Failed rescue therapy with rapamycin after paraquat intoxication

Abstract

Introduction. Ingestion of large quantities of paraquat leads to irreversible, often fatal pulmonary fibrosis. Case presentation. A 50-year-old man (body weight of 78.6 kg) ingested 500 mL Gramoxone® containing 200 g/L of paraquat in a suicide attempt. The patient did not seek medical attention until 15 h after ingestion. Initial treatment consisted of the administration of intravenous methylprednisolone, 250 mg once daily. Seventy-two hours after ingestion the patient was transferred to our tertiary care center. Paraquat concentration was 0.2 mg/L in the serum and urinary concentration was 4.42 mg/L. Antioxidative therapy including the administration of acetylcysteine and an anti-inflammatory therapy employing methylprednisolone (1 g/day) was started. Extended daily dialysis was initiated. As the high plasma concentration of paraquat indicated a 100% predicted mortality, we expanded treatment strategies by using the antiproliferative agent rapamycin. A dose of 8 mg/day was started 72 h after the intoxication. Maximum rapamycin concentrations amounted to 12.9 μg/L. Despite these efforts, the patient died on day 18 after intoxication from respiratory failure caused by severe pulmonary fibrosis. Conclusion. Despite theoretical considerations suggesting the use of rapamycin in paraquat poisoning, the substance failed to halt the progression of pulmonary fibrosis in this case.

Keywords:

• Paraquat
• Intoxication
• Hemodialysis
• Fatal
• Acute renal failure

Introduction

Paraquat (1,1-dimethyl-4,4′-bipyridylium chloride) is the most important member of the bipyridyl herbicides, widely used in agriculture to desiccate crops for harvesting and to kill weeds. After accidental or suicidal ingestion, paraquat leads to the generation of superoxide, singlet oxygen, hydroxyl, and peroxide radicals. Clinical symptoms after oral ingestion start with buccal and/or esophageal ulcerations. Acute kidney injury may occur within 2–6 days of ingestion, which further impairs paraquat excretion.¹ Based on the quantity of paraquat ingested, the pulmonary involvement can progress to an irreversible, often fatal pulmonary fibrosis.² Paraquat was banned in the European Union (EU) in 2007 for “not meeting health standards” (http://www.epha.org/a/826). Treatment options in paraquat poisoning are limited. Although repeated pulses of methylprednisolone and cyclophosphamide with continuous dexamethasone have shown a promising effect in a randomized controlled trial,³ the sample size precluded a definitive conclusion as to the efficiency of this treatment strategy.⁴ We present a case of paraquat intoxication, in which a fatal amount (based on patient history and 24 h urine concentration) was ingested. This is the second report on the use of the mammalian target of rapamycin (mTOR)-inhibitor rapamycin,⁵ which we administered on top of established treatment regimes for paraquat intoxication. The rationale to use rapamycin was to take advantage of its antiproliferative effect in light of imminent pulmonary fibrosis.

Case presentation

A 50-year-old man with a body weight of 78.6 kg, allegedly ingested 500 mL Gramoxone® containing 200 g/L of the herbicide paraquat (1,1′-dimethyl-4,4′-bipyridylium dichloride) in a suicide attempt. The patient did not seek medical attention at first, but did so 15 h after ingestion, presenting to the emergency room of a local community hospital. Initial treatment consisted of the administration of intravenous steroids, 250 mg once daily. Activated charcoal was not administered. Because Gramoxone® contains an emetic, the patient vomited spontaneously within minutes after the ingestion. The patient's vital signs and laboratory parameters were reported to be “normal” at initial presentation that luckily prevented initial oxygen therapy.

Seventy-two hours after ingestion the patient was transferred to our tertiary care center. Upon admission the patient was clinically stable with a blood pressure of 150/70 mmHg and a heart rate of 70/min. His respiratory rate was 25 breaths per minute. His physical examination was remarkable for buccal and tongue ulcerations. The blood gas analysis showed hypoxemia (pH 7.43, pO₂: 44 mmHg, pCO₂: 40 mmHg, HbO₂ 80%). We also found laboratory signs of toxic liver damage (GOT 209 U/L, GPT 356 U/L, GLDH 380 U/L, gammaGT 780 U/L, INR (international normalized ratio) 1.59, serum-albumin 28 g/L), acute kidney injury (serum-creatinine 500 μmol/L, urea 23 mmol/L) 72 h after ingestion, and paraquat was detected at a concentration of 0.2 mg/L in the serum whereas the urinary concentration amounted to 4.42 mg/L. Fatal outcomes are usually associated with plasma concentrations greater than 0.2 mg/L at 24 h after ingestion and 0.1 mg/L at 48 h or with the ingestion of 40–50 mg paraquat ion/kg body weight.⁶ Computed tomography of the chest 14 days postingestion showed diffuse proliferation of interstitial tissue indicating progressive pulmonary fibrosis.

