Ralph A. Lugo

Clinical pharmacokinetics of morphine.

Morphine, the most widely used mu-opioid analgesic for acute and chronic pain, is the standard against which new analgesics are measured. A thorough understanding of the pharmacokinetics of morphine is required in order to safely and effectively use this analgesic in a wide variety of patients with different levels of organ function. A MEDLINE search was conducted to identify literature published between 1966 and January 2002 relevant to the pharmacokinetics of morphine. These publications were reviewed and the literature summarized regarding unique and clinically important elements of morphine disposition relative to its parenteral administration (including intravenous, intramuscular, subcutaneous, epidural and intrathecal administration), absorption profile (immediate release, controlled release, and sublingual/buccal, and rectal administration), distribution, and its metabolism/ excretion. Special populations, including infants, elderly, and those with renal/liver failure, have a unique morphine pharmacokinetic profile that must be taken into account in order to maximize analgesic efficacy and reduce the risk of adverse events.

The pharmacokinetics of oxycodone.

Oxycodone is among the most commonly used opioid analgesics for the relief of moderate-to-severe pain and is pharmacodynamically comparable to morphine. Oxycodone is available in the United States in oral dosage forms and controlled-release tablets. Studies have demonstrated marked interindividual variation in the pharmacokinetics of oxycodone. The pharmacokinetics of oral oxycodone differs from oral morphine in that it has a higher bioavailability, a slightly longer half-life, and is hepatically metabolized by cytochrome P450 rather than undergoing glucuronidation. Understanding oxycodone pharmacokinetics favors safe and effective use of this analgesic in a wide variety of patients with different levels of organ function. A MEDLINE search was conducted to identify literature published between 1966 and May 2004 relevant to the pharmacokinetics of oxycodone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of oxycodone disposition including its absorption profile (immediate release, controlled release, rectal administration, and intranasal administration), distribution, and its metabolism/excretion. Special populations, including children and those with liver/renal failure, have a unique oxycodone pharmacokinetic profile that must be taken into account in order to maximize analgesic efficacy and reduce the risk of adverse events.

Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU.

Study Objective. To determine if enterally administered methadone can facilitate fentanyl discontinuation and prevent withdrawal in children at high risk for opioid abstinence syndrome.

The Use of Haloperidol in Agitated Critically Ill Children

Sedation, analgesia, and muscle relaxants are often used to control agitation and facilitate mechanical ventilation in children with acute hypoxic respiratory failure. In most children, adequate sedation can be achieved with a combination of parenteral benzodiazepines and opioids. However, long-term continuous infusions of opioids and benzodiazepines often result in physiologic tolerance and the need for dose escalation in order to maintain an appropriate level of sedation. Occasionally, mechanically ventilated children remain anxious, agitated, or combative despite escalating doses of opioids and benzodiazepines. In some children, additional doses of these agents seem to exacerbate agitation and combative-

A cost analysis of enterally administered lorazepam in the pediatric intensive care unit.

OBJECTIVE To determine the cost savings of replacing intravenous midazolam with enterally administered lorazepam in mechanically ventilated children who require long-term continuous sedation. DESIGN Retrospective review of patients treated according to a preestablished pediatric intensive care unit (ICU) sedation protocol. SETTING Twenty-six-bed pediatric ICU in a tertiary care childrens hospital. PATIENTS The records of 30 mechanically ventilated children were analyzed. The median age was 1.5 yrs and the median weight was 8.0 kg. Patients required continuous sedation for a total of 16 days (median). INTERVENTIONS According to our pediatric ICU sedation protocol, midazolam infusion was continued until the hourly midazolam requirement was stable for at least 24 hrs. Thereafter, patients with a nasojejunal tube who were likely to require a minimum of three additional days of continuous sedation were transitioned from intravenous midazolam to enterally administered lorazepam. The goal in transitioning therapy was to titrate the lorazepam dose and reduce midazolam administration while maintaining an unchanged level of sedation. MEASUREMENTS AND MAIN RESULTS The rate of midazolam administration was significantly (p<.05) reduced beginning on day 1 of lorazepam treatment. Midazolam was successfully discontinued in 24 (80%) patients in 3 days (median), and adequate and appropriate sedation was maintained with lorazepam monotherapy. Six patients in whom midazolam could not be discontinued experienced a 52% reduction in the rate of midazolam administration as a result of adding lorazepam. Total projected midazolam utilization was defined as the sum of midazolam administration before initiating lorazepam and the projected midazolam requirement after initiating lorazepam. Projected midazolam cost was calculated as the product of total projected midazolam utilization and midazolam acquisition cost. Actual expenditures for both midazolam and lorazepam were subtracted from the projected midazolam cost to calculate the estimated cost savings. Overall, midazolam utilization (in milligrams) was reduced by 46.7+/-27.6% (median 52). Total projected midazolam cost for the 30 patients was

Evaluation of intranasal midazolam in children undergoing esophagogastroduodenoscopy

90,771. The actual cost of midazolam and lorazepam combined was

Pharmacokinetics and pharmacodynamics of ranitidine in critically ill children.

