Article, Toxicology

Spectrum of corrosive esophageal injury after intentional paraquat ingestion

Brief Report

Spectrum of corrosive esophageal injury after intentional paraquat ingestion?

Tzung-Hai Yen MD, PhD?, Ja-Liang Lin MD, Dan-Tzu Lin-Tan RN, Ching-Wei Hsu MD, Cheng-Hao Weng MD, Yu-Hui Chen RN

Department of Nephrology and Division of Clinical Toxicology, Chang Gung Memorial Hospital, Taipei 105, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan

Received 18 March 2009; revised 5 June 2009; accepted 8 June 2009

Abstract

Introduction: This is an observational study that examines the clinical features, the degrees of esophageal injury, physiological markers, and clinical outcomes after paraquat ingestion and seeks to determine what association, if any, may exist between these findings.

Methods: The study included 16 of 1410 paraquat subjects who underwent endoscopies at Chang Gung Memorial Hospital between 1980 and 2007.

Results: Corrosive esophageal injuries were classified as grade 1 in 8, 2a in 5, and 2b in 3 patients. No patients had grade 0, 3a, or 3b esophageal injuries. After paraquat ingestion, systemic toxicity occurred, with rapid development of hypoxia, hepatitis, and renal failure in many cases. Hypoxia occurred in 1 (12.5%), 5 (100%), and 3 (100%) patients with grades 1, 2a, and 2b esophageal injury, respectively. There were more hypoxic patients with grades 2a and 2b than those with grade 1 esophageal injury (P b

.05). The nadir Pao2 was lower in patients with grades 2a and 2b than those with grade 1 esophageal injury (P b .05). However, there were no significant differences in terms of Acute hepatitis, peak serum alanine aminotransferase, acute renal failure, and peak serum creatinine between the 3 groups (P N .05). Kaplan-Meier analysis did not find any difference in survival between the groups (P N .05).

Conclusion: Paraquat, a mild caustic agent, produces only grades 1, 2a, and 2b esophageal injury. Our findings showed a potential relationship between the degree of hypoxia, mortality, and degree of esophageal injury, although such a low number of study subjects limits the conclusions that can be made by this study.

(C) 2010

Introduction

Accidental or Intentional ingestion of pesticides or herbicides is common in Taiwan because of easy access.

? This study is funded by Chang Gung Memorial Hospital.

* Corresponding author. Department of Nephrology, Chang Gung Memorial Hospital, Taipei 105, Taiwan. Tel.: +886 3 3281200×8181; fax:

+886 3 3282173.

E-mail address: [email protected] (T.-H. Yen).

Gramoxone (Syngenta, Taipei, Taiwan) is available as 24% paraquat in Taiwan and is used by farmers to control annual and perennial weeds for many varieties of crops. Agricultural workers and their families often have access to paraquat in places of work and in their homes, and this increases their risk of exposure.

Paraquat is a widely used bipyridyl contact herbicide with a good safety record when used properly but can cause severe morbidity and mortality after intentional ingestion. There are 3 degrees of severity for paraquat

