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Effect of pulse therapy with glucocorticoids and
cyclophosphamide in patients with paraquat
poisoning
Article in Hong Kong Journal of Emergency Medicine · July 2015
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Hong Kong Journal of Emergency Medicine
Effect of pulse therapy with glucocorticoids and cyclophosphamide in
patients with paraquat poisoning
糖皮質激素和環磷酰胺脈衝治療百草枯中毒患者的效果
A Ghorbani, K Masoumi, A Forouzan, AH Rahmani, F Rahim, B Taherinezhad Taeybi, M Feli
Introduction: Paraquat (PQ) is a widely used herbicide with a high mortality rate when ingested. The aim of the
present study was to assess the effectiveness of repeated cyclosphosphamide (CP) and methylprednisolone (MP)
combination in the treatment of PQ poisoning. Design: Randomised, double-blinded, placebo-controlled trial.
Methods: Eligible participants were 47 patients with moderate to severe PQ poisoning within 24 hours of
hospitalisation. Patients were allocated in a random fashion, 24 as the intervention and 23 as the control group.
All patients received two cycles of eight hours of haemoperfusion with charcoal, and underwent emergency
haemodialysis. After the dialysis, the intervention group received 15 mg/kg CP for two days and 1g MP for three
days. The control group received routine supportive care. Outcome parameters, including mortality, incidence of
hypoxia, hepatitis and renal failure were compared between the two groups. Results: There were no significant
differences between the two groups with regard to age, sex, baseline liver function test, creatinine, time from
poisoning to dialysis, and time from poisoning to the hospitalisation. Although the incidence of hepatitis and
acute renal failure did not differ significantly between the two groups, the incidence of hypoxia and mortality rate
was lower in the intervention group. The number need-to-treat to reduce one mortality was 2.8. Conclusion: The
results suggest that CP and MP repeated treatment can reduce the mortality rate in moderate to severe PQ
intoxication. (Hong Kong j.emerg.med. 2015;22:235-240)
簡介:百草枯(PQ )是一種廣泛使用的除草劑,食入時具有高死亡率。本研究的目的是評估重複環磷
酰 胺( CP )和甲基強的松龍( MP )組合,在 PQ 中毒治療的有效性。設計:隨機、雙盲、安慰劑對
照試驗。方法:47 例中度至重度 PQ 中毒並住院 24 小時之內的患者,符合參加者的條件。患者以隨機方
式被分配, 24 名為介入組, 23 名作為對照組。所有患者均接受八小時的木炭血液灌注兩個週期,並接受
緊急血液透析。透析後,干預組接受 15 毫克 / 千克的 CP 兩天, 1 克 MP 三天。對照組接受常規支持治療。
兩組之間進行比較的結果參數,包括死亡率,缺氧的發生率,肝炎和腎衰竭。結果:有關於年齡、性別、
基線肝功能檢查、肌酐、由中毒到透析時間、從中毒到住院時間,兩組之間沒有顯著差異。雖然肝炎和急
性腎功能衰竭的發病率兩組之間沒有顯著不同,干預組的缺氧和死亡率發生率較低。減少一個死亡需要治
療人數的比率為 2.8 。結論:研究結果表明, CP 和 MP 重複治療可降低中度到重度 PQ 中毒的死亡率。
Keywords: Dexamethasone, human, methylprednisolone, poisoning, prognosis
關鍵詞:氟甲強的松龍、人類、甲基強的松龍、中毒、預後
Correspondence to:
Arash Forouzan, MD
Imam Khomeini General Hospital, Department of Emergency
Medicine, Ahvaz Jundishapur University of Medical Sciences,
Ahvaz, Iran
Email: md_89864@yahoo.com
Kambiz Masoumi, MD
Bahareh Taherinezhad Taeybi, MD
Maryam Feli, MD
Razi Hospital, Department of Forensic Medicine, Ahvaz
Jundishapur University of Medical Sciences, Ahvaz, Iran
Ahmad Ghorbani, MD
Ali Hassan Rahmani, MD
Health Research Institute, Ahvaz Jundishapur University of
Medical Sciences, Ahvaz, Iran
Fakher Rahim, PhD
236
Introduction
Paraquat (PQ) is a widely used herbicide with high
mortality when ingested. Most cases of PQ poisoning
result from intentional or suicidal ingestion. PQ poisoning
causes death in 50-90% of the cases, and PQ related
mortality increases to near 100% when consumed
intentionally.1 Hong Kong local study by Wong et al
reported a mortality rate of around 57%.2 Generally the
severity was classified as mild, moderate, and severe. The
mild form is accompanied by oral irritation and gastric
upset and completely recoverable. In moderate to severe
poisoning, acute liver failure and pulmonary fibrosis lead
to death within two to three weeks. Acute fulminant
poisoning followed by multi-organ failure and
cardiovascular collapse leads to death of the patient
within one week.3 Retrospective studies have identified
that urine and plasma concentration of PQ during the
first 24 hours of intoxication may help in patient's
outcome prediction.4 Urine test of PQ is a quick and
convenient way for quantitative and semi-quantitative
assessment of the severity and intensity of poisoning
in the emergency department.5
The results of the review of the various treatment methods
of PQ poisoning, including prophylactic absorbents,
pharmacological assessment, radiotherapy,6 haemodialysis
and haemoperfusion7 were disappointing. Although a
number of studies suggested that high doses of
cyclophosphamide and dexamethasone therapy, had 75%
survival,8 but others did not specify the usefulness of these
findings.9 Thus, efficacy of high-dose cyclophosphamide
and dexamethasone therapy remains controversial.
