Hemoperfusion with coated activated charcoal for treating acute poisoning by remedies, plant protectants, and fungi. I. Remedies (author's transl)

Hemoperfusion with coated activated charcoal is a novel procedure for treating acute poisoning. It enables the elimination of both, water-soluble and liposoluble toxins. Hemoperfusion with coated activated charcoal has proved to be superior to hemodialysis in the treatment of barbiturate or bromocarbamide poisoning both under experimental conditions as well as in the ward. Analogous statements may be made for the therapy of glutethimide poisoning. Methaqualone, on the other hand, could not be eliminated sufficiently well in animal trials. Intoxications by "mild" analgetics, such as paracetamol and acetylsalicylic acid, may be treated successfully with hemoperfusion. Treatment of acetylsalicylic acid poisoning is equally effective with hemoperfusion as with hemodialysis. Prospects for the success of hemoperfusion in treating intoxication from tricyclic antidepressants and neuroliptics are slight. It is simply the danger of antidepressant poisoning that justifies using this method of treatment in the first few hours after ingestion in order to reduced the flow of the psychopharmaceutical substance into the tissue.     

Approach to the poisoned patient

Routine poison management involves the following: (1) stabilization, (2) toxidrome recognition, (3) decontamination, (4) antidote administration, (5) enhanced elimination of toxin, and (6) supportive care. Stabilization involves airway, ventilation, and circulation support. In the patient with altered mental status, oxygen, naloxone, glucose, and thiamine should be administered. Symptom complexes that relate to specific classifications of toxins are referred to as toxidromes. Emesis by means of syrup of ipecac is rarely used for in-hospital gastric decontamination. Activated charcoal is a useful adsorbent for gastric decontamination. Whole bowel irrigation is useful for iron, lead, and lithium poisoning and for the body packer phenomenon. Enhancement of elimination may involve multiple doses of activated charcoal, hemodialysis, or charcoal hemoperfusion.     

Effect of hemoperfusion of clearance of gentamicin, cephalothin, and clindamycon from plasma of normal dogs

Nine normal dogs were divided into three groups of three. Group 1 was given an overdose of gentamicin; group 2, cephalothin; and group 3, clindamycin. Group 1 had hemoperfusion with Amberlite XE-336, and groups 2 and 3 with Amberlite XAD-4 resin adsorbents, for 6 hr with a blood flow rate of 300 ml/min. The plasma clearance and removal rates of antibiotics by the hemoperfusion columns were high. The clearance rate of gentamicin from plasma (mean +/- standard deviation) ranged from 59 +/- 30 to 199 +/- 6 ml/min, of cephalothin from 66 +/- 14 to 157 +/- 8 ml/min, and of clindamycin from 55 +/- 9 to 125 +/- 16 ml/min. Of the total dose of antibiotic administered, the hemoperfusion columns removed 67% from theplasma in group 1, 41% in group 2, and 18% in group 3. The fact that antibiotics may be rapidly removed from the blood during hemoperfusion should be considered in calculation of the therapeutic dose of antibiotic required for patients who receive this preocedure. Also, hemoperfusion can effectively and rapidly remove certain antibiotics from the blood of patients who have had a potentially toxic overdose.     

Treatment of extrahepatic occlusive jaundice with activated charcoal hemoperfusion in dogs

To find the feasibility of treatment for congenital bile duct atresia, we studied the usefullness of extracorporeal hemoperfusion over activated charcoal in canine obstructive jaundice. One, three and five weeks after ligation and disection of common bile duct in 5 dogs we performed the hemoperfusion over activated charcoal extracorporeally (group 3). In this animals we examined hematological and blood coagulation studies, serum electrolyte levels, kidney function tests and liver chemistries. As control in 5 animals we carried out after sham operation the perfusion without common bile duct ligation (group 2) and in 5 animals only common bile duct ligation without perfusion (group 1). In the liver chemistries we found 2 weeks after 2nd and 3rd perfusion (5 and 7 weeks after bile duct ligation) lower levels of serum bilirubin, GOT, GPT and SDH in treated group than in non-treated jaundiced animals. It suggest the effectiveness of hemoperfusion with activated charcoal in the treatment of occlusive jaundice. There were no alteration in the hematological studies, serum electrolyte levels and kidney function tests. PT and PTT was prolonged in the jaundiced animals there were no significant differences with and without hemoperfusion.     

