Pharmacokinetics of a 24-hour intravenous ketoprofen infusion in children

BACKGROUND: No pharmacokinetic data are available with respect to the plasma concentration of ketoprofen during intravenous infusion in children. METHODS: We present here the pharmacokinetics of ketoprofen after a 10-min intravenous infusion of 1 mg/kg followed by a 24-h infusion of 4 mg/kg in 18 children aged 7 months to 16 years. Venous blood samples were collected at 5 min, 1, 2, 4, 24 h following the loading dose, and then 1, 2 and 4 h after the end of the infusion. A validated HPLC method was used to measure plasma levels of ketoprofen. RESULTS: The steady state plasma concentration of ketoprofen was 2.0 microg/mL (range 1.3-2.7 microg/mL). The clearance of ketoprofen was 0.09 L x h(-1) x kg(-1) (range 0.06-0.13 L x h(-1) x kg(-1)). The distribution volume was 0.16 L/kg (range 0.12-0.21 L/kg). The terminal half-life was 1.3 h (range 0.8-1.7 h). CONCLUSION: The pharmacokinetics of ketopofen in children is similar to that reported in adults. Our results indicate that ketoprofen is a feasible drug for continuous intravenous infusion in acute pain treatment in children.     

Diclofenac pharmacokinetic meta-analysis and dose recommendations for surgical pain in children aged 1-12 years

Background: Diclofenac is an effective, opiate‐sparing analgesic for acute pain in children, which is commonly used in pediatric surgical units. Recently, a Cochrane review concluded the major knowledge gap in diclofenac use is dosing information. A pharmacokinetic meta‐analysis has been undertaken with the aim of recommending a dose for children aged 1–12 years. Methods: Studies containing diclofenac pharmacokinetic data were identified during a Cochrane systematic review, and authors were asked to provide raw data. A pooled population analysis was undertaken in NONMEM to define the pharmacokinetics of intravenous, oral, and rectal diclofenac in children. Simulations were performed to recommend a dose yielding an equivalent area under diclofenac concentration–time curve (AUC) to a 50‐mg dispersible tablet in adults. Results: Data from 111 children aged 1–14 years consisting of 375 samples following intravenous, oral suspension, and suppositories were used. Adult dispersible tablet and suspension data were added to provide a reference AUC and support the absorption modeling, respectively. A three‐compartment model described disposition, a dual‐absorption compartment model was used for suspension and dispersible tablet data, and single‐absorption compartment model for suppositories. The estimate of clearance was 16.5 l·h^?1·70 kg^?1 and bioavailabilities were 0.36, 0.63, and 0.35 for suspension, suppository, and dispersible tablets, respectively. Conclusions: Single doses of 0.3 mg·kg^?1 for intravenous, 0.5 mg·kg^?1 for suppositories, and 1 mg·kg^?1 for oral diclofenac in children aged 1–12 years are recommended as they yield a similar AUC to 50 mg in adults.     

Pharmacokinetics of rectal paracetamol after repeated dosing in children

Twenty-three children(aged between 9 weeks and 11 yr) were givenparacetamol suppositories 25 mgkg^–1 every 6 h (maximum5 days) after major surgery andserum and saliva concentrationswere measured. There was a good correlation(r=0.91, P<0.05)between saliva andserum concentrations. A one-compartment linearmodel withfirst-order elimination and absorption and lag-timewas fitted tothe data (ADAPT II). At steady state, the mean(SD)concentration was 15.2 (6.8) mg litre^–1. Mean (SD)time to reach 90% of the steady state concentrationwas 11.4(8.6) h. Body weight, age and body surface area were wellcorrelated(P<0.05) with clearance and apparent volume ofdistribution.There was no evidence of accumulation leading tosupratherapeuticconcentrations during this dosing schedule for a mean ofapproximately2–3 days. Br J Anaesth 2000; 85: 512–9 ^* Corresponding author     

