Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age.

BACKGROUND: Information has been very limited on the pharmacokinetics of the selective alpha(2)-adrenoceptor agonist dexmedetomidine in children, particularly in children <2 yr of age. METHODS: Eight children aged between 28 days and 23 months and eight children aged between 2 and 11 yr undergoing either elective bronchoscopy or nuclear magnetic resonance imaging were included in the study. Dexmedetomidine 1 microg kg(-1) was infused i.v. over 5 min. Blood samples for the measurement of plasma concentrations of dexmedetomidine were collected for 5 h after starting the infusion. Pharmacokinetic calculations were based on non-compartmental methods. RESULTS: In the two groups of paediatric patients, the median (range) values for total plasma clearance of dexmedetomidine were 17.4 (14.1-27.6) and 17.3 (9.3-22.5) ml kg(-1) min(-1), for volume of distribution at steady state 3.8 (1.9-4.6) and 2.2 (1.3-2.8) litre kg(-1) (P<0.05), and for elimination half-life 139 (90-198) and 96 (69-140) min (P<0.05), respectively. The volume of distribution at steady state was negatively associated with subject age (r=-0.69, P<0.05). CONCLUSIONS: To reach a certain plasma concentration, children younger than 2 yr of age evidently need larger initial doses of dexmedetomidine than the older children, as young children have a larger volume of distribution of the drug than older children and adults. Since the total plasma clearance of dexmedetomidine is independent of age, similar rates of infusion can be used in younger and older children to maintain a steady-state concentration of dexmedetomidine in plasma.

A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla disease.

OBJECTIVE: To determine whether N-acetylaspartate (NAA) is reduced in patients with Salla disease, a neurodegenerative disorder. BACKGROUND: 1H MRS allows the brain metabolism to be studied noninvasively in vivo. N-acetyl (NA) is composed primarily of NAA, which is regarded as a neuronal marker. The NA signal in 1H MRS is reduced in several neurodegenerative disorders. Increased NA signal has thus far only been found in Canavan's disease as a result of NAA accumulation in the brain tissue. In Salla disease, an autosomal recessive free sialic acid storage disorder, N-acetylneuraminic acid (NANA), accumulates in lysosomes of brain tissue. METHODS: The authors studied eight patients with Salla disease (age range, 6 to 44 years) and eight age-matched healthy volunteers using quantitative 1H MRS. The spectra were obtained from two selected 8-cm3 volumes of interest localized in the basal ganglia and in the parietal white matter using conventional 1.5-T MRI equipment. The spectral resonance lines of NA groups, creatine and phosphocreatine (Cr), and choline-containing compounds (Cho) were analyzed quantitatively. All MR images were evaluated to verify the state of myelination. RESULTS: 1H MRS from parietal white matter revealed 34% higher NA and 47% higher Cr concentrations, and a 35% lower Cho concentration in the patients with Salla disease compared with the age-matched control subjects. The patients had a 22% higher water content in their parietal white matter, whereas in the basal ganglia the water concentrations did not differ significantly. In the patients' basal ganglia the Cr concentration was 53% higher. CONCLUSIONS: NAA is considered to be a neuronal marker that, except for Canavan's disease, has been found or assumed to be either stable or reduced. However, in Salla disease the high NA signal may have a contribution from accumulated lysosomal NANA, which offsets the possible loss of NAA. The high Cr is in line with the increased glucose uptake found in our earlier 2-fluoro-2-deoxy-D-glucose-PET study, reflecting increased energy demand. It is worth noting that in a conventional 1H MRS ratio-based analysis these underlying abnormalities would have remained undetected. Our study thus emphasizes the importance of a quantitative assessment of metabolite concentrations in 1H MRS for detecting altered brain metabolism.

Increased brain glucose utilization in Salla disease (free sialic acid storage disorder).

UNLABELLED: Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelination, but the biological mechanism of the brain dysfunction is unknown. METHODS: Nine patients with Salla disease (age 2.5 mo-42 y) presenting the disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-D-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGlc) in individual brain regions were compared with controls. RESULTS: The FDG PET results showed significantly increased LCMRGlc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum. CONCLUSION: The increased cerebral glucose utilization is a constant finding in Salla disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms.

