Analysis of Prognostic Factors in Patients with Paraquat Poisoning for Better Therapy Regimen

Abstract

Background

Paraquat poisoning is associated with very high mortality rate and extremely difficult to manage due to lack of antidotes. The purpose of this study was to identify prognostic factors after paraquat poisoning and discuss the efficacy of current therapy regimen.

Methods

In this retrospective study, 211 paraquat poisoning cases admitted to the First Affiliated Hospital, School of Medicine, Zhejiang University between 1 June 2010 and 30 April 2016 were enrolled. The demographic characteristic, medical records of clinical features, laboratory parameters, therapy regimen and the prognosis were analyzed.

Results

The overall survival rate was 55.45%. the mean age was 35.85 years old. Twelve patients who ingested paraquat combined with alcohol had a higher survival rate. The patients in survival group ingested less amount of paraquat, presented with lower serum creatinine level at admission, developed lower incidence of acute kidney injury and pulmonary CT deterioration. The survivors were treated with higher dosage of methylprednisolone, daily dose of aspirin, daily dose of rapamycin and lower dose of vitamin C. The frequency of hemoperfusion was much more in the survival group. The Cox regression survival analysis demonstrated larger amount of paraquat ingestion, abnormal renal function at admission or developing acute kidney injury (AKI) after admission were independent risk factors for mortality. Higher dose of methylprednisolone and aspirin were independent protective prognostic factors.

Conclusions

Non-survivor characteristics are larger amount of paraquat ingestion, manifestation of abnormal renal function at admission or developing AKI after admission, whereas the survivor characteristics are higher dose of methylprednisolone and aspirin.

Introduction

Paraquat (N, N-dimethyl-4, 4'-bipyridinium dichloride; PQ) is a widely used herbicide in developing countries for weed elimination. It exerts herbicidal activity through redox-cycling and leads to formation of reactive oxygen species (ROS). ROS interacts with the unsaturated lipids on cellular membranes, resulting in destruction of plant organelles and inevitably leading to cell death[1].

However, PQ has been demonstrated to be highly toxic to human and animal, and PQ poisoning accounts for a high mortality rate each year either by accidental or intentional exposure for suicide[2, 3]. PQ enters into the body mainly by ingestion, dermal exposure or inhalation. Even a teaspoon of concentrated PQ can result in death, which is usually due to respiratory failure within days up to a month after exposure. Besides the lung, PQ also damages the kidneys, liver, heart and central nervous system and leads to multiple organ dysfunction[4, 5].

Unfortunately, there are neither effective antidotes nor widely accepted guidelines for treatment of PQ poisoning up till now. The therapy regimen varies from supportive care alone to various combinations of glucocorticoid, cyclophosphamide, anti-oxidants and immunosuppression therapy [6, 7]. The activated charcoal hemoperfusions are used to increase the elimination of PQ from plasma [8–11]. Even though, the overall mortality rate are still higher than 50%, ranging from 60–80%[12, 13].

Therefore, more effective therapies are urgently required. Although researchers have been dedicated to exploring new insights from numerous animal studies, conclusions from large sample clinical studies are more practical. Due to the difficulty of designing perspective clinical trials in suicide population, this retrospective study enrolled 211 PQ poisoning patients in the aim of identifying prognostic factors and determining the efficacy of therapy regimen from one single center in China.

Materials And Methods

Results

The mean age of 211 cases was 35.85 ± 15.29 (13–83) years-old with 55.45% being female. The average amount of PQ (20% concentration) ingested was 30.79 ± 39.22 (1-300) ml. The average time interval between PQ ingestion and admission was 23.00 ± 35.82 (0.2–240) hours. The overall survival rate was 55.45%. According to the prognosis, we divided the patients into the survivor (n = 117) and the non-survivor (n = 94) group. Till the end of the follow-up, the median survival time was 147 (1-1942) days. The longest survival time in the non-survivor group was 29 days.

