Hemoperfusion versus Hemodialysis in the Management of Patients Severely Poisoned by Organophosphorus Insecticides and Bipyridyl Herbicides

Organophosphorus insecticides (parathion, demeton-S-methyl sulfoxide, dimethoate) inhibit cholinesterase activity. Besides the well-known resulting biochemical changes, there is evidence of direct toxic effects due to an excess of organophosphorus in blood and tissue. The therapeutic measure described here aims at eliminating organophosphorus. Hemodialysis (HD) has no effect in parathion poisoning, but hemoperfusion with coated activated charcoal (HP-CHAR) results in a clearance of 59.20% of the blood flow (ml/min) while the HP clearance with Amberlite XAD-4 (HP-XAD) is 81.33%. HD may be used in poisoning by demeton-S-methyl sulfoxide (clearance: 52.98%), and dimethoate (clearance: 59.07%), but HP-CHAR clearance is much higher (83.70% and 87.84%, respectively). HP-XAD clearance even reaches 100% of the blood flow. Demeton-S-methyl sulfoxide and dimethoate are distributed almost equally in blood and tissue, and the effect of HP is indicated by a rapid decline in blood organophosphorus level as well as by an improvement in the signs and symptoms of the patient. Parathion accumulation is six to eight times higher in the tissue. This means there is protracted decline in blood level because of redistribution and less clinical evidence of improvement. However, animal trials demonstrate that HP-CHAR results in a significantly faster decrease in parathion concentration in muscle and brain as compared with the control group. Hence, HP is an effective method for removing toxicologically relevant amounts of organophosphorus from the body. Oral poisoning with bipyridyl herbicides such as paraquat (Gramoxone®) and diquat (Reglone®) is extremely serious. Fatal consequences occur after even one to three mouthfuls of the commercial liquid preparations. The literature reports that patients whose plasma levels within the first 48 hours exceed 0.1-0.2 μg/ml have died, regardless of therapy. Recently, two patients with severe suicidal poisonings were treated by almost continuous HP (and HD) using 12 and 21 columns, respectively, for a period of two to three weeks. Paraquat plasma levels were 1.12 μg/ml and 1.44 μg/ml, respectively, within the first 48 hours after ingestion. Both patients survived without lung damage. HP-CHAR clearance (72.7 ml/min, blood flow 100 ml/min) clearly exceeds that of HD (11.5 ml/min, blood flow 100 ml/min) at these blood levels. Probably the affinity of coated activated charcoal for paraquat is superior to that of lung tissue. Hence, continuous HP-CHAR is recommended in severe paraquat poisoning.     

Deferoxamine and coated charcoal hemoperfusion to remove aluminum in dialysis patients

We studied the in vitro and in vivo characteristics of aluminum (Al) removal by coated charcoal hemoperfusion (HP) in combination with intravenous deferoxamine (DFO). DFO enhanced the clearance of Al by HP in vitro after 180 minutes of perfusion with a solution containing 403.3 +/- 14.0 ng/ml of Al at 150 ml/min. The Al clearance was 139 +/- 1.0 ml/min with DFO and 49 +/- 10.0 ml/min (P less than 0.001) without DFO. Addition of DFO enhanced in vitro Al removal from 5.5 +/- 0.9 mg to 10.0 +/- 1.2 mg (P less than 0.05). During our in vivo studies, an HP device was in series in the dialysis circuit after a Cuprophan hemodialyzer. Eight patients with Al toxicity were studied on twelve occasions. Patients received DFO (40 mg/kg) 40 hours before the study. The total Al clearance with the combined hemodialysis (HD) and HP devices was higher than that obtained by the dialyzer alone at 30 minutes (62 +/- 4.9 ml/min vs. 25 +/- 2.5 ml/min, P less than 0.02) and after 180 to 210 minutes (32 +/- 3.0 ml/min vs. 19 +/- 2.9 ml/min, P less than 0.02). After 120 minutes the Al clearance by the HP device alone was significantly lower than the initial Al clearance by HP. Combined HD plus HP removed 2.9 +/- 0.4 mg of Al, whereas the total removal of Al by HD alone was 1.5 +/- 0.3 mg (P less than 0.01).     