High-dose cyclophosphamide and methylprednisolone
pulse therapy, in patients with severe pulmonary damage
from systemic lupus erythematous and Wegener's
granulomatosis10,11 has been used with higher efficacy,
and lower side effects than high-dose cyclophosphamide
and dexamethasone. One report 12 indicated that
cyclophosphamide and methylprednisolone pulse therapy
might be effective in the treatment of the moderate to
severe PQ poisoning.
Hong Kong j. emerg. med.  Vol. 22(4)  Jul 2015
and cyclophosphamide in patients with moderate to severe
PQ poisoning.
Methods
Study design and population
This randomised, double-blind, placebo-controlled
trial was conducted in Razi Hospital, Ahvaz, Iran
during the years 2010 to 2012. This study was approved
by Ahvaz Jundishapur University of Medical Sciences
Ethics Committee. It was also registered in Iranian
Registration of Clinical Trial (IRCT2014012611873N2).
Patient inclusion
All patients with history of exposure to paraquat
concentration in urine or plasma, who arrived at our
hospital within one week of paraquat ingestion, with a
navy blue or dark blue color in urine dithionite tests,
were classified as having PQ intoxication and were
included in this study. Patients with colorless urine
dithionite tests, who had not orally ingested PQ, who
were younger than 15 years or older than 45 years were
excluded. Moderate to severe poisoning to PQ was defined
by the color in the urine dithionite tests as navy blue or
dark blue. Urine dithionite test was a commonly adopted
point-of-care tests for the documentation of PQ exposure
which is semi-quantitative. A navy blue or dark blue color
would indicate a concentration of more than 0.1 mg/L.
Serum PQ levels was unavailable in the study centre. For
patients with mild or no documented exposure of
paraquat poisoning in urine tests (colourless or light blue),
they were excluded from the study.
Randomisation and allocation concealment
At the time of admission, demographic characteristics
and the time between PQ intake and the entrance to
the emergency department were recorded. Then patients
were allocated randomly into two groups (intervention
and control) in a 1:1 ratio using a computer program.
The investigator was provided with a sealed envelope
containing a code number for each group.
Clinical assessments and treatments
The aim of the current study was to examine the impact
on mortality rate of pulse therapy with methylprednisolone
Considering the complications of PQ poisoning,
venous blood samples were taken from all participants
Ghorbani et al./Corticosteroids in paraquat poisoning
and serum aspartate aminotransferase (AST), alanine
aminotransferase (ALT), bilirubin, and creatinine levels
were measured through at baseline and were repeated
serially. Afterwards, all patients received conventional
standard poisoning care with activated charcoal (1 g/kg
in water; maximum dose 50 g) was given as soon as
possible per oral or via a nasogastric tube to patients
who present within approximately two hours of
ingestion. Gastric lavage is contraindicated due to
paraquat-induced caustic injury. However, in cases that
present early, a nasogastric tube was inserted and the
stomach contents aspirated prior to administration of
charcoal. Lavage was performed adequately with tap
water or normal saline in adults. We introduce small
aliquots of lavage solution (200 to 300 mL) into the
stomach and then remove them. We noticed that the
amount of fluid that is returned should approximate
the amount introduced. We continue lavage until the
fluid becomes clear. Based on our protocol, two
episodes of eight-hour charcoal haemoperfusion were
performed for all subjects with a 4-hour interval.
