Toxic Fungi of Western North America

by Thomas J. Duffy, MD

Detailed treatment of amanitin poisoning

Currently penicillin G sodium treatment has fallen out of favor in the United States. No further studies with adequate statistical power have been performed and with the dramatically fallen death rates, sufficiently large studies now seem unlikely. The Penicillin G sodium doses used have to be given intravenously as the sodium salt rather than the potassium preparation or potassium toxicity occurs. Furthermore, the amounts of sodium salt required for 40 million units per day (or 1 million units per kg of body weight in children) are almost equal to the daily need for sodium and are sufficiently high that seizure precautions should be considered in children. Cephalosporins (another antibiotic class) will also bind amatoxins and should be much safer, but their efficacy remains unproven with only a few patients so treated in Europe. (71)

American conservatism leads to marked differences between most European and American treatment programs. A typical European protocol is that of Centre-Anti-Poisons CHU of Grenoble. (72) This group advises that at least one tube be advanced just within the duodenum by visual control. Their next step is chemotherapy with IV penicillin G and silibinin.

Some European treatment sheets show as many as 20 chemical interventions in the first 36 hours. European treatment also often includes hemoperfusion. In this procedure, arterial blood is sent through an activated charcoal or resin cartridge to bind amanitin, although viable pig and human liver have been used on occasion. Pig liver was used in two San Francisco cases as a last resort, but both patients died after severe acidosis could not be reversed. (60)

American treatment varies somewhat. Double lumen tubes with gastric and duodenal openings have been used. The gastric lumen is used to cleanse the stomach and to suck out gastric fluid. The duodenal lumen is used to give activated charcoal to absorb the amatoxins. Presently the use of wide bore gastric tubes is the most common. The first step is washing out the stomach with saline to remove all food and then pushing in a slurry of activated charcoal in 6-8 ounces of fluid. Another option is the use of the more highly absorbing resins such as Amberlite XAD-2, but this remains experimental. The initial dose of activated charcoal is usually 50-100 grams or 1 mg per kg of body weight.

Despite the diarrhea, there is often a mild ileus with slight abdominal bloating and reduction of normal bowel sounds. Moderate ileus is an indication for low dose charcoal. Very severe ileus is extremely rare, but other methods of amatoxin removal such as biliary cannulation, extremely vigorous diuresis (preferably with right atrial intracardiac pressure measurements) and hemoperfusion should be considered within the first 36 to 48 hours of ingestion.

Amanitins are absorbed from the duodenum, carried to the liver by portal veins and a portion is then re-secreted into the systemic circulation by the hepatic veins. However, a goodly amount is excreted in the bile and goes back by the common bile duct to the duodenum to be absorbed again. (73) This vicious cycle of re-absorption and excretion leads to repeated bombardment of the liver by amatoxins.

After the initial dose of charcoal, 10-30 grams of activated charcoal is given every 2-4 hours into the stomach or duodenum. If the double lumen tube is used or a duodenal tube only, then 2-4 hours of charcoal placement into the duodenum is followed by at least 1 hour of duodenal suction. A possible hazard, if a long duodenal tube with a weight is placed into the duodenum using only x-ray confirmed placement, is the possibility of passing the tube into an area, which is not near or even past the actual entry of the bile duct. There is considerable variation of bile duct anatomy. A long duodenal tube that is not anchored firmly may also drift after the abdominal x-ray is taken.

Another option is passing a thin plastic catheter directly into the bile duct and removing amatoxin by very low pressure suction. After discussion with the author in 1982, a Santa Cruz (California) gastroenterologist, Dr. Larrimore Cummins, performed the first (and only) biliary cannulation on an Amanita phalloides victim. The patient did extremely well, but the biliary drainage and serum samples for amatoxin analysis were lost.(74) Since that time, the concerns noted above (and the obscure journal in which it was published) have been followed by no further trials. A simpler treatment has been used in Europe: aspiration of bile from the duodenum without using any charcoal. (75)

Various methods of toxin removal directly from the systemic blood circulation have been explored over the past 25 years and the best of these appears to be hemoperfusion, if done within the initial 36 hours. (48f) This procedure in which the patient’s blood is directly passed through a resin cylinder has been uncommonly done. Most of these procedures have been done on very ill patients. These fatality rates, however, are about the same as those of patients treated in the standard way. A paper from the Slovak Republic found that the resin, Amberlite XAD-2, was experimentally more effective in removing amatoxins than Amberlite XAD-4 and that activated charcoal hemoperfusion was less effective than either resin. (76)

With just adequate fluids alone, about 85% of amatoxins are excreted by the kidneys within six hours of poisoning. It is not known how low the levels of amanitins in blood have to be in order to cease damaging organs. Sensitive assays show low blood toxin levels after 36 hours. However, amatoxins have been found in urine as late as 96 hours. The authors of that study suggest forcing urine output to 100-200 ml each hour with isotonic fluid during the initial 48 hours after amanitin exposure.(77) The amount of amatoxin present in the urine, however, correlates poorly with the severity of poisoning. (49b) Amatoxins in blood and bile are usually assayed by a very sensitive radioimmunoassay or with high-pressure liquid chromatography.

