Laurie S. Mauro

Meperidine-Related Seizures Associated with Patient-Controlled Analgesia Pumps

OBJECTIVE: To report three cases of meperidine-related seizures when meperidine was administered via patient-controlled analgesia pump (PCAP) and to review literature related to meperidine-associated seizures. DATA SOURCES: Case reports and review articles identified by a computerized search (MEDLINE) and manual search (Index Medicus). DATA SYNTHESIS: PCAPs are being used frequently to relieve the pain of sickle cell crisis as well as pain from many other etiologies. We report three cases of meperidine-related seizures associated with its administration via PCAP. Each of the patients received either relatively high doses, long-term therapy, or both. Meperidine has been associated with seizure activity when administered via traditional routes. Previously identified risk factors for the development of meperidine-related seizures include renal failure, high meperidine dosages, and coadministration of hepatic enzyme-inducing medications or phenothiazines. CONCLUSIONS: Meperidine administered via PCAP may be associated with seizures. Optimally, an alternative analgesic should be administered when this route is used.

Amantadine Enhancement of Arousal and Cognition after Traumatic Brain Injury

Objective: To determine the role of amantadine therapy tor early arousal and improved cognition in traumatic brain injury (TBI). Data Sources: Literature was accessed through MEDLINE (1950–August 2007) using the MeSH terms amantadine, brain injuries, cognition, and arousal. PubMed (through August 2007) terms included amantadine, traumatic brain injury, and cerebral injury. Study Selection and Data Extraction: All studies ol amantadine (used <6 mo after injury) for enhancement of arousal or cognition in patients with TBI were reviewed. Data Synthesis: Many cases of TBI are associated with frontal lobe injury. As a dopamine agonist, amantadine is thought to be involved in frontal lobe stimulation. Two case reports, 3 retrospective studies, and 2 randomized, double-blind, controlled trials of amantadine therapy for early arousal in TBI were identified and reviewed. Limitations of the available studies include open design, retrospective design, and heterogeneous brain injury types. Results have been inconsistent between studies, largely due to variability in designs, heterogeneity in patient populations, time following injury, and use of numerous different outcome measures. Despite these limitations, improvements in arousal and cognition, as documented by the Glasgow Coma Scale and olher measures, have been observed in patients with TBI when amantadine has been initiated 3 days to 5 months after injury. Conclusions: At doses of 200–400 mg/day, amantadine appears to safely improve arousal and cognition in patients with TBI. Additional prospective controlled studies with homogeneous patient populations will better define the role of amantadine for early arousal.

Impact of ginkgo biloba on the pharmacokinetics of digoxin

Many medications are known to alter digoxin pharmacokinetics, including the herbal medication St. Johns wort. An open-labeled, randomized, crossover trial was conducted in eight healthy human volunteers to determine if ginkgo biloba (GB) also alters the pharmacokinetics of digoxin. On two occasions separated by 2 weeks, subjects ingested digoxin, 0.5 mg. One week prior to each study phase, half of the volunteers were randomly initiated on GB therapy, 80 mg three times daily, that continued until the end of the study phase. Immediately prior to and for 36 hours following digoxin ingestion, multiple blood samples were collected for digoxin plasma concentration determination. No significant difference between treatments was observed with respect to AUC0−∞ (digoxin alone: 21.0 ± 8.6 [ng/mL] × h; digoxin + GB: 25.6 ± 13.2 [ng/mL] × h). Additionally, no significant difference between therapies was observed with respect to Cmax, Tmax, or Clo. In six subjects, ke and t1/2 were able to be determined. These parameters also did not differ significantly between treatments. In conclusion, within the context of the specific GB product used during this investigation, the concomitant use of GB and digoxin did not appear to have any significant effect on the pharmacokinetics of orally administered digoxin in healthy volunteers.

Enhancement of phenytoin elimination by multiple-dose activated charcoal.

The effect of multiple-dose activated charcoal on the elimination of intravenously administered phenytoin was studied. Seven normal volunteers received phenytoin sodium 15 mg/kg IV with and without activated charcoal. During the charcoal phase, a total dose of 300 g was administered in repeated doses over 48 hours with sufficient sorbitol to produce one to two bowel movements per day. Serum phenytoin concentrations were determined from one to 72 hours after the infusions and were fitted to a one-compartment linear elimination model. The administration of multiple-dose activated charcoal reduced the phenytoin half-life from 44.5 to 22.3 hours. In addition, phenytoin area under the curve was decreased and the elimination rate was increased. Multiple-dose activated charcoal is effective in enhancing the elimination of phenytoin in normal volunteers. Although future studies are needed to determine its role in treating patients with phenytoin toxicity, multiple-dose activated charcoal may provide a readily available, inexpensive therapeutic intervention.