Haemodialysis was also arranged for renal replacement
if necessary. For arrangement of double blindness
setting, we prepared calculated cyclophosphamide
in 200 ml dextrose saline 5%, calculated
methylprednisolone in 200 ml dextrose saline 5% and
placebo (only 200 ml dextrose saline 5%) in similar
and unknown sets which neither patient nor nurse/
physician could not differentiate between them. After
dialysis, the intervention group underwent pulse
therapy, i.e. 15 mg/kg cyclophosphamide in 200 ml
dextrose saline 5% and 1 g methylprednisolone in
200 ml dextrose saline 5% were intravenously infused
for two hours per day. The two medications were
prescribed with short intervals. The treatment with
cyclophosphamide continued for two consecutive days
and the treatment with methylprednisolone repeated for
three consecutive days. Control group only received
routine supportive care and placebo. Throughout the
hospitalisation, daily examinations were conducted to
assess systemic, hepatic, and renal complications and the
side effects of medicines including cyclophosphamideinduced thrombocytopenia13 and methylprednisoloneinduced leukocytosis.14 In order to do so, daily arterial
and venous blood samples were obtained to analyse blood
gases and measure blood cell count, creatinine, ALT,
237
AST, and bilir ubin levels, respectively. Chest
radiography was also used to assess possible respiratory
complications.
Outcome measures
The primary outcome was mortality within three days.
The secondary outcomes were hepatic complications,
renal failure (serum creatinine higher than 1.4 mg/dl)
Hepatitis was defined as ALT and AST greater than
70 U/l or total bilirubin more than 3 mg/dl.
Statistical methods
Quantitative variables were compared with Student's
t-tests. Chi-square tests were also applied to compare
the two groups in terms of qualitative variables and
outcomes. Relative risks and their 95% confidence
intervals were calculated. The number-need-to-treat
was calculated for mortality. All statistical analyses were
conducted with SPSS for Windows 20.0 (IBM SPSS
Statistics for Windows. Armonk, NY: IBM Corp). All
statistical inferences adopt a significance level of 5%.
Results
Th is c linical tria l evalua ted 47 P Q-po ison ed
individuals in two groups of intervention (n=24) and
control (n=23). There were no significant differences
between two groups on age, gender, baseline AST,
ALT, bilirubin and creatinine. Besides, time from
poisoning to hospitalisation and time from poisoning
to dialysis were comparable between two groups
(Table1).
O ver a ll, 20 (4 2 . 6%) a n d 2 6 (5 5 .3 %) o f th e
participants developed hepatitis and renal failure,
respectively. A total of 18 subjects (38.3%) suffered
from both complications. The frequency of patients
with both hepatitis and renal failure was significantly
lower in the intervention group than in the control
group [29.2% (n=7) vs. 47.8% (n=11); p=0.188].
Of the 20 cases who died, 16 subjects (88.9%)
including five from the intervention group and 11 from
the control group had both hepatitis and renal failure.
The mean time from poisoning to death was 8.64.6
Hong Kong j. emerg. med.  Vol. 22(4)  Jul 2015
238
Discussion
hours. Table 2 compared the two groups in terms of
frequency of the studied outcomes and changes in
laboratory indices. The mortality rate was significantly
lower in the treatment group (25%) compared to the
control group (60.9%) (p=0.013). The number-needto-treat to reduce one death was 2.8. Likewise, AST
showed significantly higher changes in the intervention
group. For the secondary outcomes, while pulse
therapy had no significant effects on the incidence of
hepatitis and renal failure, it had a preventive effect
on the incidence of death. Moreover, hypoxia was
significantly lower in the intervention group (RR=0.564,
p=0.025).
In the present study, 42.5% of all PQ-poisoned
patients and 60.9% of controls died. Kim et al15 and
Kang et al16 followed patients for 30 days and calculated
mortality rate as 43% and 73.5%, respectively. Similar
studies by Lee et al 17 and Weng et al 18 indicated a
mortality rate as 81.6% and 54%, respectively. In
1982, a review of 28 studies revealed the rates to vary
between 33% and 78%. 19 Apparently, the mortality
rate in the control group of the current study was
higher than the values reported by a number of
previous studies. The reason might relate to the long
Table 1. Comparison of baseline characteristics between the two groups
Intervention
Control
p value
Age (years)*
22.55.0
23.75.0
0.416
Gender (male)**
17 (70.8)
17 (52.2)
0.188
15 (75)
11 (39.1)
0.728
Time from poisoning to hospitalisation (hours)*
Time from poisoning to dialysis
6 (25)
5 (21.7)
0.792
Alanine aminotransferase (mg/dl)*
35.8841.08
47.5255.55
0.417
Aspartate aminotransferase (mg/dl)*
39.9641.08
70.1795.51
0.163
Bilirubin (mg/dl)*
1.571.76
1.500.70
0.849
Creatinine (mg/dl)*
1.582.85
1.450.81
0.838
*N (%); **meanstandard deviation
Table 2. Comparison of outcomes and changes in biochemical factors between the two groups
Intervention(n=24)
Control (n=23)
Relative risk
p value
Hepatitis*
9 (37.5)
11 (47.8)
0.784 (0.401-1.532)
0.474
Acute renal failure*
11 (45.8)
15 (65.2)
0.703 (0.415-1.191)
0.181
6 (25)
14 (60.9)
0.411 (0.191-0.884)
0.013
Death*
Time to death (hours)**
11.04.9
6.22.7
--
<0.001
73. 623.5
59.720.6
--
0.03
10 (41.6)
17 (73.9)
0.564 (0.331-0.960)
0.025
Change of alanine aminotransferase (mg/dl)**
29.762.6
61.082.4
--
0.149
Change ‡ of aspartate aminotransferase (mg/dl)**
14.442.0
57.488.1
--
0.042
Change of bilirubin (mg/dl)**
1.66.4
1.50.7
--
0.762
Change ‡ of creatinine (mg/dl)**
0.83.6
2.22.4
--
0.126
PaO 2 (mmHg)**
Hypoxia*
†
‡
‡
*N (%); **meanstandard deviation; †O2 sat <90% in repeated or continuous pulse-oximetry; ‡a mean for peak concentration of parameters in
each group and shows its comparison to baseline data.
