0.20 to 0.29), with no statistical significance (P = 0.73).

Secondary outcomes

Effect on functional outcome (mRS <= 2)

The modified Rankin Scale was known as a reliable method for the assessment of handicap. 0 score indicated the absence of symptoms and 5 scores represented severe disability [22]. The number of patient with mRS <= 2 was used to evaluate the functional outcome in all the five included studies. Five included studies provided the data regarding

the functional outcome of patients between experimental (acetamino- phen) group and control (placebo) group. In the results, Fig. 5 demon- strated that the fixed effect model was applied, the pooled RR and its 95% CI were 1.08 (0.88, 1.32), with no statistical significance (P = 0.45).

Adverse events

Serious adverse events were defined as any potentially life-threatening deterioration in health status within the study-monitoring period. They mainly included pneumonia, urinary tract infection, sepsis, liver function dis- turbance (aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (AF), or total bilirubin levels exceeding twice the local Upper limit of normal), Liver failure, gastrointestinal haemorrhage, any Neurological deterioration (i.e. a decrease in level of consciousness of more than one point on the Glasgow Coma Scale, or an increase of two or more points on the NIHSS) and death etc. [16,18-21]. In the results, Fig. 6 demonstrated that the difference of serious adverse events between acet- aminophen and placebo was 0.86 (95% CI: 0.62 to 1.2), with no statistical sig- nificance (P = 0.27).

Discussion

It was believed that fever or the increase in body temperature had prominent effects on cell damage in acute stroke [23-25]. One retrospec- tive study reported that fever and modeST elevations of body tempera- ture (between 37.5 ?C and 38.0 ?C) could worsen residual symptoms of stroke [20]. And temperature was found to significantly influence initial stroke severity, infarct size, mortality, and morbidity [5]. In another trial, patients with fever in the first 7 days after stroke showed 3.4-fold higher

Fig. 2. Meta-analysis of the change in body temperature at 24 h from the start of treatment. Vertical line indicated no difference between the compared two groups (acetaminophen vs. placebo). Squares indicated point estimates of Risk Ratio (RR) in each individual study, the size of the squares indicated the weight of the corresponding study in the meta-analysis, 95% CIs of point estimates were shown by horizontal lines. Pooled RR and its 95% CI were shown by diamond shape. (It was the same in Figs. 3-6).

Fig. 3. Meta-analysis of body temperature at 24 h from the start of treatment.

Fig. 4. Meta-analysis of the change in body temperature after 5 days from the start of treatment.

Fig. 5. Meta-analysis of functional outcome (mRS <= 2).

Fig. 6. Meta-analysis of serious adverse events including pneumonia, urinary tract infection, sepsis, liver function disturbance, liver failure, gastrointestinal haemorrhage and death etc.

odds of poor outcome than those without fever [26]. This study aimed to determine the efficacy of acetaminophen on body temperature reduc- tion and outcome through meta-analysis.

The meta-analysis of the body temperature reduction at 24 h from the start of treatment showed an importantly statistical significance between acetaminophen group and placebo group (P = 0.007). This was consistent with the meta-analysis of the body temperature at 24 h from the start of treatment, in which significant difference was found between these two groups (P b 0.00001). These implied that acetaminophen had substantially favorable influence on body temperature reduction in patients with acute stroke in the first 24 h. However, when analyzing the body temperature re- duction after 5 days from the start of treatment, there was no significant difference between acetaminophen group and placebo group (P = 0.73), revealing that acetaminophen has no obvious effect on body temperature change compared to placebo after 5 days. In addition, acetaminophen was not associated with a significantly improved functional outcome as evi- denced by mRS <= 2 analysis (OR = 1.08; 95% CI = 0.88 to 1.32; P = 0.45). In terms of the adverse events, there was no significant difference between acetaminophen group and placebo group (P = 0.27), and the pooled RR and its 95% CI were 0.86 (95% CI: 0.62 to 1.2). These indicated that the adverse events of acetaminophen group were relative less than placebo group, but this effect was not statistically significant. Death and pneumonia occurred with the greatest frequency, and were more seri-

ous than other serious adverse events.

The quality assessment showed that in general, these five clinical trials had relatively good quality. But there are several limitations of our study: firstly, the methods and dosages of acetaminophen were different. Second- ly, the total included trials were limited and only five studies met the inclu- sion criteria. Thirdly, the data regarding body temperature reduction or body temperature at 24 h from the start of treatment were not provided in the some included trials.

Conclusions

Acetaminophen was found to have some potential in body temperature in patients admitted with acute stroke, but showed no important influence on improving functional outcome and reducing adverse events of patients.

Competing interests statement

The authors declare no conflict of interest.

Funding

None.

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