0735-6757/$ – see front matter (C) 2010 doi:10.1016/j.ajem.2009.06.001

poisoning [1]. Mild poisoning causes oral irritation and gastrointestinal upset, but eventually results in Complete recovery. Moderate to Severe poisoning produces acute renal failure and, in severe cases, acute hepatitis followed by pneumonitis or pulmonary fibrosis, often leading to death in 2 to 3 weeks. Acute fulminant poisoning results in death within a week due to multisystem organ failure and Cardiovascular collapse. Many treatment modalities have been developed for Paraquat poisoning, such as adsorbents, hypo-oxygenation, lung radiotherapy [2], prolonged extra- corporeal detoxification [3], and lung transplantation. The efficacy of these therapeutic methods is uncertain. Although a previous study [4] showed that treatment with high-dose cyclophosphamide and dexamethasone obtained a 75% survival rate after paraquat poisoning, this study did not use a control group, and only a few patients with Plasma paraquat levels were included. A subsequent controlled study [5] did not demonstrate similar efficacy. In previous studies [6,7], we have demonstrated that an initial pulse therapy of cyclophosphamide (15 mg kg-1 d-1) for 2 days and methylprednisolone (1 g/d) for 3 days simultaneously, followed by dexamethasone (20 mg/ d) for 14 days, may be effective in treating patients with moderate to severe paraquat poisoning. In another study [8], 23 paraquat-Poisoned patients with 50% to 90% predictive mortality based on plasma paraquat levels were prospectively and randomly assigned to the control and study groups at a proportion of 1:2. The control group received conventional therapy, and the study group received the repeated pulse treatment with long-term Steroid therapy. The mortality rate of the control group (85.7%, 6/7) was higher than that of the study group (31.3%, 5/16; P = .0272). These data suggest that anti- inflammatory treatment can reduce the mortality of patients with severe paraquat poisoning.

Literature on the spectra of corrosive injury to the

esophagus after paraquat or diquat ingestion is sparse and confined to case reports [9-12]. There are occasional reports of severe damage to the esophagus. However, the location, extent, and severity of the damage have not been clearly defined. Furthermore, the role of endoscopic examination of the upper gastrointestinal tract has changed considerably. In the past, endoscopy was discouraged because of a high rate of perforation from rigid endoscopes. However, the use of flexible fiber-optic endoscopes has allowed for safer evaluation of the upper gastrointestinal tract after caustic ingestion [13-15].

In this study, we examined the clinical features, the spectra of esophageal injury, and outcomes after intentional paraquat ingestion. Because all patients experienced severe oral irritation and gastrointestinal upset after paraquat ingestion, we were interested in the degree of corrosive damage after caustic agent ingestion and seek to determine what association, if any, may exist between the degree of corrosive damage and systemic complications (pulmonary, hepatic, or renal).

Methods

This clinical study followed the Declaration of Helsinki and is compatible with the Medical Ethics Committee of Chang Gung Memorial Hospital. Furthermore, written consents were obtained from the patients or their families before the Endoscopic procedures.

Patients

This observational study included 16 of 1410 intentional paraquat ingestion patients who underwent endoscopic evaluation at Chang Gung Memorial Hospital between 1980 and 2007. Paraquat poisoning was confirmed by urine sampling for paraquat by the sodium dithionite reaction and by blood sampling for serum paraquat levels via spectro- photometry (Hitachi, Tokyo, Japan). [16]. The sodium dithionite test is based on the reduction of paraquat by sodium thionite under alkaline conditions to form its stable, blue-colored radical ion. A strong navy or dark blue generally indicates significant paraquat ingestion and often forebodes a poor prognosis [6-8]. Patients were included if they were older than 18 years and had urine paraquat tests that showed positive dark or navy blue coloring (N5 ppm). Patients were excluded from this study if paraquat exposure was dermal

[17] or intravascular [18]. They were also excluded if they did not have detectable paraquat levels in the urine and blood; had major comorbidities such as cancer, heart, lung, renal, or liver diseases; or simply did not give informed consent for endoscopic examination. The diagnoses of major comorbid- ities were based on detailed clinical, physical, and laboratory examinations. Patients with preexisting serum creatinine greater than 1.4 mg/dL or alanine aminotransferase (ALT) greater than 36 mg/dL or total bilirubin greater than 3 mg/dL were excluded.

Definitions of clinical events

Acute renal failure was diagnosed if serum creatinine increased to greater than 1.4 mg/dL (reference range, 0.4-1.4 mg/dL) [6-8]. Acute hepatitis was diagnosed when serum ALT was greater than 70 U/L (reference range, 0-36 mg/dL) or when total bilirubin was greater than 3.0 mg/dL (reference range, 0-1.3 mg/dL) [6-8]. Hypoxia was diagnosed if a patient had an arterial blood gas analysis of Pao2 less than 70 mm Hg in normal air [6-8,19]. A light smoker was defined as a current smoker who smokes less than 20 cigarettes per day [20]. A heavy smoker was defined as a current smoker who smokes 20 cigarettes or more per day, or a former smoker who smoked 20 cigarettes per day. A light drinker was defined as alcohol drinking of not more than 1 to 2 units per week or per occasion [21]. A moderate drinker was defined as alcohol drinking of not more than 3 to 6 units per week or 3 to 5 units per occasion. A heavy drinker was defined as alcohol drinking of 7 or more units per week or 6 or more units per occasion.

