Article, Emergency Medicine

Hemodynamic changes in patients with influenza A after propacetamol infusion in the emergency department

a b s t r a c t

Objectives: Recently, there has been an emerging clinical data suggesting that intravenous propacetamol may cause iatrogenic hypotension. The primary objective of this study was to evaluate hemodynamic changes after propacetamol infusion in the emergency department (ED) with the patients of influenza A. Secondary objective was to assess the incidence of propacetamol-induced Significant hypotension and to evaluate factors associated with this adverse effect by comparing two groups of patients with or without a significant reduction in Blood pressure .

Methods: We retrospectively reviewed the medical records of the patients with laboratory-confirmed influenza A who received intravenous propacetamol for the control of fever in the ED during the 2015-16 influenza season. Results: 101 patients of influenza A were included in this study. Overall, all the vital signs including BP, pulse rate and body temperature recorded after propacetamol administration were lower than the pre-infusion values. A significant reduction in BP was observed in 30 (29.7%) patients and 6 (20%) of them required crystalloid infusion. Interestingly, pre-infusion BPs were higher in the group of propacetamol-induced significant hypotension, yet there was no difference in post-infusion BPs between the groups.

Discussion: To our knowledge this is the first study on the effect of intravenous propacetamol in the ED patients with influenza A infection. We hypothesized that the group with a significant reduction in BP could have higher sympathetic tone, consequently showing higher pre-infusion BPs and pulse rate. And there was no difference in post-infusion BPs because baroreflex homeostasis could compensate further decrease in BPs.

(C) 2017


During the 2015-16 influenza season, N 665,000 specimens tested were positive for influenza virus in the United States [1]. In the absence of specific treatments for influenza, management has been focused on the relief of associated symptoms such as fever or myalgia. Guidelines recommend that antipyretic treatment with paracetamol is routinely administered to adults who develop an influenza-like illness during an epidemic or pandemic [2]. This recommendation is qualified by accu- mulated experience which suggests that it may help and is unlikely to be harmful [3].

Paracetamol (acetaminophen) is a selective inhibitor of cyclooxy- genase-2, which has been used as an analgesic and antipyretic agent since 1950 [4]. A prodrug of paracetamol, propacetamol shows addi- tional benefits of being water soluble and convertible by plasma ester- ase [5]. A 2 g dose of propacetamol yields 1 g paracetamol [6]. This intravenous (IV) formulation, propacetamol is widely used in the

* Corresponding author at: Department of Emergency Medicine, Inha University Hospital, 7-206, Shinheung-Dong, Jung-Gu, Incheon 400-711, Republic of Korea.

E-mail address: [email protected] (A. Durey).

emergency department (ED) because it reaches peak plasma concentra- tions faster (15 min vs. 2 h) than oral paracetamol [7].

Recently, there has been an emerging clinical data suggesting that IV propacetamol may cause iatrogenic hypotension. Even though there has been little scientific evidence in the ED regarding this adverse effect, hy- potension associated with the IV administration of propacetamol is well known to ED nurses and doctors. Therefore, in this present study, we evaluated the hemodynamic effects of IV propacetamol in ED with pa- tients who have laboratory-confirmed influenza A infection. We evalu- ated hemodynamic changes after its administration and attempted to identify clinical factors related to significant reduction of blood pressure (BP) as well.


Study design

We retrospectively reviewed the medical records of the patients with laboratory-confirmed influenza A who received IV propacetamol for the control of fever in the ED during the 2015-16 influenza season (August 1, 2015-August 31, 2016).

0735-6757/(C) 2017

2 H.J. Lee et al. / American Journal of Emergency Medicine 36 (2018) 14

The primary objective of this study was to evaluate hemodynamic changes after administration of IV propacetamol in the ED with the pa- tients of influenza A. Secondary objective was to assess the incidence of

Table 1

Comparison of baseline characteristics and hemodynamic parameters between patients with and without significant reduction in blood pressure.

propacetamol-induced significant hypotension in these patients and to evaluate factors associated with this adverse effect by comparing two groups of patients, one with a significant reduction in BP after

Total patients (n

= 101)

Significant reduction in BP p value No (n = 71) Yes (n = 30)

propacetamol infusion and the other without it.