Efficacy of Tamsulosin with Extracorporeal Shock Wave Lithotripsy for Passage of Renal and Ureteral Calculi

Objective: To review the evidence for the safety and efficacy of adjunctive tamsulosin in enhancing the efficacy of renal and ureteral stone clearance when used with extracorporeal shock wave lithotripsy (ESWL). Data Sources: A search of MEDLINE (1950-January 2008), PubMed (1950-January 2008), and the Iowa Drug Information System (1966-January 2008) was performed using the search terms tamsulosin and extracorporeal shock wave lithotripsy. MeSH headings included lithotripsy and adrenergic α-antagonists. Additional references were found by searching bibliographic references of resulting citations. Study Selection and Data Extraction: All studies utilizing tamsulosin therapy after a single session of ESWL or after the development of steinstrasse, an accumulation of stone fragments that obstructs the ureter, were included. Data Synthesis: To date, 5 prospective studies have evaluated the efficacy of tamsulosin combined with ESWL in enhancing the passage of renal and ureteral stones. in one trial, 12-week renal stone clearance was 60% in the control group compared with 78.5% in the tamsulosin group (p = 0.037). Among trials that evaluated overall ureteral stone clearance, efficacy rates were 33.3-79.3% in the control groups compared with 66.6-96.6% in the tamsulosin groups. Reports of pain and supplemental analgesic dosing were consistently lower with tamsulosin, but data on the incidence of subsequent retreatment with ESWL or ureteroscopy was rarely reported. Adjunctive tamsulosin particularly enhanced the passage of renal stones 10-24 millimeters in diameter. Overall, tamsulosin was well tolerated. Conclusions: Overall, evidence suggests that adjunctive tamsulosin therapy combined with ESWL is safe and effective in enhancing stone clearance in patients with renal stones 10-24 millimeters in diameter. Evidence regarding ureteral stone clearance is inconclusive, although adjunctive tamsulosin has been reported to reduce painful episodes. Larger prospective trials evaluating different dosages and stone locations, as well as the ability of tamsulosin to reduce repeat ESWL or more invasive methods such as ureteroscopy should be performed.

Pharmacologic Expulsive Treatment of Ureteral Calculi

Objective: TO evaluate the role of nifedipine and the α1-adrenoreceptor antagonists tamsulosin, terazosin, and doxazosin in the expulsive treatment of ureteral calculi. Data Sources: Literature was searched via MEDLINE (1966–February 2006) with subsequent bibliographic review. MeSH headings included ureteral calculi, nifedipine, doxazosin, and adrenergic α-antagonists. Key terms were ureteral calculi, nifedipine, tamsulosin, terazosin, and doxazosin. Study Selection and Data Extraction: Trials evaluating nifedipine, tamsulosin, terazosin, and doxazosin for expulsion of ureteral stones were reviewed. All were published in English-language, peer-reviewed journals. Data Synthesis: Several trials have evaluated the effects of nifedipine and tamsulosin on ureteral stone passage rates and mean time to stone passage in stones no larger than 15 mm. In 28 day trials, the rates of ureteral stone passage were 35–70% in the control groups compared with 77.1–80% in patients treated with nifedipine and 79.3–100% in patients treated with tamsulosin. Average number of days to stone passage in the control groups was 4.6–20, and the time to stone passage was only 5–9.3 days in patients receiving nifedipine and 2.7–7.9 days in those receiving tamsulosin. The stone passage rates and time to stone passage appeared to be similar in one trial that compared tamsulosin with terazosin and doxazosin. Limited data suggest that these agents may have a role as adjuncts to shock wave lithotripsy. Adverse drug reactions were uncommon. Conclusions: Nifedipine, tamsulosin, terazosin, and doxazosin are safe and effective options in enhancing ureteral stone expulsion in selected patients with uncomplicated presentations.

Misadventures with Activated Charcoal and Recommendations for Safe Use

OBJECTIVE: To review published reports of adverse effects associated with single- and multiple-dose activated charcoal therapy, and to formulate recommendations for safe use of activated charcoal therapy. DATA SOURCES: A manual search of Index Medicus from 1970 to December 1993 was conducted for English language articles; bibliographies of the resultant articles were also scanned. STUDY SELECTION: Cases were included if they were described in full detail, resulted in significant morbidity or mortality, and uniquely contributed to the formulation of recommendations for safe use of activated charcoal therapy. DATA SYNTHESIS: The major causes of morbidity and mortality secondary to activated charcoal therapy are aspiration of charcoal, gastrointestinal obstruction, and fluid and electrolyte abnormalities. Aspirations have occurred as a result of a number of circumstances that may be avoided. These include use in patients with unprotected airways, use of excessive charcoal dose, administration of inappropriately diluted charcoal, and administration of charcoal in the field. Gastrointestinal obstruction has occurred when multiple doses of activated charcoal have been administered without a cathartic and in cases in which a cathartic was administered if the patient had impaired peristalsis. Fluid and electrolyte abnormalities have occurred secondary to excessive cathartic administration. CONCLUSIONS: Activated charcoal therapy should be used judiciously so that related morbidity and mortality can be prevented. Adequate consideration for the patients airway protection capability is necessary. Judicious dosing of charcoal and concomitant cathartic therapy, along with adequate monitoring of fluid and electrolyte status, abdominal physical assessment, and clinical condition are all vital to the safe use of activated charcoal therapy.

