Article, Emergency Medicine

Hemodynamic changes after propacetamol administration in patients with febrile UTI in the ED

a b s t r a c t

Objectives: Clinical studies have indicated that transient hypotension can occur after propacetamol administra- tion. This study aimed to analyze the hemodynamic changes after propacetamol administration in patients visit- ing the ED due to febrile UTI. We also examined the incidence of propacetamol-induced hypotension and compared the clinical characteristics of patients with persistent hypotension, defined as requiring additional fluids or vasopressors, to those with transient hypotension.

Methods: A retrospective analysis of the electronic medical records of patients who visited the ED between June 2015 and May 2016, were diagnosed with febrile UTI, and treated with propacetamol, was conducted.

Results: We included 195 patients in this study; of these, 87 (44.6%) showed hypotension. In all patients, signif- icant decreases in systolic blood pressure (SBP; 135.06 +- 20.45 mm Hg vs 117.70 +- 16.41 mm Hg), diastolic blood pressure (DBP; 79.74 +- 12.17 mm Hg vs 69.69 +- 10.96 mm Hg), and heart rate (97.46 +- 17.14 mm Hg vs 90.72 +- 14.90 mm Hg) were observed after propacetamol administration. The basal SBP and DBP were higher in the hypotension than in the non-hypotension group (basal SBP: 144.4 +- 22.3 mm Hg vs 127.6 +- 15.3 mm Hg; basal DBP: 83.3 +- 12.6 mm Hg vs 76.9 +- 11.0 mm Hg). Patients with persistent hypotension had a lower Baseline BP, which was not elevated despite fever, and a higher rate of bacteremia than those with transient hypotension. Conclusions: Although febrile UTI patients treated with propacetamol in the ED showed hemodynamic changes, these changes did not have a large effect on their prognosis. However, in patients who showed bacteremia or a normal initial BP despite fever, the possibility of developing persistent hypotension should be considered.

(C) 2017

Introduction

Oral paracetamol was first sold in the 1950s; an intravenous (IV) for- mulation was introduced in 1985 and began to be sold in the United States in 2010. Since IV paracetamol became commercially available, a post-marketing survey reported that the main indications, in order, are non-specific pain, surgery-related pain, and fever reduction [1].

IV paracetamol is very useful to treat patients who cannot take med- ication orally and has mostly been used to control postoperative pain or accomplish fever reduction in patients in the intensive care unit (ICU). Since this is no different than the use of paracetamol in febrile patients

Abbreviations: ABGA, arterial blood gas analysis; BP, blood pressure; BT, body temperature; CI, confidence interval; DBP, diastolic blood pressure; CRP, C-reactive protein; ED, emergency department; HR, heart rate; ICU, intensive care unit; IV, intravenous; MAP, mean arterial pressure; qSOFA, quick sequential organ failure assessment; RR, respiratory rate; SBP, systolic blood pressure; SD, standard deviation; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; UTI, urinary tract infection.

* Corresponding author at: Department of Emergency Medicine, Inha University Hospital, 27, Inhang-Ro, Jung-Gu, Incheon 22332, Republic of Korea.

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

in the emergency department (ED), IV paracetamol is also sometimes administered to patients who need to fast for other examinations, those who are unable to take medicine orally due to their condition, and those who complain of severe discomfort and require rapid treat- ment to relieve their symptoms.

Because paracetamol is not readily soluble in water, its prodrug propacetamol is often used as a soluble formulation for IV administra- tion. Propacetamol 1 g is equivalent to paracetamol 500 mg; a dose of 1-2 g of propacetamol is typically used for fever reduction [2].

Although IV paracetamol/propacetamol is convenient to administer and effective for fever reduction, hemodynamic changes have been re- ported to occur frequently in febrile patients after administration of these medications. These changes are known to be especially significant in critically ill patients in the ICU, owing to the high degree of severity [3-6].

As propacetamol is frequently used for fever reduction in the ED, transient hypotension after its administration has been observed in fe- brile patients [7]. Patients at risk of hypotension need to be identified to avoid propacetamol-induced hypotension in ED patients. Therefore, in this study, we analyzed the hemodynamic changes after propacetamol administration in patients with no hypotension at

https://doi.org/10.1016/j.ajem.2017.10.054 0735-6757/(C) 2017

presentation and examined the characteristics of patients who devel- oped propacetamol-induced hypotension. Moreover, we compared the clinical characteristics of patients with persistent hypotension, defined as who required further treatment with fluids or vasopressors, to those with transient hypotension.

