Use of sirolimus in a case of severe paraquat poisoning

To the Editor:

Ingestion of more than 40 to 50 mg paraquat ion/kg is considered to have a 100% mortality rate, with patients often dying from cardiogenic shock or multiorgan failure (14). Patients who survive the acute phase may die later from pulmonary fibrosis with resultant hypoxia. We describe the management of a man who ingested paraquat in an amount that would typically be considered fatal.

A 27-year-old man, in a suicide attempt, ingested half a cup (4 ounces, approximately 120 mL) of Gramoxone Inteon® (Syngenta Crop Protection, Greensboro, North Caro-lina), a formulation containing 240 g/L paraquat ion, from a supply stored in his landscaping truck. Thirty minutes after the ingestion, he vomited several times and went to a community emergency department (ED). He complained of burning in his chest and mouth. He was admitted and underwent EGD, which showed a hiatal hernia, a small triangular ulcer (<1.5 mm) at the esophageal/gastric junction, and diffuse erythema with punctate ulcerations of the stomach and antrum. The patient was discharged after 24 hours of observation but returned 3 days later with hemoptysis and shortness of breath. He was immediately transferred to a tertiary care facility.

He had no relevant medical or surgical history. He was on no medications. Social history showed he drinks alcohol 2 or 3 days a week and has used marijuana and cocaine in the past. Vital signs were temperature 102.3°F, pulse 108 beats/minute, blood pressure 132/71 mm Hg, respiratory rate 31 breaths/minute, pulse oximetry 90% on room air. The patient was well-nourished and in moderate respiratory distress.

Head and neck examination revealed no oropharyngeal burns or ulcerations. Lung examination showed diffuse rhonchi and tachypnea but no accessory muscle use. Cardiovascular examination indicated tachycardia but no murmur, rub, or gallop. Abdominal examination was benign, and neurologic examination revealed an alert and oriented man with no focal deficits.

Laboratory investigation included a comprehensive metabolic panel, with the following results: Na⁺ 132 mEq/L, K⁺ 3.0 mEq/L, Cl^- 95 mEq/L, CO₂ 22 mmol/L, BUN 57 mg/dL, creatinine 6.0 mg/dL, Ca²⁺ 9.2 mg/dL, phosphorus 3.5 mg/dL, Mg²⁺ 2.0 mg/dL, aspartate aminotransferase 24 U/L, alanine aminotransferase 78 U/L, total bilirubin 0.6 mg/dL. Complete blood cell count revealed: white blood cell (WBC) count 18.0 K/mcL; hemoglobin 11.7 g/dL, hematocrit 33.5%, platelets 162 K/mcL. A chest radiograph showed bilateral diffuse patchy infiltrates, worse on the right than left. Arterial blood gas analysis on room air gave the following results: pH 7.47, PCO₂ 36 mmHg, PO₂ 56 mmHg, HCO₃ 25 mmol/L. The serum paraquat concentration measured spectrophotometrically 4 days post-ingestion by National Medical Services, Inc. (NMS) was 0.08 mcg/mL (reference value <0.06 mcg/mL) and urine paraquat concentration was 0.76 mcg/mL (per NMS, asymptomatic sprayers up to 0.3 mcg/mL urine).

After arrival at the tertiary care center, the patient was started on methylprednisolone 1 g IV each day for 3 days and dexamethasone, 6 mg IV every 6 hours. He was also started on a cycle of cyclophosphamide 1.7 g IV each day for 2 consecutive days (FIG. 1). An IV infusion of N-acetylcysteine at a rate of 685 mg/hr was administered for 7 days. Supplementation with vitamin C and vitamin E was given throughout the hospitalization. The patient underwent continuous veno-venous hemodialysis for 3 days, followed by intermittent hemodialysis for 3 more days, until his creatinine normalized to 1.4 mg/dL on hospital day 6. At that point, hemodialysis was discontinued. The patient's respiratory status worsened, requiring oxygen supplementation (FIG. 1). On hospital day 8, computed tomographic scan of the chest revealed diffuse pulmonary fibrosis and pneumomediastinum. An esophagram indicated no signs of perforation.

Fig. 1.  Correlation of pulse oximetry readings with therapeutic interventions.

Sirolimus therapy was initiated on hospital day 12 to limit further pulmonary fibrosis and continued for 15 days. The patient became neutropenic secondary to cyclophosphamide (WBC count 0.2 K/mcL) prompting treatment with filgrastim. In response, the WBC count peaked at 29.6 K/mcL but returned to normal limits at 10.2 K/mcL. On hospital day 14, an iliofemoral deep venous thrombosis developed at the site of a central venous catheter, leading to the initiation of enoxaparin and coumadin therapy. After hospital day 39, the patient's resting pulse oximetry level was 90% on 2 L of oxygen via nasal cannula. He was able to perform basic activities of daily living and was transfered to the inpatient psychiatric ward.

The reported ingestion of an expected fatal dose of this new formulation of paraquat was associated with survival in this case. Decreased absorption in this case may have been due to the new formulation, historical inaccuracy of the ingested dose, or rapid vomiting before the included emetic was effective. The patient self-reported ingesting 4 ounces (approximately120 mL) of Gramoxone Inteon® containing 240 g/L paraquat ion, equivalent to several lethal doses.

The initial treatment for this patient mirrored a protocol developed by Lin et al. (5), which achieved a decrease in mortality from 85.7% to 31.3%. It must be emphasized that with renal failure and gastric lesions present, his mortality was expected to be extremely high and thus felt the risk-benefit ratio favored aggressive management. When it appeared that the hypoxia was worsening despite this therapy, sirolimus was administered.

Pulmonary fibrosis is an inflammatory response to lung injury, mediated by growth factors and cytokines and leading to deposition of extracellular matrix proteins into the pulmonary interstitium (6). Sirolimus interferes with the inflammatory response in a different mechanism than cyclophosphamide or steroids by inhibiting the proliferation of growth-factor–stimulated adult lung fibroblasts (7,8). Sirolimus is a triene macrolide immunosuppressant as well as an anti-tumor and anti-fungal agent that has antiproliferative effects on fibroblasts and on lymphoid and non-lymphoid tumor cells (9). We reasoned that sirolimus in conjunction with cyclophosphamide and steroids may be of benefit in halting the progression of paraquat-induced pulmonary fibrosis.

Acknowledgment

We thank Dr Martin Wilks (Senior Medical Adviser, Syngenta Crop Protection AG, Basel, Switzerland) for valuable discussions and background information on Gramoxone Inteon®.