Thrombolytic fibrin specificity influences activated partial thromboplastin time prolongation in vitro.

Despite limited comparative data, guidelines suggest the same concomitant unfractionated heparin (UFH) dose for all fibrin-specific thrombolytic agents in acute myocardial infarction. Since a supratherapeutic activated partial thromboplastin time (aPTT) correlates with adverse outcomes, clarifying effects of various agents on aPTT are needed. The present in vitro study evaluated the influence of alteplase (rt-PA), reteplase (r-PA), and tenecteplase (TNK) on aPTT prolongation. Blood samples from healthy volunteers (n = 12) were treated with equipotent concentrations of rt-PA, r-PA, and TNK, with and without UFH. Samples of each treatment group were incubated at 37 degrees C; aPTT and fibrinogen activity were measured after 4 h. Mean aPTT values for rt-PA alone and r-PA alone were prolonged versus those of TNK alone (P = 0.001 for both). Combined with UFH, rt-PA and r-PA increased the aPTT versus UFH alone (P < 0.05 for both). Interestingly, TNK + UFH reduced the aPTT versus UFH alone (P < 0.001). A negative correlation existed between fibrinogen activity and aPTT for all treatments, except TNK alone. The present investigation illustrates that an agent with maximal fibrin specificity (TNK) has minimal effect on the aPTT, while agents with less fibrin specificity are more likely to prolong the aPTT, with and without UFH present.

Toxic metronidazole-induced MRI changes.

OBJECTIVE: To report a case of changes documented by magnetic resonance imaging (MRI) of the head probably due to accumulation of metronidazole in a patient with liver dysfunction. CASE SUMMARY: A 34-year-old Hispanic man with cirrhosis and hepatitis C being treated with metronidazole for Bacteroides fragilis meningitis and bacteremia developed ataxia, disorientation, and peripheral neuropathy. An MRI at the time meningitis was diagnosed was negative. After the patient received > 60 g of metronidazole, an MRI revealed increased signal intensity below, behind, and lateral to the fourth ventricle. Concomitant metronidazole serum concentration was toxic at 35.1 micrograms/mL. DISCUSSION: This is the second reported case of metronidazole-induced MRI changes. Metronidazole is known to accumulate in patients with liver dysfunction and can cause peripheral neuropathy and central nervous system (CNS) dysfunction; these effects may take up to two years to completely resolve. CONCLUSIONS: Metronidazole dosages should be reduced in patients with liver dysfunction to prevent the accumulation of metronidazole, which can lead to CNS dysfunction and peripheral neuropathy.

Administration of medications through enteral feeding catheters.

BACKGROUND: Enteral feeding catheters are commonly used to administer both nutritional feedings and oral forms of medications. Obstruction of the catheters is a major concern. OBJECTIVES: To study characteristics of obstruction of enteral feeding catheters in ICU patients and current knowledge and practices of ICU nurses of administering medications through such catheters. METHODS: A postcard invitation to participate in this descriptive survey was mailed to a random sample of 12,069 members of the American Association of Critical-Care Nurses. The 52-item investigator-designed questionnaire was mailed to the 1700 critical care nurses who agreed to participate; 1167 (68.6%) returned completed survey questionnaires. RESULTS: Nurses estimated that 33.8% of their patients received 8.9 doses of medication per day through the enteral feeding catheter. The rate of obstruction of the tube by medications was 15.6%. Crushed medications contributed to obstruction, although liquid forms of the medications often were available. Nurses' primary source of knowledge about administering medications through enteral feeding catheters was clinical practice (56.9%) and consultation with peers (21.7%); only 19% had had inservice training on the topic. Written agency guidelines varied considerably, and 74% of nurses used two or more techniques that were contrary to recommendations. Factors significantly associated with lower rates of obstruction of enteral feeding catheters included (1) assistance from the pharmacy service to ensure liquid forms of medications, (2) nurses' attendance at a relevant seminar or inservice training program, and (3) not routinely crushing and administering enteric-coated or sustained-release medications through the enteral feeding catheter. CONCLUSIONS: Collaboration between nursing and pharmacy services to ensure delivery of liquid medications and avoid use of crushed medications may reduce the high rate of catheter obstruction due to medications. Research-based guidelines and a more formal dissemination of information to nurses are needed.

A nursing survey to determine the characteristics of medication administration through enteral feeding catheters.