Methods

Study design and population

A retrospective review of electronic medical records of patients who were diagnosed with a urinary tract infection or acute pyelone- phritis who and were administered IV propacetamol at the ED of our university hospital (a tertiary referral medical institution with 54,000 patients visiting the ED in 2015) from June 2015 to May 2016 was con- ducted. IV Propacetamol (Denogan(R), Propacetamol hydrochloride 1 g/ ampule; Young-Jin Medical, Korea) 1-2 g was administered in normal saline 150 mL.

We included patients with a fever (body temperature [BT], >= 38 ?C) who visited the ED, were diagnosed with a UTI (or acute pyelonephri- tis), were given IV propacetamol, and had an initial systolic blood pres- sure [SBP] of >= 90 mm Hg. Patients who were transferred to another hospital, were self-discharged against medical advice, who had a Do- Not-Resuscitate order, or whose vital signs were not assessed within 90 min of propacetamol administration were excluded from this study. The UTI diagnosis was defined as patients having both 1) new-onset urinary symptoms such as dysuria, frequency, urgency, flank pain, or costovertebral tenderness; and 2) pyuria (white blood cell count

>= 10/mm3 or positive Leukocyte esterase results), a positive urine culture (>= 105 CFU/mL), or findings specific of UTI on computed tomography of the abdomen.

Data collection

The following patient baseline data were collected from the elec- tronic medical records: age, sex, mental changes, presence of chills, ar- terial blood gas analysis (ABGA) results, platelet count, C-reactive protein (CRP), hemoglobin, blood urea nitrogen, serum creatinine, total bilirubin, albumin, urine culture and blood culture results, dosage, length of stay at the hospital (in days), Systemic Inflammatory Response Syndrome , Sequential Organ Failure Assessment score, and quick SOFA (qSOFA) score. Vital signs (SBP, diastolic blood pressure [DBP], heart rate [HR], respiratory rate [RR], and BT) were recorded at presentation to the ED and within 90 min after administration of propacetamol.

Outcomes

The primary outcome of this study was the incidence of hemody- namic changes (changes in SBP and DBP) within 90 min of propacetamol administration, and the extent of these changes.

Secondary outcomes included the clinical characteristics of the pa- tients who showed Significant hypotension after propacetamol administration.

Fig. 1. Flow chart of the study population. DBP, diastolic blood pressure; DNR, Do-Not-Resuscitate; MAP, mean arterial pressure; SBP, systolic blood pressure; UTI, urinary tract infection.

Table 1

Comparison of baseline characteristics and hemodynamic parameters between non-hypotension and hypotension group.

All

Non-hypotension

Hypotension

P valuea

(n = 195)

(n = 108)

(n = 87)

Age, yr

59.4 +- 19.5

55.9 +- 19.1

63.8 +- 19.2

0.005??

Male sex, no. (%)

50(25.6)

27(25)

23(26.4)

0.819

Mental changes, no. (%)

25(12.8)

10(9.3)

15(17.2)

0.097

Chill, no. (%)

104(n = 191, 54.5)

55(n = 105, 52.4)

49(n = 86, 57)

0.526

Vital signs on presentation

SBP, mm Hg

135.1 +- 20.5

127.6 +- 15.3

144.4 +- 22.3

b0.001??

DBP, mm Hg

79.7 +- 12.2

76.9 +- 11.0

83.3 +- 12.6

b0.001???

HR, beats/min

97.5 +- 17.1

95.5 +- 16.6

99.9 +- 17.6

0.070

RR, breaths/min

19.2 +- 2.9

18.8 +- 2.1

19.7 +- 3.5

0.040?

BT, ?C

38.9 +- 0.7

38.8 +- 0.7

39.1 +- 0.8

0.006??

Arterial blood gas

n = 166

n = 89

n = 77

pH

7.46 +- 0.05

7.46 +- 0.05

7.46 +- 0.05

0.514

PCO2, mm Hg

29.4 +- 4.8

29.6 +- 4.8

29.2 +- 4.7

0.562

PO2, mm Hg

82.4 +- 23.2

82.1 +- 18.8

82.7 +- 27.5

0.853

HCO3-, mmol/L

20.6 +- 3.4

20.8 +- 3.2

20.4 +- 3.7

0.436

SpO2, mm Hg

96.4 +- 2.4

96.6 +- 2.0

96.1 +- 2.8

0.231

Leukocyte count, x109 cells/mL

11.8 +- 5.1

11.7 +- 4.9

11.8 +- 1.9

0.833

Hemoglobin, g/dL

12.2 +- 1.9

12.4 +- 1.9

13.2 +- 13.2

0.027?