Clinical studies on paraquat poisoning; prognosis and severity index of paraquat poisoning using the urine levels

The prognosis of paraquat poisoning has been assessed from serum paraquat levels using e.g. produfoot survival curve. The prognosis of paraquat poisoning has not been investigated from urinary paraquat levels. The purpose of this study is to clarify whether the prognosis of paraquat poisoning can be determined by urinary paraquat levels or not. Urinary severity index of paraquat poisoning (U-SIPP) was employed. U-SIPP is calculated as hours between ingestion of paraquat and start of intensive treatment multiplied by the paraquat level in the urine at the same time. Urinary excretion of paraquat is correlated with renal function. The prognosis of paraquat poisoning using U-SIPP was further discussed, based on creatinine clearance (Ccr) and the relation between serum and urine paraquat levels. The following results were obtained. 1) When creatinine clearance was greater than 20 ml/min, patients who died of circulatory failure were with U-SIPP level over 1250, patients who died of respiratory failure were with U-SIPP level between 1250 and 250, and survivors were with U-SIPP below 250. 2) Survival duration was closely correlative with U-SIPP in cases with Ccr greater than 20 ml/min (r = 0.8123, p less than 0.025). 3) When Ccr was greater than 20 ml/min, urinary paraquat levels were correlated very well with the serum levels at admission, even during direct hemoperfusion (DHP) treatment. 4) When diuretic agents such as furosemide was effective, the assessment of the prognosis of paraquat poisoning using urinary paraquat levels seemed to be possible. Urinary paraquat level was approximately measured by an applied qualitative analysis method with using a dilution method.     

Comparison of a pulsatile blood pump and a peristaltic roller pump during hemoperfusion treatment in a canine model of paraquat poisoning

Abstract:  This study examined the treatment efficacy and the damage to the blood during hemoperfusion for treating paraquat poisoning using two blood pump mechanisms. Paraquat-poisoned animal models were prepared. A conventional hemodialysis machine, AK90, with a peristaltic roller pump and a cardiopulmonary support system, T-PLS, with a pulsatile blood pump were used during the animal experiments. A total of 12 dogs were treated with hemoperfusion using a charcoal column. Six dogs were treated with hemoperfusion and T-PLS, and the other six were treated with AK90. A paraquat dose of 30 mg/kg was administrated by an intravenous injection. Both pumps maintained blood flow rates of 125 mL/min measured by an ultrasonic flowmeter. For anticoagulation, heparin was administrated by an initial bolus (250 IU/kg) and a continuous injection (100 IU/kg/h). During the experiments, T-PLS and AK90 showed a similar toxin removal efficacy. Both devices decreased the plasma paraquat concentration to 10% of the initial dose within 4-h hemoperfusion. The two pumps showed similar hemolysis properties with acceptable levels. Although T-PLS was developed as a cardiopulmonary bypass system, it can also be used as a hemoperfusion treatment device.     

Influence of Hemoperfusion on the Concentrations of Calcitonin, Testosterone and Cortisol in Blood Plasma

The influence of hemoperfusion with a cellulose-acetate-coated charcoal column (Adsorba 300-C, Gambro, Lund, Sweden) on plasma concentrations of calcitonin, testosterone and cortisol was studied in five psoriatic patients during 12 treatment periods. Calcitonin, testosterone and cortisol were effectively removed from blood plasma by the charcoal column with average plasma clearances of 34.0, 14.5 and 27.6 ml/min, respectively, at 30 minutes of hemoperfusion, and 4.9, 15.4 and 24.4 ml/min, respectively, at 180 minutes of hemoperfusion. After three hours of hemoperfusion, significant decreases of testosterone and cortisol were found in peripheral venous blood, while calcitonin fell insignificantly. It remains to be elucidated whether long-term use of hemoperfusion would require a detailed control of possible effects on the endocrine status of patients.     