Protocol for paraquat detoxification

The protocol [6-8] includes gastric lavage with large amounts of normal saline, followed by infusion of 1 g/kg activated charcoal and 250 mL magnesium citrate via a nasogastric tube. Charcoal hemoperfusion was performed for 8 hours using a charcoal-containing (Adsorba, Gambro, Ger- many) dialysis machine (Surdial, Nipro, Japan) if the urine paraquat was more than 5 ppm. The extracorporeal technique was repeated if the urine paraquat was still more than 5 ppm at 4 hours after the first extracorporeal detoxification. Furthermore, all patients received pulse therapies of cyclophosphamide (15 mg kg-1 d-1) for 2 days and methylprednisolone (1 g/d) for 3 days, simultaneously, followed by dexamethasone (20 mg/d) for 14 days. The steroid pulse therapy was repeated if the Pao2 was less than 60 mm Hg, whereas cyclophosphamide pulse therapy was repeated if the white cell count was more than 3000/m3 at 2 weeks after the first cyclophosphamide treatment. Finally, normal-inspired oxygen therapy (FiO2 21%) was used for all patients throughout hospitalization.

Endoscopy

After an overnight fast, Upper gastrointestinal endoscopy was performed using standard flexible endoscopes. Injury to the upper gastrointestinal tract was reported as described by Zargar et al [13-15]: grade 0: normal findings; grade 1: edema, hyperemia of mucosa; grade 2a: friability, blisters, hemorrhaging, erosions, whitish membranes, exudates, and superficial ulcerations; grade 2b: grade 2a plus deep discrete or circumferential ulcerations; grade 3a: small scattered areas of multiple ulcerations and areas of necrosis (brown-black or grayish discoloration); and grade 3b: extensive necrosis. Different gastroenterologists who were not blinded to clinical data performed the endoscopies. In addition, the timing of endoscopic evaluations was not standardized among all subjects, but endoscopic studies were avoided between 7 and 21 days after paraquat ingestion. This is because mucosal sloughing usually occurs 4 to 7 days after the initial corrosive injury, followed by bacterial invasion, inflammatory response, and finally development of granula- tion tissue [13]. Because collagen deposition may not begin until the second week, the tensile strength of the healing tissue is lowest during the first 3 weeks [13].

Statistical analysis

Data were expressed as mean +- SD or number and percentage in parentheses, unless otherwise stated. All analyses were performed using SPSS 11.0 for Mac OSx (SPSS Inc, Chicago, Ill). Data were routinely tested for normality of distribution and equality of SDs before the analysis. For comparisons between patient groups, Student t test was used for quantitative variables, whereas ?2 or Fisher exact test was used for categorical variables. Cumulative

Fig. 1 Patient survivals examined by Kaplan-Meier analysis. There were no significant differences in patient survival between the 3 groups (logrank, P N .05).

incidence of patient survival was calculated by Kaplan-Meier method, and the difference was determined by logrank test. The criterion for significance was the 95% confidence interval to reject the null hypothesis.