Platelet, x103/ul

208.6 +- 77.0

210.7 +- 80.0

205.9 +- 73.4

0.665

CRP, mg/dL

9.9 +- 8.3

9.4 +- 8.2

10.5 +- 8.4

0.363

Blood urea nitrogen, mg/dL

17.1 +- 11.3

16.0 +- 8.0

18.4 +- 14.4

0.145

Serum creatinine, mg/dL

1.08 +- 0.74

1.03 +- 0.61

1.16 +- 0.88

0.216

Total bilirubin, mg/dL

0.76 +- 0.50

0.76 +- 0.55

0.77 +- 0.43

0.910

Albumin, g/dL

3.7 +- 0.8

3.6 +- 0.7

3.7 +- 0.8

0.379

Positive urine culture

150 (n = 191, 78.5)

82 (n = 105, 78.1)

68 (n = 86, 79.1)

0.870

E.coli, no.(%)

101(52.9)

55(52.4)

46(53.5)

0.879

Klebsiella, no.(%)

7(3.7)

4(3.8)

3(3.5)

N 0.95

Enterococcus, no.(%)

8(4.2)

5(4.8)

3(3.5)

0.732

Pseudomonas, no.(%)

3(1.6)

2(1.9)

1(1.2)

N 0.95

Enterobacter, no.(%)

4(2.1)

1(1)

3(3.5)

0.329

ESBL E.coli, no. (%)

24(12.6)

12(11.5)

12(14)

0.600

Others, no.(%)

3(1.6)

3(2.9)

0(0)

0.254

Bacteremia

61 (n = 183, 33)

33 (n = 100, 33)

28(n = 83, 33.7)

0.916

Propacetamol Dose,g

1.1 +- 0.4

1.2 +- 0.4

1.0 +- 0.2

0.002??

Hospital days

9.7 +- 12.8

8.3 +- 12.0

11.4 +- 13.6

0.095

SIRS

2.6 +- 0.9

2.5 +- 0.9

2.9 +- 0.8

0.003??

QSOFA

0.3 +- 0.5

0.2 +- 0.5

0.3 +- 0.5

0.147

SOFA

1.5 +- 1.5

1.3 +- 1.4

1.8 +- 1.6

0.053

BT, body temperature; CRP, C-reactive protein; DBP, diastolic blood pressure; ESBL, extended-spectrum beta-lactamase; RR, respiratory rate; SBP, systolic blood pressure; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; qSOFA, quick sequential organ failure assessment.

a P value obtained using t-test, Chi-square test or Fisher exact test.

* p b 0.05.

?? p b 0.01.

??? p b 0.001: significant difference between Non-hypotension and Hypotension.

Definitions

We defined hypotension as 1) SBP <= 90 mm Hg or DBP <= 60 mm Hg or a >= 30 mm Hg decrease in SBP; or 2) a N 15% decrease in mean arterial pressure (MAP) after propacetamol administration. If a patient’s SBP or DBP was within the hypotensive range after propacetamol adminis- tration but the decrease was <= 10 mm Hg, the patient was not defined as having hypotension.

Among patients who showed hypotension after propacetamol ad- ministration, we defined those who required further treatment in the ED with fluids or vasopressors such as dopamine or norepinephrine as having persistent hypotension; in contrast, those who did not require fluids or vasopressors were defined as having transient hypotension.

Bacteremia was defined as isolation of bacteria in both blood and urine cultures. The presence of coagulase-negative staphylococci was considered a contamination.

Statistical analysis

We show the means and standard deviations (SD) or medians and interquartile ranges for continuous variables. For categorical variables, numbers and percentages are given. The normality of the distribution

of continuous variables was tested using the Shapiro-Wilk test, and the groups were compared using the t-test or Mann-Whitney U test. For categorical variables, the groups were compared using the Chi- square or Fisher’s exact test. The paired t-test or Wilcoxon signed-rank test was used to examine hemodynamic changes between baseline and after propacetamol administration. The t-test was also used to com- pare the extent of these changes between the patient groups.