Hyperoxalemia in renal failure and the role of hemoperfusion and hemodialysis in primary oxalosis

Measurement of oxalate levels in 14 patients with chronic renal failure, treated by maintenance hemodialysis, revealed elevated plasma oxalate concentrations in all patients 1,075.7 +/- (SEM) 253 micrograms/dl. In 7 of these subjects the oxalate concentration was more than three times higher than the upper limit of normal. Furthermore, a strong positive correlation (r = 0.75) between serum creatinine and plasma oxalate concentration was found. A combination of hemodialysis and hemoperfusion procedure was carried out in a dialysis patient with primary oxalosis as a cause of renal failure. The average oxalate clearance of the hemodialyzer during seven hemodialysis/hemoperfusion procedures was 91 ml/min and that of the charcoal detoxifier was 24 ml/min. The amount of oxalate removed during 4 1/2 h of the hemodialysis/hemoperfusion procedure was 429 mg. This amount was calculated to be produced in about 87 h, with an oxalate generation rate of 4.9 mg/h.     

Development of an Intravascular Pumping Oxygenator Using a New Silicone Membrane

Abstract: A new intravascular pumping oxygenator (IVPO) was developed for intravascular gas exchange and circulatory assistance in critically ill patients with respiratory and circulatory failure. The IVPO utilizes new silicone hollow fibers (diameter. 1 mm: membrane width, 50 μm) and consists of two driving tubes for the oxygenation and pumping of circulating blood. The performance characteristics of the IVPO were studied using an experimental ex vivo model. With a mean hemoglobin concentration of 10.5 ± 2.3 g/dl, total oxygen transfer was 5.6 ± 1.5 ml/min at a blood flow of 200 ml/min and 6.3 ± 2.2 ml/min at a blood flow of 250 ml/min. Total CO₂ transfer was 3.8 ± 1.4 ml/min at a blood flow of 200 ml/min and 4.2 ± 1.6 ml/min at a blood flow of 250 ml/min during IVPO pumping. This preliminary experiment demonstrated that the IVPO has the capacity to function both as a circulatory assist pump and as an intravascular hollow fiber oxygenator.     

A fatal case of paraquat poisoning following minimal dermal exposure

Paraquat is a pesticide widely used in agriculture. Numerous cases of paraquat intoxication have been reported either accidentally or intentionally as a suicidal attempt. The most severe cases of paraquat poisoning refer to oral ingestion. Complications include respiratory, hepatic, and renal failure, and are usually fatal. Dermal exposure is less frequent and rarely fatal. This article reports a case of an 81-year-old man with minimal skin burn after accidental paraquat exposure. The patient developed acute renal and respiratory failure and, despite aggressive treatment with hemodialysis, hemoperfusion, and mechanical ventilation, died two days later.     

Novel Composite Sorbent Beads for Paraquat Removal by Hemoperfusion

The present report describes the development and performance of a column that is to be used for removal of paraquat from circulating blood in a hemoperfusion-type set-up. The key element of the system is a newly developed sorbent material containing fuller's earth entrapped in cross-linked agarose beads (Talosit). The technique produces a sorbent material exhibiting a very large active surface area while allowing for high mobility of paraquat molecules within the beads and favorable flow characteristics of packed column. Cross-linking of the agarose (by epichlorohydrin) also has a most beneficial effect on the mechanical strength of the beads as well as on their stability to sterilization in an autoclave. The composite beads exhibit good blood compatibility. A scanning electron microscope analysis of the beads showed no adherence of cellular blood components after contact with blood. Moreover, no significant changes in plasma composition had taken place when the beads were properly conditioned prior to contact with fresh human blood. A comparative study of paraquat removal from saline solution by the new beads and by cellulose-coated activated charcoal (Adsorba-300C) indicates a higher removal rate with the former. The results obtained so far with this new sorbent are very promising and extension of these studies to in vivo hemoperfusion is under way.     

A Fatal Case of Paraquat Poisoning Following Minimal Dermal Exposure

Paraquat is a pesticide widely used in agriculture. Numerous cases of paraquat intoxication have been reported either accidentally or intentionally as a suicidal attempt. The most severe cases of paraquat poisoning refer to oral ingestion. Complications include respiratory, hepatic, and renal failure, and are usually fatal. Dermal exposure is less frequent and rarely fatal.

This article reports a case of an 81-year-old man with minimal skin burn after accidental paraquat exposure. The patient developed acute renal and respiratory failure and, despite aggressive treatment with hemodialysis, hemoperfusion, and mechanical ventilation, died two days later.     