Ghorbani et al./Corticosteroids in paraquat poisoning
interval (10 hours on average) between poisoning and
referring to the hospital.
Previous studies have reported different ranges for the
frequency of renal failure following PQ poisoning.
While Kim et al found the complication in 34.7% of
the patients,20 another study in China suggested 73.0%
of PQ-poisoned individuals to develop acute kidney
injury. 21 We found kidney failure in 55.3% of all
par ticipants. Furthermore, despite the higher
frequency of the complication in the control group,
the difference between the two groups was not
statistically significant. In recent years, restrictions on
the use of PQ have decreased the frequency of PQ
poisoning in developed countries. However, the
problem is still quite prevalent in areas where PQ
i s e m p l o y e d f o r a g r i c u l t u r a l p u r p o s e s . 22
Complications of PQ poisoning depend widely on
the dose and type of exposed, as well as severity of
po is on in g an d ma y va r y f ro m th e ab senc e of
complications in mild cases to death in 100% of
severe cases. While the exact mechanism of PQ
toxicity is not clear, this herbicide seems to induce
mucosal side effects in various organs by releasing
free oxygen radicals (superoxide and hydrogen
peroxide) near mucous membranes. 23
The conventional treatments for PQ poisoning, i.e.
using adsorbents, supportive therapy, haemodialysis,
and haemoperfusion, are not effective in moderate
to severe cases. 12 Hence, finding a novel, strong
anti-inflammatory treatments is a major concern for
researchers in this field. Pulse therapy is recently
proposed to reduce the inflammation caused by PQ
poisoning. Addo and Poon-King were among the first
scientists who assessed the efficacy of high-dose
corticosteroids and reported a 75% improvement in
survival.8 Lin et al used high-dose cyclophosphamide
and methylprednisolone in pulse therapy and found a
significant mortality reduction in the intervention
group despite the absence of any significant differences
between the inter vention a n d c o n t r o l g r o u p s
regarding baseline characteristics and inter val
b et we en p o is o n in g a n d h o s p i t a l is a t io n . 12 In
Hamadan (Iran), Afzali et al studied 45 PQ-poisoned
239
patients among whom 20 had moderate to
severe poisoning. Of these 20 subjects, 11 were
treated with standard suppor tive therapy and
nine received the conventional treatment accompanied
by 15 mg/kg cyclophosphamide for two days, 1 g
methylprednisolone for three days, and mesna for four
days. The mortality rate was 81.8% in the control
group and 33.3% in the pulse therapy group.
Moreover, the two groups had a significant difference
in the incidence of death.24 In another study, Lin et al
administered repeated pulse therapy and observed
significantly lower mortality in the pulse therapy
group compared to the control group. 25 Similarly,
Ghaffari et al indicated that cyclophosphamide and
methylprednisolone could significantly decrease
mortality related to pulmonary fibrosis. 26 Previous
studies suggested that severe inflammation and
fibrosis of lung might cause hypoxia and play a role in
increasing mortality in PQ poisoning.12,24 Our results
supported this hypotheseis.
Limitations
For this current study, serum PQ was not measured.
The determination on the severity of poisoning was
based on qualitative urine tests. We were unable to
discriminate between moderate and severe cases of
poisoning. Secondly, we only evaluated death in a
three-day period, thus longer follow-up for at least one
month could reveal more useful findings.
Conclusions
Our findings suggest that cyclophosphamide and
methylprednisolone pulse therapy can reduce hypoxia
and mortality rate in moderate to severe PQ poisoning
patients.
Acknowledgement
This study is used by one author named Dr Bahareh
Taherinezhad Tayebi, as the postgraduate thesis and
was supported by a grant from Ahvaz Jundishapur
University of medical sciences.
Hong Kong j. emerg. med.  Vol. 22(4)  Jul 2015
240
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