Discussion

Management of PQ poisoning is a medical challenge due to its high toxicity without effective antidote. PQ is rapidly distributed to lung, liver, kidney and muscle upon ingestion and selectively accumulates in the lungs, leading to irreversible pulmonary fibrosis and resulting in death within days up to a month. The clinical manifestations depend upon the quantity ingested. Large amounts of liquid concentrate (> 50–100 ml of 20% ion w/v) could result in fulminant organ failure and death within several hours to a few days, while smaller quantities could be harmful to the key target organs (kidneys and lungs) and develop over the next 2–6 days with the mortality rate still over 50%[14].

In the present study, our retrospective analysis revealed that the mortality rate was 44.55%, a little better than the previous reports. Most baseline variables had no significant differences between the survivor and non-survivor group. However, patients in the survivor group ingested less amount of PQ, which is consistent with previous reports[14]. We also found patients presented with lower serum creatinine level and higher glomerular infiltration rate at admission, developed lower incidence of acute kidney injury in the survivor group (Table 1). Cox regression survival analysis revealed that patients with abnormal renal function at admission or developed AKI after admission were high-risk population for mortality (Table 2). In the present study, 54.50% patients presented with normal renal function at admission and 45.22% patients among them developed AKI. The AKI incidence rate was similar with a previous study (51.4% reported by Hong et al. in 2009)[15]. In their study, AKI developed fully at the fifth day after PQ ingestion and normalized within 3 weeks without exception; Serum uric acid level could be a marker for mortality and acute kidney injury in patients with acute PQ intoxication[15, 16]. We could not characterize the evolution of AKI in present study because six patients who had impaired renal function at discharge did not have further renal function examinations. We could not find the association between serum uric acid level and AKI development or prognosis, but Cox regression analysis demonstrated that the amount of PQ ingested was the only independent risk factor for the development of AKI [HR 1.042, 95% CI (1.016–1.069), p = 0.002].

The percentage of abnormal pulmonary CT imaging in the survivor group was lower than the non-survivor group (41.88% vs 57.45%, p = 0.025) in our study, the lesions were consisted of pulmonary segment involvement, effusion, consolidation and fibrosis, or rapid lesion progression. Previous study reported that CT imaging could be a prognostic indicator for patients with pulmonary injury from acute PQ poisoning[17]. However, Cox regression analysis in the present study could not identify it as an independent risk factor for the prognosis. Further study should put emphasis on unified grouping of pulmonary lesion and identify characteristic early features.

Another interesting finding was that 12 Patients who ingested PQ combined with alcohol had a higher survival rate than those ingested PQ alone. PQ induced redox cycling rapidly oxidizes NADPH and leads to secondary changes on cellular metabolism and impairs defenses against oxidative stress[18]. Previous animal studies and medical case reports drew different conclusions about the impact of ethanol on PQ poisoning. Ethanol may decrease PQ toxicity partly through competitive consumption of NADPH and oxygen during the metabolism process [19–23]. The acute and chronic ethanol ingestion may have different impact on PQ metabolism. Further detailed studies are needed.

As to the therapy regimen, the survivors in the present study were treated with higher dosage of methylprednisolone, aspirin and rapamycin. The frequency of hemoperfusion was more in the survivor group. In the past decades, attempts to reduce absorption by gastric lavage, administration of Fueller’s earth and skin decontamination have been used routinely[24]. Early hemoperfusion is suggested in the aim of eliminating plasma PQ [9, 25]. A combination of glucocorticoid and cyclophosphamide was reported to be beneficial[26]. The survival benefit of additional immunosuppressive treatment has been demonstrated in the combination of methylprednisolone, cyclophosphamide and daily dexamethasone [6]. Intravenous anti-oxidants such as N-Acetylcysteine, L-Glutathione, vitamin C, vitamin E and thioctic acid have been used with various success[7, 27]. Our previous animal study revealed that rapamycin has significant inhibitory effects on progressive pulmonary fibrosis in the PQ intoxication mice model which may be partly ascribed to the inhibition of TGF-β1[28], however, the results in clinical settings differed[29, 30]. Some other potential agents, such as docosahexaenoic acid[31], naringin[32] and lysine acetylsalicylate[33] have been shown to ameliorate PQ-induced pulmonary fibrosis in animal models. Our results demonstrated positive effects of the therapy regimen consisted of cyclophosphamide, methylprednisolone, vitamin C, aspirin and rapamycin combined with hemoperfusion, higher dose of methylprednisolone and aspirin were protective factors for survival.