Aluminum removal with hemodialysis, hemofiltration and charcoal hemoperfusion in uremic patients after desferrioxamine infusion. A comparison of efficiency

In order to compare the effectiveness of aluminum removal in uremic patients during extracorporeal treatment, 17 patients with endstage renal failure were given a desferrioxamine infusion of 40 mg/kg body weight after an ordinary dialysis treatment. Forty-eight hours later 7 patients were treated with hemodialysis, 6 with hemofiltration and 4 with a combination of hemodialysis and hemoperfusion. The clearance of aluminum was measured at different intervals. It was found that the aluminum clearance was 75 +/- 18 ml/min in hemofiltration compared to 30 +/- 10 ml/min in hemodialysis (p less than 0.001). A combination of hemodialysis and hemoperfusion with a charcoal column containing 100 g activated charcoal in series gave a total aluminum clearance of 56 +/- 11 ml/min. The total amount of aluminum in the ultrafiltrate after hemofiltration was found to be approximately 3 times as high (1,728 +/- 156 micrograms) as the total amount of aluminum in the hemodialysis water that had passed a single pass system during a 4-hour dialysis (576 +/- 104 micrograms). Our results indicate that hemofiltration or a combination of hemodialysis and hemoperfusion should be used to remove aluminum in patients with signs of severe aluminum accumulation such as encephalopathy or painful bone disease, because these methods are 2-3 times as effective as ordinary hemodialysis. In patients where aluminum has been accumulated but no severe symptoms occur hemodialysis gives a significant clearance of the aluminum desferrioxamine complex.     

Removal of Inhibitors of Brain Na+, K+-ATPase by Hemoperfusion in Fulminant Hepatic Failure

Serum from patients with fulminant hepatic failure inhibits rat brain Na+, K+-ATPase activity in vitro. The effect of hemoperfusion on the level of inhibition was investigated with both resin and charcoal columns in clinical use. In the patient perfusions, the mean inhibitory activity of serum fell from 34.7 +/- 1.6 (SE) to 20.9 +/- 1.5% compared with pooled control serum when a resin column was used for the first time and from 26.9 +/- 2.2 to 20.4 +/- 1.7% with charcoal hemoperfusion, a statistically significant (p less than 0.01) removal in both groups. Column chromatography on Sephadex G-25 of material eluted from the resin column post-hemoperfusion and of serum ultrafiltrates before and after in vitro adsorption with charcoal showed considerable overlap in the profile of the substances removed, but with some peaks removed by only one adsorbent. Combinations of resin and charcoal in one hemoperfusion should remove a wider range of potentially toxic substances.     

Failure of chemotherapy and radiotherapy in pulmonary fibrosis caused by paraquat

A case is reported of severe interstitial paraquat poisoning in a 23 year old man. Initial treatment consisted of gastric lavage, fuller's earth, haemoperfusion on activated charcoal and peritoneal dialysis. On the third day, appeared both renal and early respiratory failure, with hypocapnia and hypoxia. Peritoneal dialysis was kept up to the thirteenth day. Pulmonary function tests showed a restrictive syndrome. Chemotherapy with 1 mg.kg-1.24 h-1 prednisone and 3 mg.kg-1.24 h-1 cyclophosphamide was started on day 4. Radiotherapy (13 Gy) was also given to both lung fields between days 6 and 10. Despite this treatment, respiratory failure worsened, and the patient died at the 28th day, with resistant severe hypoxaemia and pneumothorax on fibrous lungs. Several reports have shown conflicting results with chemotherapy and radiotherapy in the treatment of pulmonary fibrosis due to paraquat poisoning. The failure of such treatment in the case reported showed the need for large prospective clinical trials of the treatment of paraquat poisoning, as well as for urgent preventive measures.     