Barbiturate anesthesia and brain proton spectroscopy.

BACKGROUND AND PURPOSE: Thiopentone reduces CBF and metabolic rate. Still, it is widely used for sedation during MR spectroscopy. We investigated whether barbiturate anesthesia and preanesthetic fasting have an effect on metabolic ratios in proton MR spectroscopy of the brain. METHODS: Eight healthy, consenting, male volunteers were studied twice in a random, crossover fashion. The study sessions were conducted during fasting (F) and nonfasting (nonF), with glucose infusion mimicking the fed state. During both sessions, two sets of spectroscopic data were collected, one during the awake state (F or nonF) and one under barbiturate anesthesia (F+B or nonF+B), using TEs of 135 and 270. Spectral areas of N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine plus phosphocreatine (Cr) were calculated, and the presence of lactate or lipid was noted. Venous blood samples for glucose, beta-hydroxybutyrate, lactate, and electrolytes were collected. RESULTS: Barbiturate anesthesia caused a 42% reduction in blood lactate levels during fasting, but not during glucose infusion. There were no differences in NAA/Cho, NAA/Cr, or in Cho/Cr between the groups F, nonF, F+B, or nonF+B. No lactate or lipid resonances were detected. CONCLUSION: Barbiturate anesthesia with preanesthetic fasting can be used for proton spectroscopy at TEs of 135 or 270 without interference from NAA/Cho, NAA/Cr, or Cho/Cr or from the appearance of lactate or lipid.

Effect of substrate manipulation on reducing ischemia/reperfusion injury in isolated perfused rat hearts.

The objective of this investigation was to assess the effect of substrate manipulation on reducing ischemia/reperfusion injury (IRI). Isolated rat hearts were perfused with modified Krebs-Henseleit buffer containing either (in mM): glucose 11 (G1), glucose 22 (G2), or glucose 11 with either xylitol 11 (GX), mannitol 11 (GM), L-leucine 1 (GL), or L-glutamic acid 2 (GGA), respectively. Hearts were subjected to 10 min of global no-flow ischemia, followed by 20 min of reperfusion. Mean tissue perfusion, oxygen consumption, and peak left ventricular pressure (PLVP) were determined at baseline, in the first minute of regular heart rhythm following ischemia, and after 20 minutes of reperfusion. Reperfusion arrhythmia (in sec) was significantly (all p < 0.05) shorter in GGA (115 +/- 33) vs G1 (315 +/- 29) and G2 (273 +/- 33), and also in GL (161 +/- 26) vs G1. Dry/wet heart weight ratios were also greater in GGA (0.20), when compared with G2 (0.16), GX (0.17), GM (0.17), GM (0.17), and GL (0.17) (all p < 0.02), suggesting less cellular/interstitial edema. Percent recovery in PLVP was improved (p < 0.03) in GL (81 +/- 2) and GGA (81 +/- 2) vs. G2 (71 +/- 3), without significant alterations in oxygen consumption. Thus, cardiac IRI can be diminished by substrate manipulation, especially by augmentation of glutamate and leucine, most likely due to an improved anaerobic energy generation and utilization.

Branched-chain amino acids and respiration.

A series of investigations suggest a specific role for BCAA in the regulation of respiration. In vitro incubation studies have shown that BCAAs improve the recovery of muscle force after fatigue. Further investigations revealed that leucine plays a key role in this action and acts in a manner not dependent on its use as an energy substrate. In humans, solutions enriched with BCAA have decreased PCO2 and stimulated the ventilatory response to hypercapnia, thereby corresponding to an enhanced ventilatory sensitivity with the administration of BCAA. The mechanisms for these actions are unknown. The most viable hypothesis is based on the ability of BCAA to decrease the synthesis of serotonin due to altered transport of AAs, including tryptophan, to the brain. Clinical studies have suggested a potency of BCAA in the treatment of respiratory dysfunction of preterm infants, as well as of patients with sleep apnea related to various disease states. The clinical applications of BCAA-enriched mixtures in respiratory diseases are still experimental, and many controversies exist concerning the validity of BCAA in clinical practice. Most TPN regimens contain BCAA approximating the average intake of BCAA in the Western diet. The question therefore remains whether additional BCAA supplementation is useful to achieve the suggested metabolic and pharmacological effects. Meticulous future studies are needed to establish the therapeutic value of BCAA in the treatment of various respiratory functions.

