Comparison between Kidney and Hemoperfusion for Paraquat Elimination

Paraquat (1,1'-dimethyl-4,4'-bipyridium dichloride, PQ) is one of the most widely used herbicides in the world. In humans, intentional or accidental, ingestion of PQ is frequently fatal, resulting from significant lung injury (1). Over the past 30 yr, several methods for modifying the toxicity of PQ have been examined including prevention of absorption from the gastrointestinal tract (2, 3), removal from the bloodstream (4, 5), prevention of accumulation in the lungs (6, 7), scavenging oxygen free radicals (8, 9), and prevention of lung fibrosis (10, 11). Unfortunately, most of these methods have not been effective; the outcome is determined by the degree of exposure to PQ.

The mortality rate after PQ poisoning is strongly affected by the plasma PQ levels as well as the amount of the PQ intake (12-15). Consistent with this, it is clear that hemodialysis (HD) or hemoperfusion (HP) is a critical factor during the initial stages of intoxication. In agreement with previous reports, we recently reported that PQ clearance is more effective with HP than with HD (16). However, there are no reports on the positive effects of HP after PQ poisoning (17-20). Therefore, it is unclear to nephrologists and/or the toxicologist how to eliminate PQ from the system of patients with acute PQ intoxication. We have reviewed previous reports to determine what the specific concerns have been with HP and PQ elimination. We found that the efficacy of HP elimination was not evaluated properly in most prior studies (17-21).

The kidney has been shown to eliminate PQ very effectively, even better than creatinine elimination (22, 23). However, some degree of renal failure is frequently observed with acute PQ intoxication (21-24). This study was designed to determine the efficacy of PQ elimination with HP, taking into account renal elimination, in acute PQ intoxication.

This study was approved by ethics committee of Soonchunhyang University Cheonan hospital and received a written consent from the subjects and/or their family. Ten patients (6 males and 4 females, between 25 and 70) with acute PQ intoxication were enrolled in this study (Table 1). The ingestion amount of PQ was 153.0±89.3 mL of 23.1% PQ solution and the time lag from PQ ingestion to the emergency room evaluation was 4.5±2.8 hr. The dithionite urine test was strongly positive in all of the subjects. Two patients survived and eight patients within the fifth hospital day. Table 2 summarizes the laboratory findings measured in the emergency room.

Table 1
Age, sex, and PQ levels of the subjects at emergency room

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Table 2
Laboratory findings of the cases at the emergency room

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The dithionite urine test was carried out in the emergency room, as soon as the patient arrived and was considered to have acute PQ intoxication. All of the patients underwent HP as long as the vital signs were stable. HP was carried out through a jugular venous catheter for three hr at a blood flow rate of 200 mL/min. The HP membrane used was an adsorba 300 C, Gambro (Gambro Dialysatoren GmbH Co., KG Hechingen, Germary) that had polypropylene housing material, activated charcoal adsorbent, a 300 m² surface area, and cellulose coating material for the adsorbent.

Blood samples for PQ and creatinine were obtained from the arterial and venous lines of the tubing system at time 0,1 hr, 2 hr, and 3 hr of HP. Urine samples were collected every hour during the HP procedure through a urinary catheter. Plasma and urine samples for the PQ assay were stored at -70℃ until high performance liquid chromatography was performed.

The plasma PQ level changes by unique kinetics, reaching a peak level very early about 60-90 min after ingestion upon disruption of the gastric mucosal barrier (22, 25). Once the peak is reached, the level slopes down rapidly even without extracorporeal elimination (22). Therefore, the toxicokinetics at a given time should be interpreted along with the plasma levels of PQ. A three-compartment model has been proposed for the most accurate description of the PQ distribution: 1) Plasma compartment, 2) Compartment with rapid uptake and removal such as the kidney, and a 3) Slow uptake compartment such as the lungs, reaching a maximum concentration about 4-5 hr after ingestion regardless of the plasma PQ level (22). This model explains the plasma PQ level changes by not only renal excretion factors but also the involvement of other tissue adsorption of PQ.

The efficacy of HP in eliminating PQ is a function of the reduction rate of the HP cartridge, the blood flow and the plasma levels. In our study, the reduction rate was 0.94±0.04, which showed high efficacy throughout the three hours of HP in all subjects. With an almost constant reduction rate and a fixed value for the blood flow, the main variable factor of the HP for the elimination of PQ appears to depend on the plasma levels of PQ. A linear correlation between the eliminated amount of the PQ and the plasma PQ levels suggests that an earlier initiation of HP, as early as the PQ peak, would be the most effective method for the elimination of PQ.

The frequent deterioration of kidney function after PQ intoxication makes its role in eliminating PQ complicated. In agreement with previous reports (23, 24), the kidney eliminates more PQ than the HP, and can be very effective when the creatinine clearance remains in the normal range (Fig. 1, 2). However, once the renal function begins to deteriorate so does the ability to eliminate PQ (Fig. 1, 2).

Therefore, the efficacy of the kidneys and HP in the elimination of PQ varies depending on a number of factors. The kidney is very effective in eliminating PQ but vulnerable to PQ injury. PQ is metabolized very poorly, and is excreted intact in the urine (26). Renal injury is caused by reactive oxygen species (ROS); their presence progresses very rapidly, causing life threatening clinical features with acute PQ intoxication (27, 28). Deterioration of renal function is frequently observed early in patients with acute PQ intoxication when the PQ level is more than the lethal level (21-24). Therefore, renal protection is critical during the early treatment of PQ intoxication.

The elimination of PQ during HP is limited by the blood flow dynamics which is driven through a jugular venous catheter at a rate of 200-300 mL/min in adults. Keeping in mind both the large PQ distribution volume of 1.0-1.5 L/kg body weight (22, 25) and the very rapid progression of ROS injury with PQ intoxication, the PQ elimination process is pressed for time and blood flow.

In conclusion, our results suggest that early HP must be provided for life saving treatment in patients with acute PQ intoxication, especially in early deterioration of renal function or high plasma levels of PQ.