umstances it may be necessary to nebulize into a tent or croupette, and this method of use must be individualized to take into account the available equipment and the patient's particular needs. this form of administration requires very large volumes of the solution, occasionally as much as 300 ml during a single treatment period. if a tent or croupette must be used, the recommended dose is the volume of acetylcysteine (using 10% or 20%) that will maintain a very heavy mist in the tent or croupette for the desired period. administration for intermittent or continuous prolonged periods, including overnight, may be desirable. direct instillation when used by direct instillation, 1 to 2 ml of a 10% to 20% solution may be given as often as every hour. when used for the routine nursing care of patients with tracheostomy, 1 to 2 ml of a 10% to 20% solution may be given every 1 to 4 hours by instillation into the tracheostomy. acetylcysteine may be introduced directly into a particular segment of the bronchopulmonary tree by inserting (under local anesthesia and direct vision) a small plastic catheter into the trachea. two to 5 ml of the 20% solution may then be instilled by means of a syringe connected to the catheter. acetylcysteine may also be given through a percutaneous intratracheal catheter. one to 2 ml of the 20% or 2 to 4 ml of the 10% solution every 1 to 4 hours may then be given by a syringe attached to the catheter. diagnostic bronchograms for diagnostic bronchial studies, two or three administrations of 1 to 2 ml of the 20% solution or 2 to 4 ml of the 10% solution should be given by nebulization or by instillation intratracheally, prior to the procedure. administration of aerosol materials acetylcysteine may be administered using conventional nebulizers made of plastic or glass. certain materials used in nebulization equipment react with acetylcysteine. the most reactive of these are certain metals (notably iron and copper) and rubber. where materials may come into contact with acetylcysteine solution, parts made of the following acceptable materials should be used: glass, plastic, aluminum, anodized aluminum, chromed metal, tantalum, sterling silver, or stainless steel. silver may become tarnished after exposure, but this is not harmful to the drug action or to the patient. nebulizing gases compressed tank gas (air) or an air compressor should be used to provide pressure for nebulizing the solution. oxygen may also be used but should be used with the usual precautions in patients with severe respiratory disease and co 2 retention. apparatus acetylcysteine is usually administered as fine nebulae and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes. commercially available nebulizers will produce nebulae of acetylcysteine satisfactory for retention in the respiratory tract. most of the nebulizers tested will supply a high proportion of the drug solution as particles of less than 10 microns in diameter. mitchell 2 has shown that particles less than 10 microns should be retained in the respiratory tract satisfactorily. various intermittent positive pressure breathing devices nebulized acetylcysteine with a satisfactory efficiency including: no. 40 de vilbiss (the de vilbiss co., somerset, pennsylvania), and the bennett twin-jet nebulizer (puritan bennett corp., oak at 13th., kansas city, missouri). the nebulized solution may be inhaled directly from the nebulizer. nebulizers may also be attached to the plastic face masks or plastic mouthpieces. suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (ippb) machines. the nebulizing equipment should be cleaned immediately after use because the residues may clog the smaller orifices or corrode metal parts. hand bulbs are not recommended for routine use in nebulizing acetylcysteine because their output is generally too small. also, some hand-operated nebulizers deliver particles that are larger than optimum for inhalation therapy. acetylcysteine should not be placed directly into the chamber of a heated (hot pot) nebulizer. a heated nebulizer may be part of the nebulization assembly to provide a warm saturated atmosphere if the acetylcysteine aerosol is introduced by means of a separate unheated nebulizer. usual precautions for administration of warm saturated nebulae should be observed. the nebulized solution may be breathed directly from the nebulizer. nebulizers may also be attached to plastic face masks, plastic face tents, plastic mouth pieces, conventional plastic oxygen tents, or head tents. suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (ippb) machines. the nebulizing equipment