Ananieva et al. reported that salicylic acid (SA) mediates tolerance in barley plants to PQ, exogenous treatment with SA could antagonize PQ toxicity via elicitation of an antioxidative response in barley plants over ten years ago[34]. Recent studies have shown that salicylates, including sodium salicylate (NaSAL)[35, 36] and lysine acetylsalicylate (LAS)[33] may form complexes with PQ, prevent its toxicity through anti-inflammatory, anti-oxidant and anti-thrombogenic properties. LAS (also named Aspirin-DL-Lysine) has been shown to be a promising intravenous antidote for the treatment of PQ poisoning in animal studies[33]. To our knowledge, there have been no published human studies about the SA therapy in PQ poisoning. The present study firstly reported beneficial effect of oral aspirin therapy in PQ poisoning patients. Because LAS are not available in our hospital, we used oral aspirin in 72 patients (34.12%) with a mean daily dosage of 110.58 mg. Patients treated with aspirin had superior survival (73.61% vs 46.04%, log rank test, p < 0.001). Larger trials will be needed to verify the effect of aspirin on survival in patients with PQ poisoning.

Previous study showed that the addition of high-dose vitamin C to the treatment can reduce the development of acute kidney injury and mortality in PQ poisoning patients [7]. The optimal dosage of vitamin C is unknown. Hong et al. suggested that the loading and maintenance dosages should be 2278 mg and 146 mg/h based on pharmacokinetic data in patients with PQ intoxication[27]. A much larger dose (1.5 g/kg or daily 10 g) of vitamin C recommended as the upper limit has been beneficial for the treatment of pancreatitis and advanced malignancies[37, 38]. In the present study, the median daily dosage of vitamin C was 3000 mg. Further investigation is needed to determine the optimal dosage of vitamin C.

There are some limitations in present study. First, we used the amount of PQ ingestion as a variable. It’s not accurate because sometimes the patient provided mistake information. We used semi-quantitative urine PQ test instead of quantitative dithionite concentration determination. As we know, 90% of the absorbed PQ is rapidly excreted unchanged in urine within 12–24 h after ingestion[39], the urine test has a good correlation between PQ concentration and intensity of the blue color formed[40]. However, due to the different time interval between ingestion and admission, we could not decide the therapy intensity according to the urine semi-quantitative results alone. Second, the dosage of aspirin was determined according to our own experience; further studies are needed to verify the conclusion and illuminate the optimal dosage.

Conclusions

In conclusion, patients who ingested larger amount of PQ and presented with abnormal renal function at admission or developed AKI after admission are high-risk population for mortality after PQ poisoning. Present study proved that either higher dose of methylprednisolone or aspirin help to improve survival. As to our knowledge, it’s the first report about the efficacy of aspirin on PQ poisoning. However, further investigations are needed to determine the optimal dosage.

Abbreviations

Declarations

Ethic approval and consent to participate

This study was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (Reference Number 2016-273). Because all information obtained from the medical records was kept confidential, the review board of the Ethics Committee stated that written consent from patients was not required.

Consent to publication

Not appliable.

Availability of data and material

The datasets generated and analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by Zhejiang Province Department of Science and Technology (grant number 2017C37097).

Authors’ contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ying Xu, Yang Chen, Jingyun Le and Zhimin Chen. The first draft of the manuscript was written by Ying Xu and Yang Chen. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Zhejiang Science and Technology Project for Public welfare technology application research (Analytical test, grant number 2017C37097).

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