Effect of 24-hour ureteral obstruction on subsequent ischemic damage in rat kidney

The effects of prior 24-hour ureteral obstruction on ischemic renal damage were studied in rats. Rats were divided into 6 groups with different times of ischemia (0, 60 and 90 min) and with or without 24-hour ureteral obstruction. Following a 4-week recovery period, contralateral nephrectomy was performed and the rat was sacrificed 24 h later for the determination of serum creatinine and for histologic examination of the affected kidney. A preceding ureteral obstruction for 24 h made no difference to the renal damage with 60 min of ischemia or without ischemia. However, kidneys with 90 min of ischemia and 24 h of ureteral obstruction were more damaged than those with 90 min of ischemia only. These results suggested that the hydronephrotic kidney was more susceptible to long periods of ischemia than the normal kidney.     

The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study

Analgesic acetaminophen plasma concentrations are not known. We investigated in a randomized, double-blinded study the pharmacokinetics and analgesic efficacy of small- (AS; 20 mg. kg(-1)) and larger- (AL; 40 mg/kg) dose rectal acetaminophen and compared it with the combination (C) of rectal diclofenac (100 mg) and acetaminophen (20 mg/kg) in 65 women undergoing hysterectomy. Suppositories were administered after the induction of a standardized general anesthesia. Pain (measured by using a 10-cm visual analog scale) and morphine consumption (patient-controlled analgesia) were repeatedly assessed for 24 h. Acetaminophen plasma concentrations were measured by using a fluorescence polarization immunoassay. Antipyretic plasma concentrations (10-20 mg/L) after 40 mg/kg acetaminophen were not associated with improved analgesia or decreased opioid requirements; 20 mg/kg acetaminophen produced subtherapeutic plasma levels (<10 mg/L). Maximal plasma concentrations of 17.2 and 10.4 mg/L (P < 0.01, analysis of variance) were achieved after 4.2 and 3.6 h for the AL and AS groups, respectively. The only difference in clinical outcome was lower visual analog scale scores after acetaminophen/diclofenac (C 2.0 versus AS 3.2 and AL 3.4) 4 h after the induction (P < 0.05, analysis of variance). Acetaminophen pharmacokinetics in adults were similar to those observed in children. Analgesic plasma concentrations are likely to be higher than antipyretic plasma levels, which were only attained after twice the recommended rectal dose was administered. Analgesic plasma concentrations have yet to be determined but may be higher than those associated with antipyresis. IMPLICATIONS: Acetaminophen pharmacokinetics were comparable in adults and children. Plasma concentrations known to reduce fever did not produce better pain relief and were only achieved after twice the conventional dose was administered. Analgesic plasma concentrations have yet to be determined but may be higher than those associated with antipyresis.     

Technique and experience with 24-hour esophageal pH monitoring in children.

The technique and scoring system of 24-hr pH esophageal monitoring has been modified to evaluate gastroesophageal reflux in infants and children. The data from two pediatric controls and five clinical cases are presented and compared to normal adult values. This test has better objectivity, precision, sensitivity, and reliability than contrast studies, endoscopy, esophageal biopsy, acid perfusion, or acid reflux tests. The 24-hr pH monitoring assists the evaluation of sphincter maturation, pulmonary disease, and the significance of body position. With more experience, this technique could identify children at risk fo developing severe complications of reflux esophagitis and aid in the selection of candidates for surgical intervention.     

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.     

Midazolam as an induction agent in children: a pharmacokinetic and clinical study

The pharmacokinetics of midazolam was studied in 21 children undergoing elective surgery at five different dose levels for induction of general anesthesia and were compared with a control group (n = 6) given thiopental, 5 mg/kg. The clearance of midazolam was found to be dose-related. The elimination half-life varied from 0.79 to 2.83 hr, which is shorter than in adult patients. Even a dose of 0.6 mg/kg midazolam was found to be unreliable as an agent for induction of anesthesia. Compared with thiopental 5 mg/kg, significantly longer times of onset to closing of the eyes (P less than 0.01) and the disappearance of eyelid reflex (P less than 0.01) were seen with midazolam.     