Clinical and toxicological data in fenthion and omethoate acute poisoning

This study paper reports on two cases of poisoning with the organophosphorus insecticides, fenthion and omethoate. The two victims were admitted in the Intensive Care Unit (ICU) a few hours after ingestion of the two insecticides. They received appropriate treatment for organophosphorous poisoning (gastric lavage, activated charcoal, atropine and pralidoxime) and supportive care. Both patients survived. Organophosphate blood levels were determined on admission (fenthion 2.9 micrograms/ml, omethoate 1.6 micrograms/ml) and during the hospitalisation and proved to be considerably high. Slow elimination rate of the poison already distributed in the body was indicated for both pesticides. The patient with omethoate poisoning remained clinically well (Glasgow Coma Scale: 15) and was discharged three days later. The patient with fenthion poisoning, who had also ingested 30 mg of bromazepam and 720 mg of oxetoron, developed cholinergic crisis six hours after admission and was intubated for 24 days, with concomitant complications.     

Haemoperfusion treatment in pigs experimentally intoxicated by paraquat

1. Because of their similarity in renal morphology and physiology to humans, domestic pigs (gilts, 70 kg) were bolus treated by intramuscular injection of 74, 17, and 6 mg kg-1 and by oral loading (70 mg kg-1 n = 4) of paraquat. The concentration peak of plasma paraquat was reached at 1.5 - 2.5 h. Renal clearance of paraquat rose to its maximum at 5-6 h after intoxication and then sharply decreased indicating renal failure. All the intoxicated pigs died. 2. An additional 10 gilts were also orally treated with 70 mg kg-1 paraquat but received haemoperfusion from 2 h post intoxication for either 2 h (n = 6) or 6 h (n = 4). The 2 h haemoperfusion resulted in a 5.1% toxin removal but failed to save any of six poisoned pigs. Prolonged 6 h haemoperfusion successfully rescued three out of four intoxicated pigs. 3. The plasma paraquat concentrations of the three surviving pigs were above 2 mg l-1 at 10 h post intoxication. This level is not only similar to those of untreated animals that died later, but also well beyond the suggested limit for survival of poisoned patients. 4. Pigs proved to be a good animal model for studies in paraquat poisoning and/or haemoperfusion. It is also suggested that early haemoperfusion is effective in treating paraquat poisoning even in very severe cases due to its possible detoxicating effect in addition to toxin removal.     

Oral activated charcoal and dapsone elimination

The effect of orally given activated charcoal on the elimination of therapeutic and toxic doses of dapsone was studied in 5 healthy subjects and in 2 intoxicated patients. In a randomized crossover study the subjects took a total dose of 500 mg dapsone over 4 days; 10 hr after the last 100-mg dose of dapsone 50 gm activated charcoal as a water suspension (or water) was taken, followed by 4 consecutive doses of 17 gm at 12-hr intervals. The half-life (t 1/2) of serum dapsone was 20.5 +/- 2.0 hr during the control period and 10.8 +/- 0.4 hr during the charcoal period (p less than 0.01). The t 1/2 on serum monoacetyldapsone (MADDS) was shortened from 19.3 +/- 1.2 hr to 9.5 +/- 0.7 hr (p less than 0.01) by charcoal. The t 1/2s of dapsone and MADDS, calculated on the basis of urinary excretion rate, were shortened by charcoal; Two patients had taken large doses of dapsone in suicide attempts. The use of activated charcoal, 80 gm/day for 1 or 2 days, increased (3 to 5 times) the rate of elimination of both dapsone and MADDS, as reflected in serum concentration and urinary excretion data. The use of multiple doses of charcoal seems to be indicated as supplementary treatment of certain intoxications during the postabsorption phase if the drugs have a long t 1/2 and if they are secreted into the gut with subsequent reabsorption.     