Study population

This study was conducted in a university hospital in Korea which is a tertiary hospital with 54,000 patients according to an annual census of ED visits. We included normotensive febrile patients with laboratory- confirmed influenza A. Patients whose age >= 16 years, initial BPs were

>= 120/80 mm Hg, and tympanic temperature was >= 38 ?C were enrolled.

Influenza A was diagnosed with a rapid influenza antigen kit; nasopha- ryngeal swabs were obtained using Copan Floq swabs and the presence of influenza antigens was investigated using the BD Directigen Flu A + B

Age, yr 43.6 +- 16.3 43.2 +- 16.4 44.4 +- 16.3 0.741

Male sex, no. (%) 37 (36.6) 28 (39.4) 9 (30.0)

Onset of fever, no. (%)

b24 h 60 (59.4) 44 (61.9) 16 (26.6)

24 h <= b 48 h 24 (23.7) 16 (22.5) 8 (33.3) 0.420

>= 48 h 17 (16.8) 11 (15.4) 6 (35.2)

Dose of propacetamol, no. (%)

1 g 26 (25.7) 17 (23.9) 9 (30.0) 0.526

2 g 75 (74.2) 54 (76.0) 21 (70.0)

Comorbid conditions, no. (%)

Hypertension 8 5 3 0.691

(Directigen; Becton-Dickinson, Sparks, MD).

Diabetes mellitus





Propacetamol (Denogan(R), Propacetamol hydrochloride 1 g/ample,

Heart disease





Young-Jin Medical, Korea) was infused over 30 min after mixing it






with 100 mL of 5% dextrose water or normal saline. Considering the du- ration of infusion and a previous study by Boyle et al. who provided ev-


Liver disease 6 5 1 0.631

Renal disease 0 0 0

idence that IV paracetamol can cause reduced BP up to 60 min [8], we included patients whose follow-up vital signs within 90 min after the order of IV propacetamol in the ED were recorded.

Data collection and outcomes

Neurodegenerative disease Hematologic disease Rheumatologic disease

4 3 1 1.000

2 2 0 1.000

4 4 0 0.315

We collected data on patient demographics, comorbidities and labo- ratory results. Duration of fever upon arrival at the ED were grouped

Cancer 5 3 2 0.631

Vital signs on presentation


into three categories: duration b 24 h, 24 h <= duration b 48 h, and dura-

SBP, mm Hg 134.9 +- 20.0 124




b 0.0001

tion >= 48 h. Dose of propacetamol and any interruption of infusion were recorded. Vital signs including systolic blood pressure (SBP), diastolic

blood pressure (DBP), pulse rate (PR) and body temperature (BT)

DBP, mm Hg 77.8 +- 10.2 76 (70-80) 86 (80-90) b 0.0001???

PR, beats/min 100.2 +- 17.1 99.0 +- 17.8 102.9 +- 15.4 0.307

RR, breaths/min 18.8 +- 1.8 18 (18-20) 18 (18-18) 0.298

were collected. We defined the vital signs at the time of ED presentation as baseline (pre-infusion) parameters. Follow-up vital signs within 90 min after the order of IV propacetamol were collected as post-infu- sion hemodynamic parameters. If there were more than one follow-up

Body temperature,


Laboratory findings Leukocyte count, cells/mL

38.6 +- 0.5 38.6


7518 +- 8814 6075








vital signs, the lowest values were recorded. A significant reduction in BP were defined as SBP b 90 mm Hg or DBP b 60 mm Hg, or a drop in

Hemoglobin, g/dL 13.2 +- 1.9 13.3





SBP >= 30 mm Hg. For the patients with significant reduction in BP, addi-

platelet counts,


184.5 +- 55.9 170.5





tional treatments were recorded such as a fluid bolus or use of vasopressor.