All tests were two-sided, and p values b 0.05 were considered statis- tically significant. IBM SPSS statistics for Windows version 19.0 (IBM Corp. Armonk, NY, USA) was used for all statistical analyses.

Results

General patient characteristics

During the study period, a total of 214 patients were diagnosed with UTIs and were administered propacetamol at our hospital’s ED. After ex- cluding those for whom vital signs were not measured within 90 min of propacetamol administration, who self-discharged against medical ad- vice, who had a Do-Not-Resuscitate order, or who were transferred to another hospital, 195 patients were included in the final analysis (Fig. 1).

Table 2

Differences in baseline and post-infusion vital signs between non-hypotensive and hypotensive group

Total (n = 195) Non-hypotension (n = 108) Hypotension (n = 87) P valueb

Baseline

After propacetamol

P valuea

Baseline

After propacetamol

P valuea

Baseline

After propacetamol

P valuea

Vital sign SBP, mm Hg

135.1 +- 20.5

117.7 +- 16.4

b0.001???

127.6 +- 15.3

122.8 +- 14.5

b 0.001???

143(30)c

110(22)c

b0.001???

b 0.001???

DBP mm Hg

79.7 +- 12.2

69.7 +- 10.9

b0.001???

76.8 +- 11.0

74.2 +- 9.5

0.002?

83.3 +- 12.6

64.2 +- 10.1

b0.001???

b 0.001???

HR, beats/min

97.5 +- 17.1

90.7 +- 14.9

b0.001???

95.5 +- 16.6

88.9 +- 13.9

b 0.001???

99.3 +- 17.6

92.9 +- 15.8

b0.001???

0.827

RR, beats/min

19.2 +- 2.9

18.5 +- 1.8

b0.001???

18(2)c

18(0)c

0.030?

18(2)c

18(2)c

0.005??

0.788

BT, ?C

38.9 +- 0.7

38.1 +- 2.8

b0.001???

38.7(0.8)c

38.2(0.88)c

b 0.001???

39(1)c

38.2(0.9)c

b0.001???

0.092

BT, body temperature; DBP, diastolic blood pressure; HR, heart rate; RR, respiratory rate; SBP, systolic blood pressure.

a Difference before and after administration of propacetamol, P value obtained using paired t-test or Wilcoxon signed-rank test.

b Difference between non-hypotensive group and hypotensive group before and after administration of propacetamol. P value obtained using t-test or Mann-Whitney U test.

c Data are presented as medians (interquartile ranges).

* p b 0.05.

?? p b 0.01.

??? p b 0.001: significant difference between baseline and after propacetamol; between Non-hypotension and Hypotension.

The mean age of the patients was 59.4 +- 19.5 years, and 50 patients (25.6%) were men. Mental changes and chills were observed in 12.8% and 54.5% of patients, respectively. The mean BT of the study partici- pants was 38.9 +- 0.7 ?C, and their mean CRP level was 9.9 +-

8.3 mg/dL. Bacteria were isolated from 150 of 191 patients (78.5%) who underwent urine culture tests; the isolatED strains were Escherichia coli in 52.9%, enterococci in 4.2%, and extended-spectrum beta- lactamase E. coli in 12.6% of cases. Bacteremia was observed in 61 out of 183 patients (33%) who underwent blood culture tests (Table 1).

Hemodynamic changes after propacetamol administration

A total of 87 patients (44.6%) fit our definition of hypotension. The hy- potension group had a baseline SBP of 144.4 +- 22.3 mm Hg and baseline DBP of 83.3 +- 12.6 mm Hg; these values were significantly higher than those observed for the non-hypotension group (baseline SBP, 127.6 +- 15.3 mm Hg; baseline DBP, 76.9 +- 11.0 mm Hg; p b 0.001; Table 1). The hypotension group also had higher baseline RR and BT than the non-hypotension group (p = 0.04 and 0.006, respectively; Table 1).

After propacetamol administration, the BT, SBP, DBP, and HR de- creased significantly in all patients (p b 0.001; Table 2). When we com- pared the decreases in SBP and DBP between the hypotension and non- hypotension groups, we observed more significant decreases in the hy- potension group; this effect was larger for SBP than DBP. No differences in the decreases of the patients’ HR and RR were observed between the two groups (p = 0.827 and 0.788, respectively; Table 2).

