See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/280570374 Effect of pulse therapy with glucocorticoids and cyclophosphamide in patients with paraquat poisoning Article in Hong Kong Journal of Emergency Medicine · July 2015 CITATIONS READS 0 78 7 authors, including: Ahmad Ghorbani Kambiz Masoumi Ahvaz Jondishapour University of Medical … Ahvaz Jondishapour University of Medical … 16 PUBLICATIONS 7 CITATIONS 30 PUBLICATIONS 27 CITATIONS SEE PROFILE SEE PROFILE Arash Forouzan Fakher Rahim 37 PUBLICATIONS 19 CITATIONS Ahvaz Jondishapour University of Medical … SEE PROFILE 191 PUBLICATIONS 606 CITATIONS SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Available from: Kambiz Masoumi Retrieved on: 22 September 2016 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 8.64.6 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)* 22.55.0 23.75.0 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)* 35.8841.08 47.5255.55 0.417 Aspartate aminotransferase (mg/dl)* 39.9641.08 70.1795.51 0.163 Bilirubin (mg/dl)* 1.571.76 1.500.70 0.849 Creatinine (mg/dl)* 1.582.85 1.450.81 0.838 *N (%); **meanstandard 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)** 11.04.9 6.22.7 -- <0.001 73. 623.5 59.720.6 -- 0.03 10 (41.6) 17 (73.9) 0.564 (0.331-0.960) 0.025 Change of alanine aminotransferase (mg/dl)** 29.762.6 61.082.4 -- 0.149 Change ‡ of aspartate aminotransferase (mg/dl)** 14.442.0 57.488.1 -- 0.042 Change of bilirubin (mg/dl)** 1.66.4 1.50.7 -- 0.762 Change ‡ of creatinine (mg/dl)** 0.83.6 2.22.4 -- 0.126 PaO 2 (mmHg)** Hypoxia* † ‡ ‡ *N (%); **meanstandard 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 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Vale JA, Meredith TJ, Buckley BM. Paraquat poisoning: clinical features and immediate general management. Hum Toxicol 1987;6(1):41-7. Wong OF, Fung HT, Kam CW. Case series of paraquat poisoning in Tuen Mun Hospital. Hong Kong J Emerg Med 2006;13(3)155-60. Hart TB, Nevitt A, Whitehead A. A new statistical approach to the prognostic significance of plasma paraquat concentrations. Lancet 1984;2(8413): 1222-3. Scherrmann JM, Houze P, Bismuth C, Bourdon R. Prognostic value of plasma and urine paraquat concentration. 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