should be cleaned immediately after use, otherwise the residues may occlude the fine orifices or corrode metal parts. prolonged nebulization when three fourths of the initial volume of acetylcysteine solution has been nebulized, a quantity of sterile water for injection, usp (approximately equal to the volume of solution remaining) should be added to the nebulizer. this obviates any concentration of the agent in the residual solvent remaining after prolonged nebulization. compatibility the physical and chemical compatibility of acetylcysteine solutions with certain other drugs that might be concomitantly administered by nebulization, direct instillation, or topical application has been studied. acetylcysteine should not be mixed with certain antibiotics. for example, the antibiotics, tetracycline hydrochloride, oxytetracycline hydrochloride, and erythromycin lactobionate, were found to be incompatible when mixed in the same solution. these agents may be administered from separate solutions if administration of these agents is desirable. the supplying of these data should not be interpreted as a recommendation for combining acetylcysteine with other drugs. the table is not presented as positive assurance that no incompatibility will be present, since these data are based only on short-term compatibility studies done in the mead johnson research center. manufacturers may change their formulations, and this could alter compatibilities. these data are intended to serve only as a guide for predicting compounding problems. if it is deemed advisable to prepare an admixture, it should be administered as soon as possible after preparation. do not store unused mixtures. in vitro compatibility 1 tests of acetylcysteine 1. the rating, incompatible , is based on the formation of a precipitate, a change in clarity, immiscibility, or a rapid loss of potency of acetylcysteine or the active ingredient of the product and/or agent in the admixture. the rating, compatible , means that there was no significant physical change in the admixture when compared with a control solution of the product and/or agent, and that there was no predicted chemical incompatibility. all of the admixtures have been tested for short-term chemical compatibility by assaying for the concentration of acetylcysteine after mixing. 2. the active ingredient in the product and/or agent was also assayed after mixing. some of the admixtures developed minor physical changes which were considered to be insufficient to rate the admixture incompatible . these are listed in footnotes 3, 4, and 5. 3. a strong odor developed after storage for 24 hours at room temperature. 4. the admixture was a slightly darker shade of yellow than a control solution of the product and/or agent. 5. a light tan color developed after storage for 24 hours at room temperature. 6. entries are final concentrations. values in parentheses relate volumes of acetylcysteine solutions to volume of test solutions. ratio tested 6 product and/or agent compatibility acetylcysteine product rating or agent anesthetic, gas halothane compatible 20% infinite nitrous oxide compatible 20% infinite anesthetic, local cocaine hcl compatible 10% 5% lidocaine hcl compatible 10% 2% tetracaine hcl compatible 10% 1% antibacterials (a parenteral form of each antibiotic was used) bacitracin 2,3 (mix and use at once) compatible 10% 5,000 u/ml chloramphenicol sodium succinate compatible 20% 20 mg/ml carbenicillin disodium 2 (mix and use at once) compatible 10% 125 mg/ml gentamicin sulfate 2 compatible 10% 20 mg/ml kanamycin sulfate 2 (mix and use at once) compatible 10% 167 mg/ml compatible 17% 85 mg/ml lincomycin hcl 2 compatible 10% 150 mg/ml neomycin sulfate 2 compatible 10% 100 mg/ml novobiocin sodium 2 compatible 10% 25 mg/ml penicillin g potassium 2 (mix and use at once) compatible 10% 25,000 u/ml compatible 10% 100,000 u/ml polymyxin b sulfate 2 compatible 10% 50,000 u/ml cephalothin sodium compatible 10% 110 mg/ml colistimethate sodium 2 (mix and use at once) compatible 10% 37.5 mg/ml vancomycin hcl 2 compatible 10% 25 mg/ml amphotericin b incompatible 4% - 15% 1 - 4 mg/ml chlortetracycline hcl 2 incompatible 10% 12.5 mg/ml erythromycin lactobionate incompatible 10% 15 mg/ml oxytetracycline hcl incompatible 10% 12.5 mg/ml ampicillin sodium incompatible 10% 50 mg/ml tetracycline hcl incompatible 10% 12.5 mg/ml bronchodilators isoproterenol hcl 2 compatible 3% 0.5% isoproterenol hcl 2 compatible 10% 0.05% isoproterenol hcl 2 compatible 20% 0.05% isoproterenol hcl compatible 13.3% (2 parts) 0.33% (1 part) isoetharine hcl compatible 13.3% (2 parts) (1 part) epinephrine hcl compatible 13.3% (2 parts) 0.33% (1 part) contrast media iodized oil incompatible 20%/20 ml 40%/10 ml decongestants phenylephrine hcl 2 compatible 3% 0.25% phenylephrine hcl compatible 13.3% (2 parts) 0.17% (1 part) enzymes chymotrypsin incompatible 5% 400 γ/ml trypsin incompatible 5% 400 γ/ml solvents alcohol compatible 12% 10% - 20% propylene glycol compatible 3% 10% steroids dexamethasone sodium phosphate compatible 16% 0.8 mg/ml prednisolone sodium phosphate 5 compatible 16.7% 3.3 mg/ml other agents hydrogen peroxide incompatible (all ratios) sodium bicarbonate compatible 20% (1 part) 4.2% (1 part)