Plasma Cytokine Levels and Coagulation and Complement Activation During Use of the Extracorporeal Liver Assist Device in Acute Liver Failure

Multiple organ failure frequently occurs in patients with acute liver failure, and this has been associated with increased cytokine production. Treatment by hemoperfusion with an extracorporeal liver assist device (ELAD) containing human liver-derived cells was performed in 12 patients with acute liver failure. Over the first 6 h, there were significant increases in plasma tumor necrosis factor alpha (TNFα; from 114 ± 54 pg/ml [mean ± SEM] to 236 ± 161 pg/ml, p < 0.05) and interleukin (IL)-6 (260 ± 121 pg/ml to 445 ± 149 pg/ml, p < 0.05) but not in interferon gamma (IFNγ). A similar pattern with a small peak increase was observed for complement C5b-9 complex. Plasma C-reactive protein (CRP) and thrombin antithrombin (TAT) III complex showed small peaks after 24 h of ELAD hemoperfusion. No such changes were seen in 12 control patients with acute liver failure who were treated with intensive care alone. These transitory effects, without changes in blood pressure, are likely to be due to the contact of the blood with the dialyzer membrane. There was no evidence of the clearance of cytokines by the ELAD.     

Present and Future Uses of Hemoperfusion with Sorbents

International interest in the clinical uses of hemoperfusion has increasingly grown in the last ten years and, as a result, sorbent hemoperfusion has emerged as first-line management in several areas. This center and many others have shown that there is a clear role for hemoperfusion in severe self-poisoning. Plasma extraction ratios for most drugs are significantly higher for hemoperfusion over both resin (0.8) and activated charcoal (0.5; CHP) than for hemodialysis (0.27), under similar conditions of blood flow, plasma drug concentrations, etc. Using appropriate pharmacokinetic models in the analysis of plasma drug profiles, it has been shown that CHP can increase drug elimination rate constants and whole body clearance rates in experimentally intoxicated animals. Enhancement of drug elimination broadens the scope of sorbent hemoperfusion to other areas of application, such as the removal of anticancer drugs (e.g., methotrexate, adriamycin) after cancer chemotherapy. Evaluation of the role of hemoperfusion in hepatic encephalopathy or uremia is limited by the lack of knowledge regarding specific toxic molecules in these syndromes. Nevertheless, in the authors' series of ten patients with fulminant hepatic failure, four survived, in contradistinction to an 80–90% mortality for untreated patients, and virtually all awoke from deep coma. Accompanying reversal of coma, there were significant changes in plasma and cerebrospinal fluid amino acids and in cerebrospinal fluid cyclic AMP concentrations. This suggests that hemoperfusion over charcoal in hepatic encephalopathy may be a useful technique. In this series of uremic patients, although hemoperfusion with charcoal has been shown capable of adsorbing putative uremic toxins including middle molecules up to the present, hemoperfusion alone is only marginally superior to standard hemodialysis. Fouremia, it is likely that multiple specific sorbents will be required, and several compounds for urea and creatinine sorption are presently under investigation.     

The effect of coupled haemofiltration and adsorption on inflammatory cytokines in an ex vivo model.

BACKGROUND: The objective of this study was to evaluate the ex vivo removal of cytokines with an extracorporeal circuit using coupled large-pore haemofiltration and sorbent adsorption. METHODS: The setting for this study was a laboratory attached to the Intensive Care Unit of a tertiary hospital. Six healthy volunteers donated blood, which was incubated with endotoxin. Control blood was left at room temperature. Treatment blood was recirculated for 6 h through a closed circuit with a large-pore polysulfone haemofilter (average pore size 150 kDa) and an activated charcoal cartridge. Blood and ultrafiltrate were sampled hourly from three sites (pre-haemofilter for the circulating concentration, at cartridge inlet and cartridge outlet) to measure the concentrations of interleukins (IL)-1beta, -6, -8 and -10, and tumour necrosis factor (TNF). RESULTS: Control cytokine concentrations remained the same or increased slightly. Most of the preformed circuit cytokines were removed, with the exception of IL-10. The average sieving coefficients were 0.61 for IL-1beta, 1.34 for IL-6, 0.30 for IL-8, and 0.56 for TNF. Average single-pass clearances were 49, 107, 24 and 45 ml/min, respectively. The cartridge adsorbed 90% of IL-1beta, 72% of IL-6, 100% of IL-8, and 7% of TNF during each pass. CONCLUSION: The combination of a large-pore haemofilter and charcoal cartridge removed several cytokines efficiently under ex vivo conditions. This technique can now be tested for cytokine removal in vivo.     