CRP, mg/dL 2.9 +- 4.1 1.88







14.1 +- 4.8 12.6





Data analysis

Urine specific gravity

1.021 +-







In the preliminary analyses, summary statistics are presented as means with standard deviations or medians with interquartile ranges for continuous variables, and percentages for categorical variables. A paired t-test was used for comparisons of pre- and post-infusion vital signs. Categorical variables were compared using the chi-square test or Fisher exact test, as appropriate. Continuous variables were com- pared using the nonparametric Wilcoxon Signed Rank Test or the Mann-Whitney U test. All statistical analyses were performed using MedCalc for Windows, version 15.0 (MedCalc Software, Ostend, Belgium).


Patient characteristics

During the study period, 101 patients of influenza A were included in this study. The baseline characteristics of the patients are shown in Table 1. 37 patients (36.6%) were men and the median age was 43.6

+- 16.3 years. 59.4% of patients visited ED within 24 h since fever had

*p b 0.05, **p b 0.01 ***p b 0.001.

developed. Given propacetamol Dose ranged from 1 g (25.7%) to 2 g (74.2%) and infusion was never interrupted. As for comorbid conditions, the percentages were b 8% for each one.

Hemodynamic changes after IV propacetamol

Overall, all the vital signs including BP, PR and BT recorded after propacetamol administration were lower than the pre-infusion values: SBP changed from 134.9 +- 20.0 mm Hg to 116.6 +- 14.1 mm Hg (p b 0.0001), and DBP changed from 77.8 +- 10.2 mm Hg to 72.8 +-

10.2 mm Hg (p = 0.001) after IV paracetamol. The PR following propacetamol injection decreased from 100.2 +- 17.1 beats/min to

88.1 +- 12.8 beats/min, and BT improved from 38.6 +- 0.5 ?C to 38.0 +-

0.5 ?C (p b 0.0001).

H.J. Lee et al. / American Journal of Emergency Medicine 36 (2018) 14 3

Significant reduction in BP

A significant reduction in BP was observed in 30 (29.7%) of the 101 patients. Among those with propacetamol-induced hypotension, 6 (20%) required crystalloid infusion with the volume ranging from

0.3 L to 0.8 L, and none of them required use of vasopressor. Changes in hemodynamic parameters after IV propacetamol in the two groups with and without a significant reduction in BP were shown in Fig. 1.

Factors associated with propacetamol-induced hypotension

To evaluate factors associated with propacetamol-induced hypoten- sion, we compared the two groups based on baseline characteristics (Table 1). None of the baseline characteristics or laboratory results were independently associated with propacetamol-induced hypoten- sion including duration of fever and dose of propacetamol. However, in- terestingly, baseline SBP and DBP were significantly higher in the group with propacetamol-induced hypotension: 148 (140-164) mm Hg vs. 124 (119-136) mm Hg and 86 (80-90) mm Hg vs. 76 (70-80) mm

Hg, respectively (p b 0.0001). Whereas, there was no difference in post-infusion BPs between the group.


The incidence of propacetamol-induced hypotension in this study is consistent with the results of previous studies. Researchers reported in- cidence ranging from 13% [9] to 59% [8]. This large variation in incidence could be due to different definition of hypotension across the studies. For instance, Boyle et al. determined a drop >= 15% of the baseline SBP to be clinically significant [9], yet de Maat et al. defined a decrease of at least 10 mm Hg [10]. Meanwhile, Cantais et al. defined a decrease in the mean arterial pressure >= 15% in his Multicenter cohort study [11].

Not only different definitions of hypotension between previous studies, we assume one more confounding factor could possibly prevent from drawing a consistent conclusion. Given that most of those studies were performed with critically ill patients with the purpose of control- ling fever, the researchers could have overlooked the differences that may exist between the causes of fever. Fever can develop not only from infection, but also there are non-infectious causes which could result in fever in the setting of intensive care unit. Even within the infec- tious causes, different mechanism of fever could be present according to the sites of infection or the pathogens. In fact, there was a retrospective study which analyzed 1507 patients in the ED recently, and it showed biliary tract infection and bacteremia were more common in the group with significant hemodynamic alteration after IV propacetamol infusion [12].