A statewide survey was designed to develop a better understanding of the current practices and problems encountered with medication administration through enteral feeding catheters (EFCs). The sample of 223 registered nurses and licensed practical nurses estimated that a median of 10% of patients received medications through an EFC. EFC obstruction was estimated to have occurred a median of 1.5 times per week, with 50% of obstructions estimated to be due to medication administration. Nine of 14 specific medications reported as "most frequently contributing to" feeding catheter obstruction available in liquid form, yet tablets were crushed and given. When nurses perceived the pharmacy department as helping them insure that liquid dosage form was used, there was greater use of liquid forms, less use of crushed forms, and less medication-associated catheter obstruction. In this sample, the majority of nurses did not follow consistently the few recommendations available.

Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity.

OBJECTIVE: To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention. DATA SOURCES: All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers. DATA EXTRACTION: Animal, in vitro cellular, and human data are thoroughly reviewed with particular emphasis on doxorubicin-induced cardiotoxicity, including clinical manifestations, risk factors, and mechanisms of toxicity. The role of dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity is reviewed, including mechanism of effect, animal data, and human trials. DATA SYNTHESIS: Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopathy that can lead to congestive heart failure and death. The incidence of cardiotoxicity rises sharply at a total lifetime dose of more than 550 mg/m2. Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iron as a cofactor. Because of poor myocardial concentrations of superoxide dismutase, catalase, and glutathione peroxidase, these free radicals cause extensive lipid peroxidation and mitochondrial destruction. CONCLUSIONS: Dexrazoxane is hydrolyzed to its active form intracellularly and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane on the prevention of doxorubicin-induced cardiotoxicity is impressive in both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of combination chemotherapy while defining optimal dosing strategies to minimize myelosuppression and maximize cardioprotection.

Phenytoin recovery from percutaneous endoscopic gastrostomy Pezzer catheters after long-term in vitro administration.

Four in vitro administration techniques were evaluated to determine which method would produce the least amount of phenytoin lost with long-term (14 days) dosing of Dilantin Kapseals (100 mg) or Dilantin suspension 125 mg/5 mL (92 mg) through 20 French percutaneous endoscopic gastrostomy Pezzer catheters. The four in vitro techniques were (1) no dilution or irrigation, (2) irrigation with 10 mL of deionized water, (3) dilution with 10 mL of deionized water, and (4) dilution with irrigation. Similar doses and volumes (3.68 mL) of suspension and capsules were delivered to three separate catheters for each method every 8 hours for 14 days. Each catheter was encased in a 200-mm glass water jacket and maintained at 37 degrees C for the entire 14 days. Samples were collected 1 hour after administration on days 1, 3, 7, 10, and 14 and analyzed by high-performance liquid chromatography. The total mean percent change in initial phenytoin for each method was as follows (S = suspension, K = Kapseals, subscript number = method number): S1, -4.23 +/- 20.20 (mean +/- SD); S2, -7.63 +/- 14.04; S3, -0.14 +/- 2.31; S4, 3.33 +/- 5.59; K1, -9.72 +/- 4.60, K2, 1.43 +/- 3.90; K3, -3.18 +/- 5.59; and K4, 1.39 +/- 4.57.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of acetaminophen use in alcoholic patients.

Alcoholics may be predisposed to the hepatotoxicity of acetaminophen due to increased activity of the cytochrome P-450 system and decreased hepatic glutathione. To date, scattered case reports provide only a brief sketch of the frequency and pattern of acetaminophen use by alcoholics. To determine these variables, we obtained a detailed ethanol and drug history from patients answering yes to at least one of four questions on the CAGE questionnaire. Patients were classified in terms of their acetaminophen use as nonusers, users as necessary, or regular users. Regular users were further classified as nondaily or daily users, or abusers (> 4 g/day). A total of 64 patients were enrolled in the study. The average number of positive responses to the CAGE questionnaire was 3.27 +/- 0.91. Of the 64 patients, 34 (53.1%) were continuous daily drinkers, 28 (43.8%) binge drinkers, and 2 (3.1%) had completely discontinued using alcohol. By history, 32 (50)% were nonusers of acetaminophen. Of the 32 users, 12 (37.5%) stated they took it as needed and 20 (62.5%) took it regularly. Of the 20 regular users, 7 (35%) were nondaily users, 11 (55%) were daily users, and 2 (10%) were abusers. Approximately 31% of alcoholics used acetaminophen regularly, most on a daily basis, with 1 of every 10 abusing the drug. Of the 64 alcoholics interviewed, 3 (4.7%) fit the drinking and acetaminophen use patterns theoretically associated with hepatotoxicity.

Toxic carbamazepine concentrations following cardiothoracic surgery and myocardial infarction.