We immediately started an antioxidative therapy to reduce the formation of reactive oxygen species including the administration of acetylcysteine (10 g over a period of 24 h intravenously) and an anti-inflammatory therapy employing methylprednisolone (1 g/day). To enhance clearance of paraquat, the patient initially received a 4-h hemodialysis session (blood flow 270 mL/h) using the GENIUS® – system with a high-flux polysulfone dialyzer [surface area: 1.3 m² (F 60 S)] (all Fresenius Medical Care, Bad Homburg, Germany). At the evening of the first day in our hospital, a 14-h extended dialysis using the same dialyzer as mentioned above was initiated. Thereafter, he received daily extended dialysis sessions over 8–12 h until day 5 of the hospital stay. During the stay in our hospital, the patient was never anuric. After discontinuation of the dialysis therapy, the patient's renal function measured by a 24-h urine collection showed a severe renal injury (creatinine clearance: 25 mL/min). Oxygen therapy was started on day 12 postingestion. As the high plasma concentration of paraquat indicated a 100% predicted mortality⁶ and lung transplantation was not feasible given the psychiatric background of the intoxication, we decided to expand treatment strategies by using the antiproliferative agent rapamycin. A dose of 8 mg/day was started 72 h after the intoxication. Maximum rapamycin concentration amounted to 12.9 μg/L, which based on the experience from solid organ transplantation is safe in terms of side effects, yet efficient in terms of its antiproliferative effect.⁷ Despite this treatment regimen, the patient developed progressive respiratory failure with radiological signs of rapidly progressive pulmonary fibrosis and died on day 18 after intoxication (Fig. 1). One day before his death, the paraquat concentration in the urine still amounted to 0.62 mg/L.

Fig. 1.  The clinical course of the patient and therapeutic interventions.

Discussion

Treatment options in paraquat poisoning are limited and focus on the prevention or slowing of progression of the fatal pulmonary fibrosis.

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, a streptomycete species that was isolated from a soil sample collected from Easter Island (Rapa Nui).^8,9 It is widely used as an immunosuppressive agent in patients after solid-organ transplantation. Rapamycin forms a complex with the intracellular protein, FKBP12, which blocks the activation of the cell-cycle-specific kinase, mTOR. The inhibition of mTOR blocks IL-2-mediated signal transduction pathways that prevent cell cycle progression from G1 to S phase in T cells explaining its immunosuppressive and antiproliferative effect.¹⁰ In a study involving male Lewis rats, the application of rapamycin halted the development of pulmonary fibrosis induced by bleomycin.¹¹ The agent had a dramatic inhibitory effect on the lung-collagen accumulation. This was the rationale to use rapamycin in our patient as a rescue therapy before the first report on the use of rapamycin by Barrueto et al. was published.⁵ In contrast to their patient, treatment in our patient could not prevent the development of the fatal pulmonary fibrosis, despite the fact that rapamycin was started earlier, that is, 72 h after intoxication in contrast to day 12 of the hospital stay in the case reported by Barrueto. This might be due to several reasons. First, the dose of ingested paraquat in our patients was about 100 g whereas the patient reported by Barrueto et al. ingested about 29 g. This is also reflected by the fact that 72 h after ingestion our patient had a higher serum paraquat level of 0.2 mg/L as compared with 0.08 mg/L 4 days postingestion in the case report by Barrueto et al. Even 17 days after the intoxication, our patient had a urine paraquat concentration of 0.62 mg/L. Second, our patient ingested an old paraquat formulation (Gramoxone®) in contrast to the patient treated by Barrueto and colleagues who ingested Gramoxone Inteon®. This new formulation contains the polysaccharide alginate that gels on contact with gastric acid. The resulting mixture slows the dispersion and delivery of the toxic chemical to its site of absorption in the small intestine. Alginates also protect the mucosa against the damaging influence of topical gastric irritants, like paraquat.

Our case report has several limitations. First, our patient had ingested a most likely fatal dose of paraquat; therefore the administration of rapamycin, even if associated with positive effects, could not halt the progression of pulmonary fibrosis in this case. Second, the delay in treatment due to the late referral of the patient could have foreclosed possible positive effects of rapamycin. Despite the failure of rapamycin to prevent pulmonary fibrosis in our patient, this substance has several properties that could make it a potential drug to prevent pulmonary fibrosis in conjunction with other drugs such as steroids and cyclophosphamide, namely its antiproliferative effects on fibroblast and lymphoid cells.

Further studies are required to determine whether rapamycin may have a therapeutic potential in paraquat poisoning.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.