Results

Of the 1410 paraquat cases seen from 1980 to 2007, most patients were excluded from this study because they simply were not evaluated by endoscopic examination (Table 1). Corrosive esophageal injuries were classified as grade 1 in 8 patients, grade 2a in 5 patients, and grade 2b in 3 patients. None of the patients experienced grade 0, 3a, or 3b esophageal injuries. No patient had a history of Peptic ulcers. There were no significant differences in terms of age, sex, alcohol use, Tobacco use, diabetes, or hypertension between the 3 groups (P N.05). Patients who reported current

Table 1 Demographics of patients, as stratified according to local complications (endoscopic findings) after paraquat poisoning (n = 16)

Corrosive esophageal injury

Grade 1 Grade 2a Grade 2b (n = 8) (n = 5) (n = 3)

Age (y)

32 +- 8.69

44.8 +- 17.6

32 +- 8.19

Female

6 (75)

4 (80)

2 (66.7)

Alcohol

Heavy drinker

0

0

0

Light drinker

5 (62.5)

3/2 (60)

2 (66.7)

Smoking

Heavy smoker

0

0

0

Light smoker

4 (50)

2 (40)

2 (66.7)

Diabetes mellitus

0 (0)

0 (0)

0 (0)

Hypertension

1 (12.5)

1 (20)

0 (0)

Peptic ulcers

0 (0)

0 (0)

0 (0)

Data are expressed as mean +- SD or n (%).

Variables

Grade 1 (n = 8)

Grade 2a (n = 5)

Grade 2b (n = 3)

Serum paraquat level (ug/ml)

0.09 +- 0.14

0.28 +- 0.5

4.63 +- 4.91 a

Interval from poisoning to detoxification treatment (d)

1.62 +- 1.41

2.4 +- 1.34

2.67 +- 1.53

Gastric lavage

8 (100)

5 (100)

3 (100)

Activated charcoal and magnesium citrate

8 (100)

5 (100)

3 (100)

Normal-inspired oxygen therapy (FiO2 21%)

8 (100)

5 (100)

3 (100)

Glucocorticoids and cyclosphosphamide

8 (100)

5 (100)

3 (100)

Charcoal hemoperfusion

2 (25)

4 (80) b

2 (66.7) a

Hypoxia

1 (12.5)

5 (100) b

3 (100) a

Nadir arterial blood Pao2, room air (mm Hg)

85.33 +- 10.71

59.34 +- 10.88 b

54.65 +- 17.18 a

Acute hepatitis

3 (37.5)

1 (20)

1 (33.3)

Peak serum ALT (u/l)

73.43 +- 103.86

119.4 +- 204.02

108.21 +- 156.17

Acute renal failure

3 (37.5)

4 (80)

2 (66.7)

Peak serum creatinine, mg/dL

1.56 +- 1.18

5.76 +- 4.19

3.9 +- 3.54

Mortality

0 (0)

1 (20)

1 (33.3)

Data are expressed as mean +- SD or n (%).

a Significance between grades 1 and 2b.

b Significance between grades 1 and 2a.

use of tobacco or alcohol were light smokers and drinkers only, rather than heavy consumers. In addition, none of the patients developed iatrogenic esophageal perforations after endoscopic examinations.

Table 2 Methods of detoxification, mortality, and systemic complications after paraquat poisoning (n = 16)

Table 2 shows methods of detoxification, mortality rates, and systemic complications after paraquat poisoning. The exact volume of paraquat consumed was difficult to ascertain in each case, but serum paraquat levels were determined immediately upon arrival (before detoxification treatment), and the mean levels were as follows: grade 1: 0.09 +- 0.14 ug/ mL, grade 2a: 0.28 +- 0.5 ug/mL, and grade 2b: 4.63 +- 4.91 ug/mL, respectively. After comparing the mean paraquat levels of patients in each category of esophageal injury, it was found that patients with grade 2b esophageal injury had higher serum paraquat levels than those with grade 1 esophageal injury (P b .05). However, there was no significant difference in the time interval from poisoning to detoxification treatment for the 3 groups (grade 1: 1.62 +- 1.41, grade 2a: 2.4 +- 1.34, grade 2b: 2.67 +- 1.53; P N .05).