Carbamazepine is being used more frequently in the U.S. as an initial agent of choice to treat generalized tonic-clonic, mixed, and partial seizures with complex symptomatology. Carbamazepine is extensively metabolized in the liver; however, there is little information available on its pharmacokinetics in patients following surgery or myocardial infarction, or in those with liver disease. We report a case of a patient who attained toxic carbamazepine serum concentrations (ranging from 18.2 to 21.5 micrograms/mL) two days after cardiothoracic surgery and an intraoperative myocardial infarction, and experienced lethargy, diplopia, dysarthria, diaphoresis, and horizontal and downgaze nystagmus. These alterations in serum carbamazepine concentration normalized ten days after surgery. They may have been due to a combination of changes in protein binding and decreased elimination due to altered intrinsic hepatic clearance. With carbamazepine achieving a more prominent place in anticonvulsant therapy, the influence of various procedures and disease processes on the pharmacokinetics and pharmacodynamics of carbamazepine, as well as the clinical consequences of such changes, need further investigation.

Effect of pH on the equilibrium dialysis of phenytoin suspension with and without enteral feeding formula.

Significant decreases have been reported in phenytoin absorption when the suspension is combined with continuous enteral feedings. Several theories for this interaction have been proposed including binding of phenytoin to the protein constituents of the enteral formula, phenytoin binding to the calcium in the enteral formula, and inadequate dissolution of the suspension when delivered with the enteral formula due to the high pKa of phenytoin and the acidic nature of the enteral formula. We therefore evaluated the effects of pH levels 2.0, 3.5, 6.0, and 8.0 on the interaction of phenytoin suspension with enteral formula (Osmolite) with equilibrium dialysis using a Spectra/Por 1 (MWCO 6000-8000) molecularporous dialysis membrane. Phenytoin concentrations in the dialysis membrane (internal phase) mimicked the expected stomach concentrations of a 100-mg dose administered in an adult stomach containing 200 ml of gastric fluid. External phase buffers were sampled at 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 24.0 hr after the start of the dialysis. The phenytoin concentrations in the external phase were compared between buffer alone or buffer combined with enteral formula at the same pH and time intervals. With pH 2.0 and 3.5 the enteral formula formed an aggregate with suspension whereas no aggregate was formed with pH 6.0 and 8.0. The phenytoin concentrations with pH 2.0 were 26% to 44% lower and with pH 3.5 were 11.5 to 27% lower when phenytoin suspension was combined with enteral solution. However, at 24 hr there was no difference between the two conditions with both pH 2.0 and 3.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of phenytoin suspension after in vitro administration through percutaneous endoscopic gastrostomy Pezzer catheters.

Various methods of administering phenytoin suspension through a percutaneous endoscopic gastrostomy (PEG) Pezzer catheter were evaluated in vitro to determine which method resulted in the most complete recovery of phenytoin. To determine the effect of temperature on phenytoin recovery, 12 mL of phenytoin suspension (Dilantin-125, 125 mg/5 mL) was administered through three separate 35.5-cm 20 French latex PEG Pezzer catheters under each of three temperature conditions (suspension 11.8 degrees C and catheter 22 degrees C, suspension and catheter 22 degrees C, and suspension 22 degrees C and catheter 37 degrees C). To determine the effect of the administration method, 12-mL aliquots of phenytoin suspension were injected into the catheter by seven methods that varied with respect to catheter temperature, dilution of suspension, and irrigation of catheter. Each method was tested in triplicate, and samples were assayed by high-performance liquid chromatography. Varying the temperature of the catheter or suspension had little effect on the recovery of phenytoin. There was no appreciable loss of phenytoin when the suspension was undiluted, regardless of whether the catheter was irrigated. The greatest losses were seen when the suspension was diluted before administration. Irrigation also caused a decrease in recovery, but to a lesser extent than dilution. Until the effects of administering multiple doses of phenytoin through PEG Pezzer catheters are investigated, phenytoin suspension should not be diluted before administration because of decreased recovery and increased administration time.

Intravenous erythromycin lactobionate-induced severe nausea and vomiting.

Intravenous erythromycin lactobionate has been used for several years to treat various infectious diseases. Several cases of severe nausea and vomiting associated with its use have been reported in Europe but only a few cases have been reported in the U.S. The official product information does not refer to severe nausea and vomiting associated with its intravenous use; however, we report six additional cases of severe nausea and vomiting associated with rapid administration of erythromycin lactobionate, and review the current literature on the characteristics of this adverse effect.