47,867, resulting in a cost savings of

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.

42,904. CONCLUSIONS Transitioning from intravenous midazolam to enterally administered lorazepam in critically ill children who require long-term sedation results in significant cost savings. The oral formulation of lorazepam was convenient to use, inexpensive, and effective in maintaining a continuous and appropriate level of sedation once midazolam was discontinued.

The pharmacokinetics of the intravenous formulation of fentanyl citrate administered orally in children undergoing general anesthesia.

BACKGROUND Intravenous midazolam and opioids are used to produce conscious sedation in children undergoing esophagogastroduodenoscopy (EGD). However, children may experience significant fear and anxiety before receiving these medications, especially during separation from parents and during venipuncture. Intranasal administration of midazolam represents a noninvasive method of sedating children before anxiety-producing events. The objective of this study was to determine whether premedication with intranasal midazolam reduces stress and anxiety of separation from parents and of undergoing venipuncture, while maintaining adequate sedation during EGD. METHODS This was a prospective, randomized, double-blind study in 40 children, aged 2 to 12 years, who were undergoing EGD. Patients in group I were premedicated with intranasal placebo (0.9% NaCl) followed 10 minutes later by intravenous midazolam (0.05 mg/kg) and intravenous meperidine (1 mg/ kg). Patients in group II were premedicated with intranasal midazolam (0.2 mg/kg) followed by intravenous placebo (0.9% NaCl) and intravenous meperidine (1 mg/kg). Anxiolysis and sedation were scored by a blinded observer, who identified minor and major negative behaviors during four observation periods: intranasal drug administration, separation from parents, venipuncture, and EGD. RESULTS Premedication with intranasal midazolam significantly reduced negative behaviors during separation from parents (p < 0.05); however, no difference between regimens was noted during venipuncture or EGD. Negative behaviors appeared to increase during administration of intranasal midazolam or placebo. CONCLUSIONS Premedication with intranasal midazolam is effective in reducing negative behaviors during separation from parents, while it maintains sedation during the endoscopic procedure. The benefits of intranasal administration may be negated, however, by irritation, and discomfort caused by intranasal drug delivery.

Failure of nasogastric omeprazole suspension in pediatric intensive care patients.

ObjectiveTo determine the pharmacokinetics and pharmacodynamics of ranitidine in critically ill children and to design a dosage regimen that achieves a gastric pH ≥4. DesignProspective, open-label, pharmacokinetic-pharmacodynamic study. SettingPediatric intensive care unit in a tertiary care children’s hospital. PatientsMechanically ventilated, critically ill children ≥10 kg who required intravenous ranitidine for stress ulcer prophylaxis. InterventionsRanitidine pharmacokinetics were determined after a single intravenous dose. Gastric pH was monitored hourly via nasogastric pH probe. After the last blood sample, patients received an intravenous bolus of ranitidine (0.5 mg/kg) followed by a continuous infusion (0.1 mg·kg−1·hr−1). The infusion was increased incrementally (0.05 mg·kg−1·hr−1) until reaching gastric pH ≥4 for ≥75% of a 24-hr period, after which steady-state plasma concentrations were measured. Plasma concentrations were analyzed by high-pressure liquid chromatography. Measurements and Main Results Twenty-three children (ranging in age from 1.4 to 17.1 yrs) were studied. Pharmacokinetic variables included a clearance of 511.7 ± 219.7 mL·kg−1·hr−1, volume of distribution of 1.53 ± 0.99 L/kg, and half-life of 3.01 ± 1.35 hrs. After the single intravenous dose (1.52 ± 0.47 mg/kg), gastric pH increased from 1.6 ± 1.0 to 5.1 ± 1.1 (p < .001), which was associated with a plasma concentration of 373 ± 257 ng/mL. Based on the pharmacokinetic variables, the dose of intravenous ranitidine required to target 373 ng/mL as the average steady-state concentration is 1.5 mg/kg administered every 8 hrs. During the continuous infusion, the mean steady-state ranitidine concentration associated with gastric pH ≥4 was 287 ± 133 ng/mL. This concentration may be achieved with an intravenous loading dose of 0.45 mg/kg followed by a continuous infusion of 0.15 mg·kg−1·hr−1. ConclusionsThe pharmacokinetics of ranitidine in critically ill children are variable. The description of ranitidine’s pharmacokinetics and pharmacodynamics in this study may used to design an initial ranitidine dosage regimen that targets a gastric pH ≥4. Thereafter, gastric pH should be monitored and the dose of ranitidine adjusted accordingly.