Propacetamol-induced persistent hypotension

Among the patients who showed hypotension after propacetamol administration, 23 patients (11.7%) required further treatment with fluids or vasopressors (i.e., the persistent hypotension group). Com- pared to the transient hypotension group, the persistent hypotension group showed significantly lower median SBP and mean DBP (SBP: 123 (25) mm Hg vs. 148 (27) mm Hg; DBP: 75.6 +- 10.9 mm Hg

vs. 86.1 +- 12.1 mm Hg) and a significantly higher mean BT (39.6 +- 0.9 ?C vs. 38.9 +- 0.6 ?C) (Table 3).

Factors associated with propacetamol-induced persistent hypotension

We found no difference in the median age of the patients between the persistent and transient hypotension groups. In contrast, the mean pCO2, median pO2, median HCO, and median SpO were lower in the persis- tent hypotension group when compared to the transient hypotension group (pCO2: 27.3 +- 4.9 mm Hg vs. 30.0 +- 4.5 mm Hg, p = 0.022; pO2: 68 (20.40) mm Hg vs. 77.5 (27.85) mm Hg, p = 0.043; HCO: 19.5

3

3

2

(3.20) mmol/L vs. 21 (4.35) mmol/L, p = 0.013; SpO2: 95.3 (3.90)

mm Hg vs. 97.05 (2.55) mm Hg, p = 0.011; Table 3). Bacteremia was ob- served at a higher rate in the persistent hypotension group when

compared to the transient hypotension group (65.2% vs. 21.7%, respec- tively; p b 0.001; Table 3). We found no differences between the two groups in the qSOFA score or rate of SIRS (p = 0.352 and 0.74, respective- ly); however, the median SOFA was significantly higher in the persistent than in the transient hypotension group (2 (2) vs. 1 (1.75); p = 0.034; Table 3). No difference in the change between baseline and after propacetamol for any variable, except BT, was observed between the two groups (Table 4).

Discussion

This study investigated the hemodynamic changes following propacetamol administration in febrile UTI patients in the ED who did not show hypotension before receiving propacetamol and explored the factors associated with these hemodynamic changes. Moreover, we examined the characteristics of patients who showed no hypoten- sion at baseline but developed persistent hypotension requiring addi- tional fluids or vasopressors treatment following propacetamol administration. In this study, 44.6% of the included patients developed propacetamol-induced hypotension. The basal SBP and DBP were higher in the hypotension group than in the non-hypotension group. The patients in the persistent hypotension group, who received addi- tional fluid or vasopressors, were relatively normotensive compared to those in the transient hypotension group.

Fever is a common symptom in patients who are admitted to the ED. In infection-induced fever, patients may experience discomfort due to chills or an elevated HR; thus, fever, like pain, is a symptom that often needs to be controlled. Fever is not harmful in most cases, but the in- creased metabolic demand due to fever can aggravate the patient’s con- dition when there is an underlying cardiovascular or pulmonary disease; Antipyretic therapy can be utilized in such cases [8].

Paracetamol has been used for pain control and fever reduction for a long time; it is often prescribed in clinical practice because it is known to be safer than other analgesics. Although not all mechanisms of action of the drug are known, fever reduction and analgesia are accomplished by inhibition of the cyclo oxygenase 2 pathway, resulting in suppression of Prostaglandin E2 production. Propacetamol, a prodrug of paracetamol, is a soluble diethylglycidyl ester of paracetamol, and IV propacetamol formulations have been used for the last 15 years [9].

When propacetamol is administered intravenously, it rapidly be- comes hydrolyzed to produce paracetamol and N,N-diethylglycine. While N,N-diethylglycine is known to cause allergic contact derma- titis [10], there have been no reports on N,N-diethylglycine-induced hypotension. Hence, hypotension after intravenous propacetamol administration does not seem to be the direct effect of N,N- diethylglycine.

On the other hand, both propacetamol- and paracetamol-induced hypotension have been previously reported. Specifically, although para- cetamol has been shown to have little effect on hemodynamic stability

Table 3

Comparison of baseline characteristics and hemodynamic parameters between patients with transient and persistent hypotension.