Charcoal Hemoperfusion for Treatment of Ethchlorvynol Overdose

Abstract: Charcoal hemoperfusion is commonly employed to treat overdose of a number of drugs. There are varying Reports of its efficacy in the treatment of ethchlorvynol overdose. Herein is Reported a case of ethchlorvynol overdose successfully treated with charcoal hemoperfusion within 5 h of ingestion of 12.5 g of the drug. The patient was deeply comatose at that time but recovered consciousness at the end of 4 h of hemoperfusion. Ethchlorvynol clearance over the charcoal varied from 118 to 147 ml/min. There were no bleeding complications. Prompt charcoal hemoperfusion may be an effective mode of treatment in cases of ethchlorvynol intoxication.     

Fixed-bed uncoated charcoal hemoperfusion in the treatment of intoxications: animal and patient studies.

We examined the efficacy of a new, fixed-bed, uncoated charcoal device in experimentally intoxicated dogs and in drug-intoxicated as well as chemically poisoned patients. In the animal studies, 4 h of hemoperfusion resulted in a significant decrease in the blood level of phenobarbital, salicylate, pentobarbital and glutethimide. The drug clearances varied between 97 +/- 10 and 129 +/- 6 ml/min. However, the total amount of drug removed was higher for phenobarbital and salicylate which have a small apparent volume of distribution (AVD) than for pentobarbital and glutethimide which have an AVD greater than total body water. We next treated 14 patients suffering from a wide variety of intoxications. Patients intoxicated with phenobarbital, methsuximide, chlordane and Amanita muscaria all showed a significant improvement in their clinical status. Patients intoxicated with ethchlorvynol, glutethimide, methaqualone, podophyllin and fluoroacetamide did not improve. Charcoal hemoperfusion may be useful in patients poisoned with drugs characterized by an AVD smaller than total body water. No major complications were encountered during the hemoperfusions.     

Prostacyclin Eliminates the Thrombocytopenia Associated with Charcoal Hemoperfusion and Minimizes Heparin and Fibrinogen Consumption

To evaluate the effects of prostacyclin (PGI₂) on the bioin-compatibility of charcoal hemoperfusion (CHP), platelet counts, platelet aggregate formation as measured by screen filtration pressure (SFP), plasma fibrinogen levels, and heparin activity monitored by calcium-thrombin clotting times (Ca-TCT) were compared during CHP in healthy dogs with heparin alone or heparin plus PGI₂. Platelet losses (25 ± 6 vs 83 ± 2%: mean ± SEM), rise in SFP (65 ± 6 vs 249 ± 25 mmHg), and fibrinogen consumption (20 ± 5 vs 46 ± 6%) were significantly less during CHP with PGI₂ than with heparin only. In addition, rapid neutralization of heparin, as monitored by Ca-TCT, during CHP was prevented by PGL₂. The use of PGI₂ may allow a proper evaluation of the efficacy of CHP in conditions such as fulminant hepatic failure where, hitherto, incompatibility between blood and charcoal may have had deleterious effects.     

New apparatus for artificial liver support: PAT resin--removal of protein-bound substances and its effect on hepatic failure in animals

Hemoperfusion using several materials such as activated charcoal is often performed to treat the patients with hepatic failure. Polyamine triglycidylisocyanulate (PAT) resin is a newly developed artificial liver support material to adsorb protein-bound substances. In this study, the effect of PAT resin on the removal of these toxic protein-bound substances was examined and following results were obtained. PAT resin adsorbed protein-bound substances selectively in vitro. Its adsorbability was superior to those of the other conventional adsorbents such as cellulose-coated charcoal, XAD-4 and XAD-7. Serum bilirubin levels were decreased by 44% in jaundiced dogs and 45% in jaundiced rabbits after 120 minutes hemoperfusion with PAT resin. Leucocyte and thrombocyte count also fell during hemoperfusion. The fall of these blood cell counts, however, was recovered by prostaglandin D2. The survival time of dogs with ischemic hepatic failure was prolonged by hemoperfusion using PAT resin. The mean survival times were 17.6 hrs in the PAT perfusion group and 10.9 hrs in the control group. The difference of survival time between these two groups was statistically significant. (p less than 0.05). These results in animals suggest that PAT resin will be clinically useful in the therapy of hepatic failure or hyperbilirubinemia.