Isotachophoretic separations on a microchip. Normal Raman spectroscopy detection

Isotachophoretic separations of the herbicides paraquat and diquat are performed in a glass microchip etched channel and monitored on-chip by normal Raman spectroscopy. The 40-micron-wide and 75-micron-deep separation channels are chemically etched in a serpentine design to 21-cm total length. A 120-micron-thick glass cover slip is used to seal the channels. Separation field strengths up to 380 V/cm are used. The microchip is directly coupled to a Raman microprobe. No interfacing is required. Raman spectra are generated with a 2-W, 532-nm NdY-VO4 laser and collected at 8-cm-1 resolution with a holographic transmissive spectrograph and a cryogenically cooled CCD. Data acquisition is at 2-5 spectra/s. Raman isotachopherograms of the pesticides at starting concentrations as low as 2.3 x 10(-7) M (60 ppb paraquat/80 ppb diquat) are presented.     

The mechanism of increased renal clearance of amylase in acute pancreatitis

Penicillium urticae (NRRL 2159A) was grown in culture broth containing 1 muCi of [1-14C-A1acetate to produce [14C]patulin. [14C]patulin was purified from the broth and added to apple cider. After the patulin concentration of the cider was adjusted to 30 mug/ml with unlabeled patulin, the cider was subjected to various charcoal treatments. [14C]patulin was completely removed by shaking the cider with 20 mg of activated charcoal per ml and by eluting the cider through a 40- to 60-mesh charcoal column. Activated charcola at 5 mg/ml reduced patulin in naturally contaminated cider to nondetectable levels.     

On-line sample preparation of paraquat in human serum samples using high-performance liquid chromatography with column switching

A new ion-pair high-performance liquid chromatographic method with column-switching has been developed for the determination of paraquat in human serum samples. The diluted serum sample was injected onto a precolumn packed with LiChroprep RP-8 (25-40 microm) and polar serum components were washed out by 3% acetonitrile in 0.05 M phosphate buffer (pH 2.0) containing 5 mM sodium octanesulfonate. After valve switching to inject position, concentrated compounds were eluted in the back-flush mode and separated on an Inertsil ODS-2 column with 17% acetonitrile in 0.05 M phosphate buffer (pH 2.0) containing 10 mM sodium octanesulfonate. The total analysis time per sample was about 30 min and mean recovery was 98.5+/-2.8% with a linear range of 0.1-100 microg/ml. This method has been successfully applied to serum samples from incidents by paraquat poisoning.     

Activated charcoal interrupts enteroenteric circulation of phenobarbital

The possibility of activated charcoal interrupting the enteroenteric circulation of phenobarbital was conducted in rabbits prepared by colectomy biliary drainage to block enterohepatic circulation. Fifty minutes after the administration of phenobarbital IV over ten minutes, activated charcoal (N = 7) or non-adsorbent gel (N = 8) were placed into the intestine at a dose of 4 g/kg. Blood was taken hourly for 5 h from the femoral artery and portal vein for the determination of phenobarbital concentration by the homogeneous enzyme immunoassay. The arterio-portal differences of phenobarbital concentrations were significantly greater in the animals treated with the charcoal at 2, 3 and 4 h after the treatment. There were significantly shorter plasma half lives of phenobarbital in the animals given charcoal (3.8 +/- 0.3 h vs 6.9 +/- 0.9 h, p < .02). This study provided evidence of significant enteroenteric circulation of phenobarbital which can be interrupted by the activated charcoal and removed by the mechanism of intestinal dialysis.     