Erythromycin in the Treatment of Diabetic Gastroparesis.

The macrolide antibiotic erythromycin has been known to be associated with increased gastrointestinal motility since its introduction more than 35 years ago. Investigators have, thus, sought to take advantage of this side effect in patients with gastric stasis secondary to long-standing insulin-dependent diabetes mellitus (IDDM). The hormone motilin induces phase 3 contractions of the migrating motor complex (MMC) to induce peristalsis and facilitate gastric emptying in normal subjects. Patients with diabetic gastroparesis lack adequate phase 3 activity to effectively empty gastric contents. Exogenous motilin administered to animals and patients with diabetic gastroparesis has proven useful for promoting gastric emptying. However, motilin is expensive to produce and must be given intravenously. Erythromycin has been shown to induce premature phase 3 activity via stimulation of motilin receptors, so investigators evaluated its efficacy for the treatment of diabetic gastroparesis. Early studies in animals with experimental gastroparesis indicated that erythromycin may be a useful prokinetic agent. Human studies of both intravenous erythromycin and chronic oral erythromycin in patients with diabetic gastroparesis resistant to other prokinetic agents showed that gastric retention was indeed reduced and symptomatic improvement achieved. Even though erythromycin lost some of its prokinetic activity with chronic oral dosing, gastric retention was still significantly reduced compared to placebo or baseline. Although prokinetic agents like metoclopramide, domperidone and cisapride are effective for the treatment of patients with diabetic gastroparesis, tachyphylaxis and adverse effects are obstacles to their use. Erythromycin appears to be both effective and well tolerated in clinical studies. At this time it should be reserved for the treatment of patients with diabetic gastroparesis who are resistant to or intolerant of other prokinetic agents. Future research on erythromycins long-term safety and comparative efficacy will further define its role.

Accuracy of two equations in determining normalized phenytoin concentrations

The accuracy of two equations in normalizing total phenytoin concentrations in the presence of renal failure or hypoalbuminemia was evaluated in 11 renal failure and 23 hypoalbuminemic patients. Blood samples were obtained from hospitalized patients receiving phenytoin and were assayed for free and total phenytoin concentrations. Estimated normalized phenytoin concentrations based on free drug concentration were compared statistically with normalized concentrations calculated from the two equations via Students t-test. The equation for normalizing phenytoin concentrations in hypoalbuminemic patients significantly underpredicted normalized phenytoin concentrations 15.7 ± 8.5 versus 19.9 ± 12.1 mg/L(p<0.001). In patients with renal failure, the mean phenytoin concentration from the respective equations and that based on free concentration were 14.1 ± 6.2 and 14.0 ± 7.9 mg/L, respectively. However, in 5 of 11 renal failure patients the equation resulted in over- or underprediction by at least 25 percent. Neither equation should be used clinically to normalize phenytoin concentrations in these patient populations.

Beta-Agonists in the Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease

OBJECTIVE: To critically evaluate the following issues regarding the use of beta-agonists in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD): (1) optimal dose, (2) use of nebulizer (NEB) versus metered-dose inhaler-spacer devices (MDISs), (3) comparison with anticholinergic agents, and (4) use in mechanically ventilated patients. The patient populations addressed are limited primarily to emergency department (ED) and intensive care/acute care settings. DATA SOURCES: English-language journal articles published between 1977 and 1993. STUDY SELECTION: Nine studies were evaluated that included beta-agonists alone or in combination with other bronchodilators in the treatment of acute exacerbation of COPD. Many of the studies contained design flaws or were limited in size, making interpretation difficult. In studies containing both asthma and COPD patients, focus was restricted to analysis of COPD patients when possible. DATA EXTRACTION: Performed subjectively by the authors. Studies were evaluated for methodologic strengths and weaknesses. DATA SYNTHESIS: Dosing studies in patients with stable disease show a relationship between dose and the various pulmonary function tests (PFTs). Dose also correlates with duration of action and incidence of adverse effects. Four studies compared NEBs versus MDISs. Studies revealed significant improvement in PFTs for both treatments, with no significant difference between groups noted. Five studies compared various combinations of beta-agonists and ipratropium. Both ipratropium and beta-agonists caused statistically significant increases in PFTs from baseline. Combination therapy provided no further increase in spirometry compared with that of single-agent therapy. One study did report an early discharge from the ED with the addition of ipratropium. Most studies did not use large doses of beta-agonists or evaluate the effect of repeated doses. Many studies allowed concomitant therapy. Most did not include outcome measurements, such as ED length of stay, admission rates, hospital stay, or incidence of relapse. CONCLUSIONS: Dose—response studies in patients with stable disease suggest that doses of albuterol powder up to 1 mg may be tolerated safely, although use of repeated larger doses has not been well studied. Beta-agonists given by MDIS or NEB are equally effective in this setting. There is no apparent advantage to combined use of beta-agonist and ipratropium in the acute setting. Future research in this area should evaluate the use of larger or repeated doses of beta-agonists in the acute setting. Optimizing concurrent therapy and evaluating various patient outcomes should receive special attention in further investigations.