Sublingual midazolam premedication in children: a dose response study

The purpose of this study was to evaluate various doses of sublingual midazolam premedication in children. In our prospective, double-blind, placebo-controlled trial, children (n=102, age range 12 to 129 months) scheduled for day surgery were randomized to receive either midazolam in one of three doses (0.25, 0.5, or 0.75 mg·kg^?1) or placebo. Injectable midazolam was mixed with a thick grape syrup and placed under the tongue; the patient was asked to hold it as long as possible before swallowing. Children readily accepted the mixture. Analysing all patients randomized, none of the children receiving placebo vs 28% receiving 0.25 mg·kg^?1 (P=0.02), 52% receiving 0.5 mg·kg^?1 (P<0.001), and 64% receiving 0.75 mg·kg^?1 (P<0.001) of midazolam showed satisfactory sedation (drowsy) at 15 min after administration. Children receiving the two higher doses of midazolam (0.5 and 0.75 mg·kg^?1) accepted mask induction willingly, while the group receiving 0.25 mg·kg^?1 resembled the placebo group (P<0.05).     

A pharmacokinetic study of piroxicam in children

Feldene Melt (piroxicam) is commonly used for analgesia following day case surgery. The manufacturer's recommended paediatric dose is 0.4 mg.kg(-1) once daily. In children, plasma piroxicam levels of 3-5 microg.ml(-1) are associated with effective analgesia. However, in adults a single dose of 20 mg piroxicam (0.4 mg.kg(-1) for a 50-kg adult) produces plasma levels of only 1.5-2.2 microg.ml(-1). We therefore studied plasma levels achieved by 0.4 mg.kg(-1) or 1.0 mg.kg(-1) piroxicam in 22 children aged between 3 and 16 years, undergoing elective orthopaedic surgery, in order to investigate the adequacy of single dosing. The first 12 patients received 0.4 mg.kg(-1) Feldene Melt pre-operatively. Following assay of plasma piroxicam levels, a further 10 patients received 1.0 mg.kg(-1) Feldene Melt. In both groups, five blood samples were taken at 2-hourly intervals. The mean (95% CI) piroxicam level following 0.4 mg.kg(-1) was 2.90 (2.33-3.54) microg.ml(-1), compared to 5.87 (4.58-7.16) microg.ml(-1) following 1.0 mg.kg(-1) (p = 0.0003).     

Pathologic and histologic results of electrical impulses in a rabbit model of atherosclerosis: 24-hour versus 8-hour regimen

OBJECTIVE: Low frequency electrical impulses (EIs) reduce new atherosclerotic plaque formation in previously diseased arteries and may reverse the extent of previous pathologic damage in these structures. METHODS: A pacemaker was implanted on the left side of rabbit abdominal aortas, and an electrode was placed close to the other side of the aorta in the psoas major muscle. For the induction of atherosclerosis, the rabbits were placed on a high cholesterol diet (HCD) for 11 weeks. No EIs were applied to the control series I. In the experimental series, the rabbits were fed an HCD for 3 weeks, after which EIs were applied simultaneously with an HCD for 8 additional weeks (3V, 30 contractions per minute). Experimental series II had 24-hour/day EIs, and series III had 8-hour/day EIs. RESULTS: The closer to the area where the EIs were applied, the more local severity increased (atherosclerosis level and surface area). In the control series, the severity of atherosclerosis in the lower aorta assessed with an arbitrary grading system was 1.75 +/- 0.5 (versus 1.5 +/- 0.57 with 8-hour/day EIs and 0.5 +/- 0.3 with 24-hour/day EIs). The involved surface area was 32.5% +/- 9.5% (versus 1.0% +/- 0.8% with 8-hour/day EIs and 0.75% +/- 0.95% with 24-hour/day EIs). CONCLUSION: Both 24-hour/day and 8-hour/day EIs applied close to the abdominal aorta decreased the severity of atherosclerosis in rabbits placed on a HCD, but 24-hour/day EIs decreased the severity more extensively.     