All cases received gastric lavage with a large amount of normal saline, followed by infusion of activated charcoal and magnesium citrate. Supplemental oxygen was avoided in all patients. In addition, all patients received pulse therapies with glucocorticoids and cyclophosphamide as according to our protocol. Charcoal hemoperfusion was performed in 2 (25%) of 8, 4 (80%) of 5, and 2 (66.7%) of 3 patients with grades 1, 2a, and 2b esophageal injury, respectively. Therefore, patients with grades 2a and 2b esophageal injury received more charcoal hemoperfusion than did patients with grade 1 esophageal injury (P b .05).

After paraquat ingestion, systemic toxicity occurred with rapid development of hypoxia, acute hepatitis, and acute renal failure in many patients. Hypoxia occurred in 1 (12.5%) of 8, 5 (100%) of 5, and 3 (100%) of 3 patients with grades 1, 2a, and 2b esophageal injury, respectively. Therefore, there were more hypoxic patients in groups with grades 2a and 2b than

with grade 1 esophageal injury (P b.05). Moreover, the nadir arterial blood gasses were lower in patients with grades 2a and 2b than with grade 1 esophageal injury (P b .05). In addition, there were no significant differences in terms of acute hepatitis, peak serum ALT, acute renal failure, and peak serum creatinine between the 3 groups (P N .05). Finally, 2 patients (grades 2b and 2b esophageal injury each) died from pulmonary complications, whereas the other 14 patients recovered fully without any chronic disability. However, Kaplan-Meier analysis did not find any difference in survival between the 3 groups (P N .05, Fig. 1).

Discussion

This study demonstrates that in patients who have ingested paraquat, flexible endoscopy is a safe, reliable, and accurate diagnostic tool for early inspection for esophageal injury. No patients experienced endoscopy-related injuries. Of the 16 cases, corrosive esophageal burns were classified as grade 1 in 8 patients, grade 2a in 5 patients, and grade 2b in 3 patients. None of the patients experienced grade 0, 3a, or 3b esophageal burns. Therefore, it seems that paraquat is a mild caustic agent. Furthermore, the magnitude of corrosive esophageal injury (a local complication) may be associated with pulmonary toxicity (a systemic complication). In this study, 2 patients (one from grade 2a and another one from grade 2b esophageal injury) died of pulmonary complica- tions, whereas the other 14 patients recovered fully without any chronic disability. The mortality rates for grades 1, 2a, and 2b esophageal injury were 0%, 20%, and 33.3%, respectively. The Kaplan Meyer analysis did not find any difference in survival between the 3 groups (P N .05).

As previously discussed, literature on the spectrum of corrosive injury to the esophagus after paraquat or diquat ingestion is sparse and confined to case reports only [9-12]. In

1978, Ackrill et al [11] reported 2 fatal cases of esophageal perforation due to paraquat ingestion. The striking feature noted in these 2 cases was that there was total ulceration of the esophageal mucosa, but the stomach was spared. Whether the lack of gastric ulceration was due to the type of epithelium, the presence of acid, mucus, or other local factors is unknown. Valiante et al [12] later described a victim of severe panesophagitis and localized erosive hemorrhagic gastritis after accidental oral diquat exposure during work. Diquat is a widely used broad-spectrum bipyridynium herbicide that is quite similar to paraquat in its chemical, herbicidal, and biochemical effects [22,23]. Subsequently, Tanen et al [10] and Valiente et al [12] also reported a case of esophagitis after ingestion of a diluted diquat solution. Finally, Singh et al [9] presented 2 lethal cases of caustic esophageal burn after paraquat ingestion. Because ulceration of the mouth and pharynx is almost universal after paraquat ingestion [24], and pain on swallowing and severe retro- sternal discomfort are common among paraquat ingestion cases, the possible development of severe corrosive esopha- geal injury or perforation (although not present in our cases) should be kept in mind during management of these patients. Previous work on paraquat poisoning has shown that the plasma and urine concentrations obtained within the first 24 hours after ingestion are good predictors of outcome [25-27]. In a study by Proudfoot et al [26], plasma paraquat concentrations were measured in 79 patients who had ingested liquid or granular weedkillers containing paraquat. At any given time after ingestion, the plasma paraquat concentrations in the patients who died usually exceeded those in the survivors. It is suggested that measurement of plasma paraquat concentrations is useful in assessing the severity and in predicting the outcome of poisoning. Patients whose plasma concentrations do not exceed 2.0, 0.6, 0.3, 0.16, and