Successful treatment by direct hemoperfusion of coma possibly resulting from mitochondrial dysfunction in acute valproate intoxication

PURPOSE: We evaluated the efficacy of direct hemoperfusion (DHP) for treatment of acute valproate (VPA) intoxication and speculate on the biochemical perturbations that suggest a mechanism of coma induced by VPA overdose. PATIENT AND METHODS: The comatose patient was hospitalized approximately 6 h after ingesting 18 g VPA. DHP, with 200 g activated charcoal, was performed for 6 h. The plasma concentrations of VPA and Glasgow coma scale scores after admission were estimated. Before and after DHP, urine samples were tested in serial fashion for VPA metabolites, organic acids, and acyl carnitine esters of fatty acids. RESULTS: Plasma VPA was efficiently adsorbed on activated charcoal. The patient's plasma concentration of VPA decreased from 471 microg/ml (2,830 microM) to 45 microg/ml (270 microM), at which point the patient became alert. The half-life (t1/2) of VPA was calculated as 4.4 h before DHP and as 1.8 h during DHP. Before DHP, lactate and VPA-glucuronide markedly increased in urine samples, but beta-keto-VPA, a major mitochondrial metabolite, was not detected. Urinary excretion of carnitine esters of medium chain (C8-C10) dicarboxylic acids was increased. After DHP, lactate and VPA-glucuronide decreased, but a significant amount of beta-keto-VPA was demonstrated. Carnitine esters of medium chain dicarboxylic acids were decreased. CONCLUSIONS: DHP with activated charcoal was effective treatment for the patient with acute VPA intoxication and coma. The onset of coma may have been related to inhibition of beta-oxidation in the mitochondria, which was reversible by elimination of plasma VPA by DHP.     

Germ cell-specific enhancer activity of a repeated element in a variable region of the mouse genome

The initial evaluation and management of poisoned patients should be comprehensive and include an accurate history whenever possible, stabilization of the patient's condition, a physical assessment to evaluate the extent of poisoning and the presence of concurrent conditions, decontamination of the gastrointestinal tract using activated charcoal, gastric lavage, administration of ipecac or irrigation, poison-specific treatment with administration of antidotes when indicated and proper disposition. Consultation with a poison control center is often helpful in assessing and treating these patients.     

Single-dose pharmacokinetics of teicoplanin during hemodialysis therapy using high-flux polysulfone membranes

Teicoplanin is a new glycopeptide antibiotic with potent activity against Gram-positive bacteria. It has been considered to be non-dialyzable due to its high molecular weight (1875-1891 d) and high protein binding (89%). Therefore, a reduced dose was recommended for patients on hemodialysis therapy, with the loading dose being followed by a considerably lower maintenance dose and/or extension of the interval between doses. The present study was performed to evaluate the pharmacokinetics of teicoplanin during hemodialysis therapy using high flux membranes. The pharmacokinetic parameters of teicoplanin were studied in 15 patients with chronic renal failure on hemodialysis. A high flux polysulfone membrane (ultrafiltration coefficient of 40 ml/h/mmHg) was used. Teicoplanin was administered at a dosage of 10 mg.kg-1 body weight in 100 ml isotonic saline solution during the first 10 minutes of hemodialysis therapy. Pharmacokinetic analysis was performed using a three compartment analysis. After a single dose of teicoplanin plasma peak levels were 26.4 +/- 12.0 micrograms/mL (mean +/- SD) after 30 minutes. Teicoplanin concentrations rapidly declined to a nadir of 6.1 +/- 2.5 micrograms/mL at the end of the 3.5-hour session dialysis. Extracorporeal clearance was 39.7 +/- 24.5 mL/min. Removal of 19.3 +/- 7.7% of the drug was estimated if infused during hemodialysis. T 1/2 alpha were 0.37 +/- 0.25 hrs, t 1/2 beta 20.1 +/- 7.1 hrs, and t 1/2 gamma 549.7 +/- 210.5 hrs. We conclude that teicoplanin levels are reduced to a subtherapeutic range during one single high-flux dialysis session if the drug is administered during hemodialysis. Thus, in contrast to previous suggestions relevant amounts of teicoplanin are removed during hemodialysis and thus teicoplanin cannot be viewed as non-dialyzable drug. We recommend obligatory drug monitoring to achieve therapeutic plasma concentrations.     