Functional studies of the heart during a 24-hour preservation using a new autoperfusion preparation.

Serial cardiac function studies were carried out during a 24-hour preservation in a new autoperfusion multiorgan preparation using adult Yorkshire swine (n = 8). The heart was removed with the lungs, liver, pancreas, duodenum, and both kidneys while they were still perfused by the heart and oxygenated by the lungs. The organs were placed in a 32 degrees C bath solution containing lactated Ringer's, heparin, and neomycin. Fresh blood and a solution containing glucose (10%) with potassium chloride (2 gm/L), calcium chloride (1 gm/L), heparin sodium (100 mg/L), mannitol (12.5 gm/L), insulin (100 U/L), metronidazole hydrochloride (500 mg/L), penicillin (1,000,000 U/L), and methylprednisolone (250 mg/L) were given slowly through the portal vein. A fat emulsion 2 ml, methylprednisolone 30 mg, and heparin sodium 20 mg were given through the portal vein every 2 hours. No inotropic drugs were used. Aortic systolic pressures ranged from 79 to 97 mm Hg; the aortic diastolic pressures ranged from 44 to 61 mm Hg. Central venous pressures ranged from 0.4 to 2.0 mm Hg, and the heart rate was 69 to 81 beats/min. Left ventricular maximum dp/dt ranged from 1405 to 1836 mm Hg/sec, and maximum dp/dt/p ranged from 17.0 to 26.2 (sec-1). Aortic blood flow ranged from 1.2 to 1.6 L/min, and systemic resistance ranged from 33 to 53 U. Lactic acid decreased from 8.15 to 2.80 mmol/L. Myocardium wet/dry weight ratio after preservation averaged 5.13 (vs 5.09 for control). These results suggest that the heart may be preserved up to 24 hours with minimal change in function with this new autoperfusion preparation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rectal midazolam as premedicant in children: a dose response study

Rectally administered midazolam has proved to be a reliable and acceptable way of premedicating children. In order to determine the optimal dose 80 children were randomized in a double-blind manner to receive one of four different dosages of midazolam (0.2–0.3–0.4–0.5 mg·kg⁻¹) in combination with atropine 0.02 mg·kg⁻¹ rectally. Observations before and after premedication showed no clinically relevant differences in ventilatory and cardiovascular parameters. Neither did the groups differ as regards acceptance of the mask or awakening from anaesthesia. Regardless of group the level of sedation was increased, but only children receiving 0.4 or 0.5 mg·kg⁻¹ of midazolam showed an increase in the level of anxiolysis. For this reason a low dose of midazolam (0.2 mg·kg⁻¹) can be used, except in cases where pronounced anxiolysis is required.     

Arteriovenous fistula closure after renal transplantation: a prospective study with 24-hour ambulatory blood pressure monitoring

We prospectively evaluated the effects of arteriovenous fistula closure on 24-hour ambulatory blood pressure measurements and on left ventricular geometry assessed by echocardiography. Sixteen kidney transplant recipients were studied before and 1 month after surgical fistula closure. The mean of 24-hour diastolic blood pressure increased from 77+/-7 mmHg to 82+/-8 mmHg (P=0.003) without systolic changes. The diastolic blood pressure increase correlated with the reduction in left ventricular mass (P=0.0034). In multivariate analysis, the diastolic blood pressure increase best correlated with preoperative cardiac index (P=0.01). After a similar time delay between two studies, blood pressure remained unchanged in 14 kidney transplant controls with a patent fistula not scheduled for closure. Because the increase in diastolic blood pressure after arteriovenous fistula closure occurred regardless of the preoperative level of diastolic pressure, we suggest that blood pressure should be monitored after fistula closure, particularly when preoperative diastolic blood pressure is borderline or elevated.