0.1 mg/L at 4, 6, 10, 16, and 24 hours, respectively, are likely to survive. Scherrmann et al [27] developed a nonexponential equation to extrapolate the “predictive line” for plasma paraquat concentrations beyond 24 hours. Plasma paraquat concentrations were measured in 30 patients who were admitted beyond 24 hours after overdose. The extrapolated line accurately predicted the outcome in 27 of these patients. Urine paraquat concentrations were measured in 53 patients. All patients with urine paraquat concentrations less than 1 mg/ L within 24 hours of overdose survived. In contrast, patients with urine paraquat concentrations more than 1 mg/L had a high Probability of death. Therefore, even if plasma paraquat concentrations have a higher predictive value, urine data may contribute to a more rapid evaluation of prognosis. Our data could potentially add to the evidence that a simple measure of corrosive esophageal injury (a local complication) by endoscopy could potentially predict pulmonary toxicity (a systemic complication) in the paraquat cases.

In a previous study [28], we first demonstrated that the Respiratory function and Pao2 levels of paraquat-poisoned survivors could gradually improve to near-normal levels after 3 months of follow-up, even in the presence of lung fibrosis.

Hence, the severe inflammation, not the fibrosis, of lungs plays a major role in the lethal hypoxemia in patients with paraquat poisoning during the subacute period of intoxica- tion. It is known that Methylprednisolone pulse therapy and dexamethasone are strong anti-inflammatory drugs. Pulse therapy after dexamethasone treatment can attenuate the severe inflammation of paraquat poisoning; hence, the survival rate of paraquat-poisoned patients improved in our studies [6-8]. In addition, methylprednisolone pulse therapy can suppress superoxide production by neutrophils and macrophages by reducing cytokine and inflammatory med- iator release from lymphocytes [29]. Steroids also suppress the formation of superoxides in the arachidonic acid cascade. All of these effects may be why repeated methylprednisolone pulse therapy can prevent further pulmonary free radical damage and subsequent inflammation in these patients.

The reference range of Pao2 values is 75 to 100 mm Hg in our hospital, and the reference level for oxygen saturation in Healthy adults is 95% to 98%. In chronic smokers, the blood oxygen level may be reduced, and therefore, resting oxygen saturation may be lower than reference values [30]. Smoking could produce carbon monoxide, which binds to hemoglobin much more readily than to oxygen. This could reduce the hemoglobin available for transporting oxygen to the brain, causing hypemic hypoxia. Alcohol could inhibit cells from having the ability to effectively use oxygen, causing cytotoxic hypoxia. However, it was reported in a study that unlike nonsmokers, the Pao2 of a smoker does not increase fully during moderate exercise. Just as at rest, the Pao2 of a smoker performing moderate exercise remained lower than that of a nonsmoker (87.6 +- 15.8 vs 94.1 +- 10.4 mm Hg; P b

.0001) [30]. Because patients who developed major organ complications in this study were not restricted to the smoking or alcohol group, it seemed that the paraquat toxicities were not related to underlying smoking or alcohol use, which was only light use in all study patients.

In summary, endoscopy is a safe, reliable, and accurate diagnostic tool for early evaluation of the esophagus after paraquat ingestion. Paraquat is a mild corrosive agent, but the degree of esophageal injury (a local complication) may be associated with pulmonary toxicity (a systemic complication) after oral poisoning. However, the small patient population, small number of endoscopies, absence of an endoscopy protocol during the initial hospitalization and after discharge periods, lack of standardization of timing of endoscopy, lack of endoscopic evaluations performed by a single gastroenter- ologist (who was blinded to clinical data), and a relatively short follow-up period limit the certainty of our conclusions.

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