All

Transient hypotension

Persistent hypotension

P valuea

(n = 87)

(n = 64)

(n = 23)

Age, yr

69(23)b

65.5(24.75)b

72(14)b

0.118

Male sex, no. (%)

23(26.4)

17(26.6)

6(26.1)

0.965

Mental changes, no. (%)

15(17.2)

10(15.6)

5(21.7)

0.529

Chill, no. (%)

49(n = 86, 57)

32(n = 63, 50.8)

17(n = 23, 73.9)

0.055

Vital signs on presentation

SBP, mm Hg

143(30)b

148(27)b

123(25)b

0.001??

DBP, mm Hg

83.3 +- 12.6

86.1 +- 12.1

75.6 +- 10.9

b0.001???

HR, beats/min

99.9 +- 17.6

98.4 +- 14.8

104.3 +- 23.6

0.272

RR, breaths/min

18(2)b

18(2)b

18(2)b

0.147

BT, ?C

39.1 +- 0.8

38.9 +- 0.6

39.6 +- 0.9

0.004??

Arterial blood gas

n = 77

n = 54

n = 23

pH

7.46(0.04)b

7.46(0.04)b

7.46(0.05)b

0.683

PCO2, mm Hg

29.2 +- 4.7

30.0 +- 4.5

27.3 +- 4.9

0.022?

PO2, mm Hg

74(25.15)b

77.5 (27.85)b

68(20.40)b

0.043?

HCO3-, mmol/L

20.8(4.40)b

21(4.35)b

19.5(3.20)b

0.013?

SpO2, mm Hg

96.8(3.05)b

97.05(2.55)b

95.3(3.90)b

0.011?

Leukocyte count, x109cells/mL

11.8 +- 5.4

11.9 +- 5.5

11.8 +- 5.1

0.971

Hemoglobin, g/dL

12(2.1)b

12.1(3.07)b

11.8(1.7)b

0.497

Platelet, x103/ul

200(93)b

205(97.25)b

189(88)b

0.182

CRP, mg/dL

8.09(14.05)b

7.35(15.28)b

9.59(12.94)b

0.464

Blood urea nitrogen, mg/dL

15.5(11)b

13.25(9.43)b

18.8(13.9)b

0.051

Serum creatinine, mg/dL

0.92(0.37)b

0.84(0.33)b

0.98(0.82)b

0.061

Total bilirubin, mg/dL

0.7(0.6)b

0.7(0.6)b

0.9(0.7)b

0.130

Albumin, g/dL

3.7(0.8)b

3.75(0.8)b

3.5(0.6)b

0.090

Lactic acid

2(n = 36, 1.18)

1.8(n = 20, 0.97)

2.35(n = 16, 2.78)

0.062

Positive urine culture

68(n = 86, 79.1)

48(n = 63, 76.2)

20(n = 23, 87)

0.376

E.coli, no.(%)

46(53.5)

35(55.6)

11(47.8)

0.525

Klebsiella, no.(%)

3(3.5)

1(1.6)

2(8.7)

0.173

Enterococcus, no.(%)

3(3.5)

2(3.2)

1(4.3)

1.000

Pseudomonas, no.(%)

1(1.2)

1(1.6)

0(0)

1.000

Enterobacter, no.(%)

3(3.5)

3(4.8)

0(0)

0.561

ESBL E.coli, no. (%)

12(14)

6(9.5)

6(26.1)

0.076

Bacteremia

28(n = 83, 33.7)

13 (n = 60, 21.7)

15(n = 23, 65.2)

b0.001???

Propacetamol dose, g

1(0)b

1(0)b

1(0)b

0.351

Hospital days

8.0(10)b

8.0(11)b

10(11)b

0.228

SIRS

3(2)b

3(1.75)b

3(2)b

0.740

QSOFA

0(1)b

0(1)b

0(1)b

0.352

SOFA

2(2)b

1(1.75)b

2(2)b

0.034?

BT, body temperature; CRP, C-reactive protein; DBP, diastolic blood pressure; ESBL, extended-spectrum beta-lactamase; RR, respiratory rate; SBP, systolic blood pressure; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; qSOFA, quick sequential organ failure assessment.

a Differences between patients with transient and persistent hypotension before and after propacetamol administration.

b Data are presented as medians (interquartile ranges).

* p b 0.05.

?? p b 0.01.

??? p b 0.001: significant difference between transient hypotension group and persistent hypotension group.

compared to other Non-steroidal anti-inflammatory drugs, such as metamizol and dexketoprofen, since it does not significantly reduce blood pressure [11], there have been several reports of significant he- modynamic changes after paracetamol administration in patients with severe fever [3,4,12]. Paracetamol can be given orally or intravenously; however, a reduction in blood pressure has been observed within 60 min for either route of administration [13].