Therefore, we limited our study cohort to patients who were con- firmed as influenza A in the ED to minimize these confounding factors which could have an influence on the hemodynamics. Overall, both SBP and DBP showed significant reduction, and fever was improved by the infusion of propacetamol, which is consistent with the other report in acutely febrile adults with upper respiratory tract symptoms which showed a significant reduction in temperature of 1.08 ?C [13]. Our re- sults also showed that there was no relation between hemodynamic changes and the antipyretic action of propacetamol.

Furthermore, we compared two groups of patients, one with signif- icant reduction in BP after propacetamol infusion and the other without it, based on the criteria of post-infusion SBP b 90 mm Hg, post-infusion DBP b 60 mm Hg or a drop in SBP >= 30 mm Hg. Interestingly, both of pre- infusion SBP and DBP were higher in the group with propacetamol-in- duced hypotension even though there was no difference in percentages of preexisting hypertension between the groups. More interestingly, there were no significant differences in SBP or DBP after propacetamol infusion between two groups.

There have been studies which have investigated possible patho- physiologic mechanisms underlying paracetamol-induced hypotension even though they remain rather hypothetical. Boyle et al. demonstrated paracetamol to be associated with increased skin blood flow using laser Doppler flowmetry, suggesting peripheral vasodilation [9]. The investi- gators suggested that a transient systemic vasodilation and a subse- quent reduction in systemic vascular resistance could be mechanisms for the transient decreases in BP in paracetamol-induced hypotension. Recent data, however, suggested that its pharmacological value may be greater in some clinical settings compared to others.

Given that skin blood flow is controlled by both vasoconstrictor and vasodilator sympathetic nerve, we hypothesized that the group with significant BP reduction in our study could have higher sympathetic tone from the beginning of presentation to the ED, consequently show- ing higher Baseline BPs and PR than the other group. Therefore, they showed more significant propacetamol-induced hypotension, as propacetamol reduces sympathetic tone by its analgesic action [14], which was added to the expected hemodynamic effect of propacetamol. This would also explain the trend to a reduction of PR despite statistical- ly insignificance. Considering there was no difference in baseline BT be- tween the group, higher sympathetic tone could be related to higher perception of discomfort caused by influenza A infection, which de- pends on individual threshold rather. Other studies which IV paraceta- mol-induced hypotension has been produced where fever has not been specified or in afebrile Patients support this theory [15,16].

Regarding to no difference in post-infusion BPs between the groups,

we hypothesized that compensatory mechanism by baroreflex homeo- stasis responds well to acute BP changes in our patients and prevents

Fig. 1. Flowchart of patients who were enrolled in the study. The tables show initial vital signs and follow-up after infusion of propacetamol. SBP = systolic blood pressure, DBP = diastolic blood pressure, PR = pulse rate, BT = body temperature.

4 H.J. Lee et al. / American Journal of Emergency Medicine 36 (2018) 14

further decrease in BP by increasing cardiac output. This theory is sup- ported by the study conducted in healthy volunteers, which showed a relative increase in cardiac index after paracetamol administration [17]. That implies that in influenza A patients, both baroreflex and car- diac reserve were as intact as healthy volunteers. Because in the setting of critical illness, where baroreflex homeostasis may be dysfunctional [18], it is plausible that a major change in skin blood flow following paracetamol administration could result in further reduction in BP. Moreover, these hemodynamics derangements may have more impact in the patients who are already hemodynamically compromised, which supported by the study of Krajcova et al. which showed a de- creased cardiac index in intensive care patients after IV paracetamol [15].

Our present study had important limitations. The data were retro- spectively obtained from electronic medical records; hemodynamic monitoring was not protocol-based and there was no control group that did not receive propacetamol. However, to our knowledge this is the first study on the effect of IV propacetamol in ED patients with influ- enza A infection. As mentioned, we believe further studies are required to be refined depending on the causes of fever to clarify hemodynamic effects of propacetamol in different settings.


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