may reduce its effectiveness. draw blood for predetoxification acetaminophen plasma assay and baseline sgot, sgpt, bilirubin, prothrombin time, creatinine, bun, blood sugar and electrolytes. administer the loading dose of acetylcysteine, 140 mg per kg of body weight. (prepare acetylcysteine for oral administration as described in the dosage guide and preparation table). determine subsequent action based on predetoxification plasma acetaminophen information. choose one of the following four courses of therapy. predetoxification plasma acetaminophen level is clearly in the toxic range (see acetaminophen assays - interpretation and methodology below): administer a first maintenance dose (70 mg/kg acetylcysteine) 4 hours after the loading dose. the maintenance dose is then repeated at 4-hour intervals for a total of 17 doses. monitor hepatic and renal function and electrolytes throughout the detoxification process. predetoxification acetaminophen level could not be obtained proceed as in a. predetoxification acetaminophen level is clearly in the non-toxic range (beneath the dashed line on the nomogram) and you know that acetaminophen overdose occurred at least 4 hours before the predetoxification acetaminophen plasma assays discontinue administration of acetylcysteine. predetoxification acetaminophen level was in the non-toxic range, but time of ingestion was unknown or less than 4 hours because the level of acetaminophen at the time of predetoxification assay may not be a peak value (peak may not be achieved before 4 hours post-ingestion), obtain a second plasma level in order to decide whether or not the full 17-dose detoxification treatment is necessary. if the patient vomits an oral dose within 1 hour of administration, repeat that dose. in the occasional instances where the patient is persistently unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation. repeat sgot, sgpt, bilirubin, prothrombin time, creatinine, bun, blood sugar and electrolytes daily if the acetaminophen plasma level is in the potentially toxic range as discussed below. preparation of acetylcysteine for oral administration oral administration requires dilution of the 20% solution with diet cola or other diet soft drinks, to a final concentration of 5% (see dosage guide and preparation table). if administered via gastric tube or miller-abbott tube, water may be used as the diluent. the dilutions should be freshly prepared and utilized within one hour. remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours. acetylcysteine is not approved for parenteral injection.

n patients are known to have reacted previously to the inhalation of an acetylcysteine aerosol, they may not react during a subsequent treatment. the converse is also true; patients who have had inhalation treatments of acetylcysteine without incident may still react to subsequent inhalation with increased airways obstruction. most patients with bronchospasm are quickly relieved by the use of a bronchodilator given by nebulization. if bronchospasm progresses, the medication should be discontinued immediately.

ollowing ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the p-450 pathway. the increased formation of reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis. acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. its effectiveness depends on early oral administration, with benefit seen principally in patients treated within 16 hours of the overdose. acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.

or pups. females after mating were continued on treatment for the next 42 days. reproductive toxicity studies of acetylcysteine in the rat given oral doses of acetylcysteine up to 1,000 mg/kg (5.2 times the human mucolytic dose) have also been reported in the literature. 1 the only adverse effect observed was a slight non-dose-related reduction in fertility at dose levels of 500 or 1,000 mg/kg/day (2.6 or 5.2 times the human mucolytic dose) in the segment i study.