In the present study, we aimed to investigate the development of clinically significant hypotension after propacetamol administration. To minimize the effects of hypoxia, body fluid volume status, and treat- ments such as mechanical ventilation on hemodynamic indices, we ex- amined patients with a single disease (i.e., UTI). We defined hypotension as SBP <= 90 mm Hg, DBP <= 60 mm Hg, or a drop in SBP

>= 30 mm Hg, as per the studies by Kelly et al. [13], Bae et al. [7], and Hersch et al. [14]. Moreover, the absolute hemodynamic indices were considered to be more important than the size of the reduction, because clinically significant shock should be particularly considered. However, some patients who did not have hypotension at baseline but had rela- tively low baseline SBP and DBP were classified into the hypotension group, even though they only showed a small decrease in BP. To account for the patients’ baseline BP, they were only included in the hypotension group if they showed a decrease in MAP of N 15%. These criteria were

applied to include all relevant patients in the hypotension group, in con- trast to in the previous studies.

Bae et al. [7] observed hemodynamic changes after propacetamol administration in patients who were admitted to the ED and reported an incidence of hypotension of 10.7%; however, an incidence of propacetamol/paracetamol-induced hypotension of N 50% has been re- ported in other studies that applied the reduction in MAP criterion to ICU patients [5,15]. Thus, the incidence of hypotension after propacetamol administration varies depending on the definition of hy- potension and the type of patients studied. This makes it difficult to compare the incidence of hypotension comprehensively. Our study showed a decrease in BP after propacetamol administration in 44.6% of all patients.

Further, different studies reported different extents of the decrease in BP. Schell-Chaple et al. reported decreases of 24 mm Hg, 8 mm Hg, and 13 mm Hg within 2 h of paracetamol administration in febrile pa- tients for SBP, DPB, and MAP, respectively [6]. Bae et al. reported de- creases of 13.20 mm Hg for SBP and 7.72 mm Hg for DBP following propacetamol administration in febrile patients [7]. In cases of prompt administration for pain control in non-febrile patients, SBP decreased by 4.31 mm Hg (95% confidence interval [CI] 2.78-5.84 mm Hg) and DBP by 1.92 mm Hg (95% CI 0.47-3.37 mm Hg) [12]. In our study of

Table 4

Differences in vital signs before and after propacetamol administration between patients with transient and persistent hypotension.

Transient hypotension group (n = 64) Persistent hypotension group (n = 23) P valueb

Baseline

After propacetamol

P valuea

Baseline

After propacetamol

P valuea

Vital sign SBP, mm Hg

148.1 +- 19.5

116.4 +- 13.4

b0.001??

123(25)c

96(15)c

b 0.001??

0.620

DBP mm Hg

86.1 +- 12.1

66.7 +- 9.1

b0.001??

97.7 +- 19.5

57.2 +- 9.7

b 0.001??

0.740

HR, beats/min

98.4 +- 14.8

91.3 +- 14.1

b0.001??

104.3 +- 23.6

97.7 +- 19.5

0.041?

0.866

RR, beats/min

18(2)c

18(1.5)c

0.043?

18(2)c

18(2)c

0.035?

0.117

BT, ?C

38.9 +- 0.7

38.3 +- 0.6

b0.001??

39.4(1.3)c

38.5(0.9)c

b 0.001??

0.024

BT, body temperature; DBP, diastolic blood pressure; HR, heart rate; RR, respiratory rate; SBP, systolic blood pressure.

a Difference before and after administration of propacetamol, P value obtained using paired t-test or Wilcoxon signed-rank test.

b Differences between patients with transient and persistent hypotension before and after propacetamol administration, P value obtained using t-test or Mann-Whitney U test.

c Data are presented as medians (interquartile ranges).

* p b 0.05.