Organisation of the bph gene cluster of transposon Tn4371, encoding enzymes for the degradation of biphenyl and 4-chlorobiphenyl compounds

We have isolated beta-trace protein from cerebrospinal fluid, serum, plasma, and urine samples of normal volunteers and sera and hemofiltrate of patients with chronic renal failure. Blood-derived and urinary beta-trace have significantly higher molecular weights than their cerebrospinal fluid counterpart, the amino acid sequences being identical. Oligosaccharide structural analysis revealed these molecular weight differences to be due to different N-glycosylation. beta-Trace from hemofiltrate and urine has larger sugar chains and concurrently significantly higher sialylation than cerebrospinal fluid-beta-trace which bears truncated "brain-type" oligosaccharide chains (published previously). beta-Trace concentrations were about 40 ng/ml for normal sera and plasma. 2000-6000 ng/ml were measured in sera of dialysis patients whereas in normal human cerebrospinal fluid, beta-trace concentration was about 8000 ng/ml. A reduced amount of 900 ng/ml was found in a single case of hydrocephalus cerebri. The sialylated glycoforms of beta-trace detected in the blood are presumably derived from resorbed cerebrospinal fluid protein whereas beta-TP-molecules bearing asialo-oligosaccharides are absent due to their hepatic clearance. The residual, sialylated beta-TP-species are probably eliminated from the blood via the kidney. This physiological clearance mechanism for the sialylated glycoforms is disturbed in hemodialysis patients resulting in about 100-fold elevated serum concentrations. These results let us suggest beta-trace may become a useful novel diagnostic protein in renal diseases.     

Theophylline in asthma

The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 +/- 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 +/- 32.0 mug/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 +/- 20.8 mug/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.     

Mushroom poisoning. New possibilities for treatment

Poisonous species of fungi in Germany are very few. Dangerous is the ingestion of raw, spoiled or poisonous mushrooms. There exist no reliable tests to determine whether a mushroom is safe except by expert examination and identification of the mushroom. In clinical practice the classification of mushroom poisoning is possible in muscarine-syndrome, gastroenteritic syndrome and in two-phase-syndrome. 90-95% of lethal mushroom poisonings are due to ingestion of Amanita phalloides. In severe cases extensive hepatic necrosis occurs, characterized by profound abnormalities in liver function caused by hepatic coma. In deep coma mortality rates amount to 70% or more. A new therapeutic measure (coated charcoal hemoperfusion)-first applied in liver failure by Chang (1972) and Williams (1973)-has been performed in 3 patients with severe poisoning after ingestion of Amanita phalloides (each patient had eaten at least 7-10 fungi Amanita phalloides). Two of the patients survived.     

The deleterious effects of fungicides and herbicides on Xenopus laevis embryos

Groups of 30 Xenopus laevis embryos, at "tail-bud" stage (Nieukoop-Faber stages 22-24) were exposed to 0.1-2 ppm concentrations of various pesticides for 1 to 10 days. The pesticides used were chloranil and dichlone (both are fungicidal and herbicidal); diquat (herbicide); and nabam (fungicide). The parameters examined were mortality, gross morphology, histology, and behavior. Chloranil (1.25 to 1.75 ppm) treated embryos showed abnormalities of the otolith, optic cup, and general pigmentation. Their movement was sporadically convulsive and they were unable to maintain proper balance. Dichlone (0.1 to 0.15 ppm) disrupted the development of the cephalic end of the embryo. Many of these embryos developed a slightly retarded trunk and tail only. These headless embryos lived for a time and were relatively lethargic. Diquat (0.75 to 2.0 ppm) administration reduced body size and pigmentation, and altered body shape. When embryos were treated with both 1.0 ppm of diquat and 2.0 ppm of nabam the integrity of myomeres and myocommata of the musculature was disrupted. The histological bases of these morphological and behavioral changes are discussed.     

Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure

Leptin, secreted from fat cells, functions as a lipostat mechanism through modulation of satiety signals. The role of leptin in humans has been only partly revealed. However, obese patients have markedly elevated levels of this hormone, and in both normal-weight and obese subjects there is a direct correlation between serum leptin levels and the percentage of body fat. The aim of the present study was to investigate the role of leptin and its relation to body fat content in chronic renal failure (CRF), a disorder associated with decreased appetite. Serum leptin levels and body composition (dual-energy x-ray absorptiometry) were measured in a cohort of 59 patients with terminal CRF (creatinine clearance rate, 8 +/- 1 ml/min). Sixteen of the patients were re-evaluated after 12 mo of peritoneal dialysis treatment, and eight patients were re-evaluated after 12 mo of hemodialysis treatment. The mean serum leptin concentrations were markedly higher (mean +/- SEM) in patients with CRF than in healthy control subjects matched for gender and body mass index (25.7 +/- 5.2 ng/ml versus 8.4 +/- 0.9 ng/ml; P < 0.001). Patients with ongoing signs of inflammation (C-reactive protein > 10 mg/L) demonstrated higher serum leptin levels (41.9 +/- 13.7 ng/ml versus 18.6 +/- 4.2 ng/ml; P < 0.05) than patients with normal C-reactive protein. A strong positive correlation (rho = 0.83; P < 0.0001) was found between serum leptin concentrations and the percentage of body fat. After 12 mo of peritoneal dialysis, the amount of body fat increased markedly (19.0 +/- 1.5 to 25.1 +/- 2.2 kg; P < 0.001), and the changes in serum leptin concentrations correlated significantly (rho = 0.69; P < 0.01) to the changes in the body fat content. In contrast, no significant changes in either body fat content or serum leptin levels were recorded in the eight patients that were re-evaluated after 12 mo of hemodialysis. Serum leptin concentrations are approximately three times higher in patients with CRF compared with healthy control subjects with a similar body mass index. In this study, it is also demonstrated that serum leptin is a good marker for the body fat content in CRF patients and correlates strongly to changes in body fat during 12 mo of peritoneal dialysis. These findings suggest that serum leptin could serve as a valuable clinical marker for the body fat content in patients with CRF. Further studies are needed to verify the hypothesis that increased serum leptin concentrations may contribute to uremic anorexia.     

Pharmacokinetic study of an oral cephalosporin, cefdinir, in hemodialysis patients

The pharmacokinetics of cefdinir were investigated in six hemodialysis patients. For the present study, two tests were carried out, one with 4 h of hemodialysis and the other without hemodialysis. Cefdinir was given orally to each patient in a dose of 100 mg, and blood was collected serially for 48 h after dosing in the test without dialysis and for 72 h in the test with dialysis. In the test without dialysis, the maximum plasma concentration (Cmax) was 2.36 +/- 0.53 micrograms/ml (mean +/- standard deviation) and the time to Cmax was 9.00 +/- 2.45 h. The terminal elimination half-life (t1/2) and area under the concentration-time curve (AUC) were 16.95 +/- 1.20 h and 69.05 +/- 14.84 micrograms.h/ml, respectively. In the test with dialysis, t1/2 during hemodialysis decreased approximately to one-sixth of that obtained in the test without dialysis, although t1/2 in the latter elimination phase did not differ from that in the nondialysis test. AUC was reduced to 43% of that in the test without dialysis. The fractional removal of cefdinir by hemodialysis was 61%. These findings indicate that clearance of cefdinir is prolonged in patients with renal failure, and cefdinir is well removed by introduction of hemodialysis, although t1/2 (during hemodialysis) and AUC were two and eight times higher than the data previously reported for healthy volunteers, respectively. The pharmacokinetic data suggest that 100 mg of oral cefdinir once a day would result in a sufficient concentration in plasma in hemodialysis patients, but this remains to be confirmed by multiple-dose studies.