Piqueras and his group in Barcelona have shown that forced diuresis (a drug and water induced increase in urine flow) is effective. A urine output of 150-200 mL/h is able to remove 20,000-350,000 ng of amatoxin. (78) A blood purification method called plasmaphoresis removed no more than 10,000 ng. (78,79) The Barcelona group using forced diuresis and plasmaphoresis in select patients has had the best mortality rate of any good sized study to date: a 5.5% death rate of their 91 patients reported in 1989.51 Another group showed that with rapid diuresis there was no tubular re-absorption of toxin and little, if any, damage to the kidney tubules (although this has been a major concern of another expert, Dr. Faulstich in Germany). (80),(81)

ICU orders for severe poisonings should include hematology, electrolytes, calcium and phosphate levels, liver and kidney function panels, amylase, random blood glucose levels and acid/base studies. Standard cardiac and pulmonary monitoring are usually adequate. Patients in shock require more extensive evaluation including right atrial monitoring. Any changes in blood clotting or prothrombin time indicate a need for more extensive work-up including thromboplastin time, fibrinogen levels and measurements for split fibrin products. What tests are necessary rests on clinical judgment.

Renal function requires more then one gauge. Blood urea levels may be up because of dehydration, but present no problem if vascular status and fluid input/output are carefully followed. Creatinine levels will be elevated if there are severe muscle cramps, but then the muscle enzyme CPK would also be elevated. Sophisticated renal failure indices, such as the fractional excretion of filtered sodium, are not needed. The best test may be the ratio of urine osmolality to plasma osmolality. This ratio is ≤ 1.3 if the plasma volume is low (causing too little blood flow to the kidneys) and ≥ 1.2 in acute renal failure where the kidney itself is damaged.

Should muscle cramps occur, magnesium as well as calcium and phosphate levels should be checked. For grade IV and probably also for rapidly advancing grade III encephalopathy, intracranial pressure monitoring is now a standard procedure in most liver transplant centers.

There should be a near-by dialysis unit in case of kidney failure. Peritoneal dialysis is an alternative in patients with unstable blood pressures, but this procedure is contraindicated by previous abdominal surgery or infection. Liver transplantation is available only at select medical centers.

There may be a need for fresh frozen plasma or specific coagulation factor replacement. Vitamin K has little effect on the prothrombin time. (82) Since disseminated intravascular clotting (DIC) or liver depletion of clotting factors may occur, a hematology consultation is advisable if the prothrombin time is 20% less than normal, blood platelet count is diminished or unusual bleeding occurs. Fibrin split products from dissolving blood clots are found in DIC. Depletion of coagulation factors by a damaged liver is the usual cause of unexpected bleeding. Although DIC appears to be uncommon, the early stage of this disorder involves clotting and there is one report of mesenteric thrombosis. (83)

Most cardiac arrhythmias are supraventricular and not serious. There have been cases requiring a temporary transvenous pacemaker for low-grade heart block with a very slow cardiac rate. The treatment of shock is no different than in other disorders. Chest x-rays may reveal pneumonia or pulmonary bleeding.

The standard treatment of liver failure includes maintenance of normal or high normal glucose levels and avoidance of protein loads, which are poorly handled by a failing liver. Toxic nitrogenous substances are formed from protein fragments, then released into the blood and may cause brain damage. Broad-spectrum antibiotics have been used to reduce nitrogenous toxins from intestinal bacterial activity and to reduce the incidence of septicemia. The latter is a frequent and very dangerous occurrence in patients with multiple catheters and intravenous lines. When antibiotics are used to reduce nitrogenous products from intestinal bacterial activity, monitoring of antibiotic blood levels is usually necessary. Abnormally high antibiotic levels may damage organs and, in particular, kidney function and their ability to clear not only the antibiotics, but also the toxins.

Aminoglycoside antibiotics as well as atropine, barbiturates, phenothiazines, contrast media used in some x-rays and other potential liver toxins should be avoided if possible. Pain may require cautious doses of meperidine HCl (Demerol®), morphine or hydromophone HCl (Dilaudid®).

In acute liver failure, cerebral edema (brain swelling) may occur. Cerebral edema causes a quick rise in intracranial pressure, since the skull's rigidity allows the brain little room for expansion. Using a burr-hole, intracranial monitoring is safest when the monitor is placed over the dura (outer membrane around the brain). (85) Treatments for increased intracranial pressure include intravenous mannitol to move fluid from the brain to the blood stream.

A bioartificial liver may be helpful at tiding the patient over, but the technology is still evolving. (86) At present liver transplantation is the only solution for severely deteriorating liver function. Criteria for transplantation have usually been the same as those used for acute hepatitis with hepatic failure.(87) The best option is usually partial liver transplantation leaving the patient’s left liver lobe. This procedure allows that portion of the patients' own liver a chance to regenerate.

Liver regeneration therapies, which may become important in the near future, include insulin, growth hormone and liver growth factor. If blood glucose levels are normal, intravenous administration of 1 unit of insulin per hour has been suggested in severe poisoning. (75) Pure growth hormone has now been synthesized using recombinant DNA grown in cultures of the bacterium Escherichia coli. Growth hormone’s primary use is in short stature due to growth hormone deficiency, but it has been used in some cases of non-specific short stature and in some burn patients as a anabolic agent. Since growth hormone, insulin and liver growth factor reduce liver necrosis in experimental animals, cautious trials would seem reasonable in amatoxin poisoning. The recommended dose of growth hormone is 40 units per hour or the equivalent of the active portion of growth hormone. Antibodies active against amanitins have been produced in the laboratory,(90) but there has been little clinical progress in the past 10 years.