?? p b 0.001: significant difference between baseline and after propacetamol; between transient hypotension and persistent hypotension.

propacetamol administration in febrile UTI patients who did not show hypotension at baseline, the SBP and DBP decreased by 17.36 mm Hg (95% CI 14.52-20.20 mm Hg) and 10.05 mm Hg (95% CI 8.23-

11.86 mm Hg), respectively; this is similar to in the previous studies. Combining our results and the results of previous studies, a certain de- crease in BP can be seen when propacetamol is given to febrile patients. When compared to the non-hypotension group, the hypotension group showed significantly higher baseline SBP and DBP, as well as higher baseline BT, in this study. The patients did not have hypotension at baseline/before propacetamol administration but rather maintained high hemodynamic values before showing a rapid decline in BP after propacetamol administration. This decline in BP caused both the SBP and DBP to fall below a certain level. Bae et al. reported similar results to ours [7]. Although the mechanisms have not been fully elucidated, it is thought that the fever response excites the sympathetic nervous system to cause vasoconstriction; the antipyretic action of propacetamol then causes a considerable decrease in sympathetic ner- vous activity, resulting in vasorelaxation, reduced HR, and hypotension. The laboratory findings and urine culture tests did not show any sig- nificant differences between the hypotension and the non-hypotension groups in this study. Moreover, there were no significant differences be- tween the two groups for the qSOFA score and incidence of SIRS; the hy- potension group did, however, show higher SOFA scores than the non- hypotension group. This difference can be explained by the SOFA score being calculated based on vital signs, including hemodynamic indices. Moreover, we also did not find any difference between the two groups for the length of the hospital stay, suggesting that propacetamol-in-

duced hypotension does not have a major effect on prognosis.

In our study, 87 patients were classified as being in the hypotension group; of these, 23 were included in the persistent hypotension group (defined as patients who required further fluids or vasopressor treat- ment). Twenty-two patients received a large volume of fluids (300- 1450 mL) within a short time, and eight patients began treatment with vasopressors. Patients in the persistent hypotension group had a higher baseline BT, as well as lower baseline SBP and DBP, when com- pared to those in the transient hypotension group. In a study of ICU pa- tients, Kiekkas et al. found that the MAP was significantly lower in patients with a BT >= 39 ?C when compared to those with a BT b 39 ?C. They also reported that fever caused elevated BP by increasing catechol- amine secretion and the metabolic rate, but that it could also decrease BP via vasodilation and myocardial depression; thus, each patient had a different presentation [16]. Accordingly, it should be anticipated that patients with a BT >= 39 ?C and high baseline BP (within the normal range) might experience persistent hypotension alongside a decrease in BT following propacetamol administration.

In the present study, the ABGA showed lower pCO2, pO2, and HCO in the persistent hypotension group when compared to the transient hypotension group. No difference was observed for pH. Although indi- vidual differences between patients should to be considered, minimal

3

metabolic acidosis and respiratory alkalosis might have caused these ABGA results in patients with persistent hypotension. Low pO2 and lac- tic acidosis are thought to be the cause of metabolic acidosis associated with infection, sepsis, or fever [17].

The rate of bacteremic UTI was higher in the persistent hypotension group than in the transient hypotension group, which is likely, at least partially, related to the hemodynamic characteristics of persistent hypo- tension. Despite minor differences between the findings of studies on the clinical features of bacteremic UTI, these studies have shown that bacteremic UTI is characterized by a higher fever, reduced SBP, and ele- vated CRP when compared to non-bacteremic UTI [18,19]. Based on these data, the possibility of persistent hypotension after propacetamol administration needs to be carefully considered in patients showing metabolic acidosis in the ABGA and with slightly elevated SBP. As we observed no differences in the length of the hospital stay between the persistent and transient hypotension groups, we assume that patients who do not show hypotension before propacetamol administration are not expected to have a different prognosis even if they develop per- sistent hypotension after propacetamol administration.

This study has three main limitations. First, we were unable to assess the disease- or severity-related hemodynamics because of the study’s focus on febrile UTI only. Second, we only analyzed the hemodynamics once after propacetamol administration; hence, we could not assess the sequential changes in hemodynamics. Third, this was a retrospective study, and the ABGA and blood culture, urine culture, and lactic acid analyses were not performed in all patients. Especially, lactic acid or lac- tate is useful for prognostication in shock, sepsis, and other diseases. However, our study included only patients that were normotensive at the time of ED admission; thus, data of lactic acid were missing in many cases.

Conclusions

When propacetamol is administered to febrile patients, it can result in hemodynamic changes. However, this did not seem to have a signif- icant effect on the patient prognosis. In cases that show normal hemo- dynamics despite fever before propacetamol administration, hypotension requiring additional treatment can develop after propacetamol administration. Since these patients often also experience bacteremia, they require sufficient fluids, prompt antibiotic treatment, and appropriate monitoring in the ED.

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