Search

Knowledge of the kinetics of an intoxicant is required for designing potential therapies in poisoned patients. In the case of paraquat, elucidating the kinetics has been made difficult by the paraquat-induced renal failure and the consequent dose- and time-dependent elimination of the herbicide. In the current study, we have modelled the plasma and urinary concentrations of paraquat in dogs given a toxic dose, the elimination of which was nonlinear. This enabled us, in turn, to simulate the apparent concentrations of paraquat in the deep tissue compartment, part of which is constituted by the major target organ for paraquat toxicity, the lung. Finally, we defined conditions, if any, under which charcoal hemoperfusion could reduce exposure of the deep compartment to paraquat by > or = 25%. We found that the plasma concentrations of paraquat could be described by a two compartment model with non-linear elimination from the central compartment. Use of a three compartment model did not improve the fit over that for a two compartment. The volume of distribution of paraquat at steady state approximated that of total body water. Simulated hemoperfusion performed for eight or eighty hours did not reduce exposure of the deep compartment to paraquat by > or = 25%, unless begun at times < or = two hours of the infusion commencing. This is consistent with our experimental data in the dog. The lack of efficacy of hemoperfusion is due to the rapid renal elimination of most of the absorbed dose of paraquat over the first 12 hours after its administration, and the later limitation of the rate of removal of paraquat from the body by the slow efflux rate from the deep to central compartment.

Prompt hemodialysis or hemoperfusion can be of value during the first 24 hours after paraquat ingestion particularly when the patient has developed acute renal failure. However, many cases of paraquat poisoning occur in areas where hemoperfusion facilities are unavailable. In contrast, continuous arteriovenous hemofiltration (CAVH) could be instituted easily. We have measured the removal of paraquat from the body by CAVH in a 46 year old male cane farmer who ingested 70 ml, 20% paraquat and died twelve days later from pulmonary fibrosis. Renal failure developed rapidly. Concentrations of paraquat were measured by an indirect competitive ELISA using a murine paraquat monoclonal IgG antibody. Hemoperfusion was performed daily for five days, beginning 78 hours post-ingestion. By 180 hours, when the patient was in respiratory failure, hemoperfusion was replaced with CAVH which was continued for 46 hours. During this time interval, 1.1 mg paraquat was recovered in the hemofiltrate and 1.56 mg paraquat in the urine. The extraction of paraquat by the hemofilter was close to 100%. The plasma clearance of paraquat across the hemofilter was 6.1 ml/min and the renal clearance was 8.2 ml/min. The mean hemoperfusion clearance of paraquat was 50 ml/min and the total amount of paraquat removed by the 34 hours of hemoperfusion was 9 mg. Because of the relative ease with which CAVH can be performed, its low cost, compared to that of hemoperfusion or hemodialysis, and the continuous nature of the procedure, CAVH may be worth considering in paraquat poisoning. It could be used particularly in those patients who have developed renal failure or while patients are being prepared for hemoperfusion.

A 28-year-old woman ingested an estimated 58 g acetaminophen and 9 g propoxyphene 20 h before hospitalization. Her serum acetaminophen concentration at 22 h was 485 micrograms/mL and declined with an unusually long half-life of 14 h. Hemodialysis for 4 h (started at 36 h) reduced the acetaminophen concentration from 250 to 32 micrograms/mL. The patient's complete recovery was remarkable because of the large amounts of drugs ingested, the delayed treatment, and prior exposure to enzyme inducers (known to increase acetaminophen hepatotoxicity). Administration of N-acetylcysteine prevented inorganic sulfate depletion usually caused by acetaminophen and may have increased the formation of acetaminophen sulfate. Some patients eliminate large overdoses of acetaminophen very slowly. Measures to enhance the elimination of this drug and its toxic metabolite by these individuals may be useful even when diagnosis or hospitalization is delayed.

Charcoal and resin hemoperfusion or hemodialysis can accelerate theophylline elimination. Their benefit in the treatment of poisoned patients has been accepted on the basis of case reports. We reviewed the treatment of 26 patients with acute theophylline intoxication to determine how much of an effect hemoperfusion or hemodialysis had on the hospital course and outcome of the overdose. Eighteen patients received supportive care and eight patients hemoperfusion (HP) or hemodialysis (HD). The HP/HD patients had more severe theophylline intoxication on the basis of admission and peak theophylline levels, degree of hypotension and occurrence of arrhythmias. During HP/HD, theophylline concentrations decreased, heart rate slowed, blood pressure increased and evidence of central nervous system effects diminished. Despite the severe intoxication in the HP/HD groups, duration of clinical toxicity was shorter (13.5 +/- 7.1 vs. 21.6 +/- 14.1 hr) than in the control group. Seizures occurred in patients in both groups, but there was higher mortality or neurological morbidity in the supportive care (3/4) than in the HP/HD (1/5) group. Our study provides evidence that HP/HD can reduce the duration of clinical intoxication and probably reduces mortality and morbidity in patients with severe theophylline intoxication.

A 2 1/2 year old boy accidentally ingested the herbicide diquat. Progressive neurologic dysfunction preceded his death 143 hours after poisoning. Brain stem infarction and purpura were noted at post mortem and closely resembled the brain stem pathology in 3 of 7 adults who died after diquat ingestion. Renal, gastrointestinal and pulmonary involvement in this child also resembled that seen in adults after ingestion of diquat. Hemoperfusion was performed six times in an effort to lower the body diquat burden. Cellulose-coated, activated charcoal was first employed 40 hours postingestion and removed diquat from serum with clearances of 104 and 39 ml/minute at the initiation of hemoperfusion and 6 hours later, respectively. Serum diquat concentrations decreased rapidly during charcoal hemoperfusion. However, marked rebound in serum diquat concentrations were noted between charcoal treatments, indicating extensive sequestration of diquat by tissues. Thrombocytopenia and hypocalcemia, the major complications of charcoal hemoperfusion, were easily treated. Unlike charcoal, Amberlite XAD-4 resin hemoperfusion did not remove diquat from serum. Charcoal hemoperfusion may temporarily reduce serum diquat concentrations. Whether the early institution and daily performance of charcoal hemoperfusion will minimize diquat-induced damage to brain and other organs is not clear from this case and will only be determined in future studies.

A 50-year old female who was comatose from an overdose of lithium was treated with hemodialysis. Serum lithium concentrations declined 47% during a 3-h hemodialysis but increased afterwards, peaking 8 h after hemodialysis was stopped. Hemodialysis clearances were estimated by equations using extraction ratios of lithium from whole blood, serum, and red cells, and flows of whole blood, serum or red cells. The amount of lithium removed was calculated from these clearances as well as measured directly in the dialysate. Errors were introduced into the calculation of the amount of lithium removed by hemodialysis unless whole blood concentrations of lithium and whole blood flows were used. These arose because extraction of lithium from serum (0.7 +/- 0.3, mean +/- SD) was greater than that from whole blood (0.49 +/- 0.06) or from red blood cells (0.18 +/- 0.12). Despite the rapid decrease in serum concentrations of lithium during hemodialysis and rebound afterwards, the patient's neurologic status did not change concurrently. The patient did not regain consciousness until lithium concentrations fell to less than 0.4 meq/L in serum and 0.1 meq/L in cerebrospinal fluid. The lack of parallel change in serum concentrations and coma probably reflects the lag time in equilibration between lithium concentrations in serum and brain.