The use of an intravenous fish oil emulsion enriched with omega-3 fatty acids in patients with cystic fibrosis.

The effects of parenteral nutrition supplemented with a lipid emulsion enriched with the omega-3 fatty acids (FA), eicosapentaenoate (20:5n-3) and docosahexaenoate (22:6n-3), derived from fish oil were compared to a standard lipid emulsion containing omega-6 FA in patients with cystic fibrosis (CF). Patients were randomized to receive either Omegavenous 10%, which contains fish oil (IFO), or Liposyn III 10% (control) daily for 1 mo at a dose of 150 mg/kg. There were no observed allergic or toxic reactions, no abnormalities in liver function tests or coagulation parameters. To assess the bioavailability of the lipid administered, measurement of plasma free fatty acid (FFA) levels were made of the essential FA. There were no adverse changes in plasma levels of the omega-6 FA (18:2n-6, 18:3n-6, 20:3n-6, and 20:4n-6), and plasma levels of the omega-3 FA (20:5n-3 and 22:6n-3) increased significantly during the 1-mo study. There were no significant changes in plasma FFA profiles of the essential FA for the patients receiving the control lipid. The effect of treatment on pulmonary function was also investigated. There were no significant changes in FVC, FEV1, PEFR, FEV1/ FVC, or FEF25-75 (absolute value or percentage) over the 4 weeks of study in the group receiving IFO or control. This preliminary investigation suggests that intravenous administration of fish oils enriched with long chain omega-3 FA to patients with CF is safe and bioavailable.

Impact of specific substrate supply on efficiency of cardiac function: an update.

Investigations of the mechanisms that modulate energy generation during states of altered cardiac metabolism have reached a point where there is both need and demand for novel approaches. The evidence discussed here strongly suggests that both energy generation and utilization in these states may be effectively strengthened by nutritional manipulation. Compared with standard treatments for ischemia/reperfusion injury or heart failure, nutritional therapy may present an important and less toxic approach by affecting the mechanisms of energy utilization during compromised cardiac states. We provide not only a conceptual framework for further experimental studies of myocardial metabolism during ischemia and reperfusion injury but also a basis for developing clinically applicable nutrients designed to improve deranged cardiac function. The use of traditional energy substrates, in conjunction with those that may be conditionally important during compromised cardiac states, potentially offers a useful therapeutic modality in the treatment of the cardiac patient.

Long-term use of gamma-linolenic acid-enriched fat emulsion (PFE 4501): case report.

A new gamma-linolenic acid-enriched fat emulsion (PFE 4501) was given for 13 mo as part of a home parenteral nutrition regimen to a 28-yr-old patient with cystic fibrosis. Blood biochemistry, hematological data, and fatty acid profile were followed. No side effects were reported, and pulmonary function tests remained stable. gamma-Linolenic acid appears to be safe for clinical use and may benefit patients with derangements in essential fatty acid metabolism. The potential role of a gamma-linolenic acid-enriched intravenous fat emulsion is discussed.

The antinociceptive effects of branched-chain amino acids: evidence for their ability to potentiate morphine analgesia.

The effect of branched-chain amino acids (BCAA) on pain threshold was studied in rats. Nociception was induced by the hot-plate analgesia meter, a method measuring supraspinally organized pain responses. After a single intravenous injection of BCAA (320 mg/kg), the percent change in latency time to the pain response significantly increased by 19% in 60 min, and by 22% in 75 min (p < 0.005), as compared to an injection of an equal volume of a standard concentration of an amino acid solution or physiological saline. Subsequently, we studied the interaction of BCAA with opioid-type analgesia. In combination with intravenously injected morphine (3 mg/kg), BCAA significantly potentiated and prolonged the action of morphine using the hot-plate test. From 5 min after morphine injection, the latencies to a pain response were markedly higher with the combination of BCAA and morphine (+80% and +89% at 5 min after morphine injection, if BCAA was administered 45 or 60 min prior to morphine injection, respectively) when compared with the effect of morphine alone (+13% at 5 min; p < 0.005). BCAA demonstrated analgesic effects, which, in combination with morphine, potentiated and prolonged the antinociceptive action of morphine. BCAA may represent a new adjunct treatment modality for acute and chronic pain, and give us further insight into the mechanisms of pain control.

Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats.

During infusion of branched-chain amino acids (BCAAs) in humans, changes in ventilatory drive, sleeping pattern, and appetite have been reported. The mechanism by which BCAA exerts their effects on CNS remains unclear. An infusion of a BCAA solution (300 mg/kg) has previously been found to increase the seizure threshold in rats to the proconvulsant drug picrotoxin, an antagonist on the GABA-benzodiazepine receptor complex. In this study, each of the BCAAs given separately (valine, leucine, isoleucine; 300 mg/kg) (n = 10) increased the mean latency time to onset of seizures vs. placebo as an indication of an increased seizure threshold. A balanced amino acid solution (Vamin-Glucose) had no effect on the seizure threshold. Thus, these CNS effects are specific for BCAAs and occur with all three.

Branched-chain amino acids increase the seizure threshold to picrotoxin in rats.

During infusion of branched-chain amino acids (BCAAs) in humans, changes in ventilatory drive, appetite, and sleep have been reported. The mechanism by which BCAAs exert their effects on CNS remains unclear. Picrotoxin is a proconvulsant drug, acting as an antagonist on the GABA-benzodiazepine receptor complex. Twenty rats were randomized to receive either an IP injection with 4% BCAAs (300 mg/kg; 8 ml/kg) (n = 10) or placebo (saline 8 ml/kg) (n = 10). The mean latency time from injection to onset of seizures was recorded as an indication of the seizure threshold. Latency time was significantly longer for BCAAs than for placebo, 11.2 (+/- 1.9) vs. 8.3 (+/- 1.8) min. Thus, a BCAA injection increased the seizure threshold to picrotoxin (p < 0.03). This suggests that BCAA infusion may exert effects on the GABA-benzodiazepine receptor complex.

Proton spectroscopy in children with epilepsy and febrile convulsions.

An association between complex febrile convulsions and the development of hippocampal atrophy, which is characterized by neuron loss and gliosis, has been suggested but is still controversial. In proton magnetic resonance spectroscopy (1H-MRS) a reduction in N-acetylaspartate (NAA), a neuron marker, or in its ratio to other metabolites, that is, creatine and phospocreatine (Cr) and choline-containing compounds (Cho), is considered a sensitive method for detecting neuron loss. We performed 1H-MRS of mesial temporal regions, including hippocampi, in two different groups of children with epilepsy: in children with a history of complex febrile convulsions (CFCs) (n = 7; mean age 7.1 years) and in children without any history of CFCs, referred to herein as the non-CFC group (n = 6; mean age 7.6 years). Changes in the metabolite ratios were detected in 57% of children in the CFC group and in 67% of children in the non-CFC group. In both groups, NAA/(Cho + Cr), NAA/Cho, and NAA/Cr were significantly decreased ipsilaterally to the seizure focus when compared with the control group, but no significant differences were detected between the CFC and non-CFC groups. Also on the contralateral side, NAA/(Cho + Cr) and NAA/Cr were significantly decreased in both patient groups, but the differences were not significant between the CFC and non-CFC groups. Metabolite abnormalities in the mesial temporal region were detected in children with intractable epilepsy and in children whose epilepsy is well controlled by antiepileptic medication. The noninvasive 1H-MRS can be considered an additional diagnostic method to promote early detection of mesial temporal abnormalities that, in the light of this study, seem to be underdiagnosed in children with either temporal lobe epilepsy or other seizure types.

Three-year clinical performance of cast gold vs ceramic partial crowns.

Cast gold partial crowns (CGPC) and partial ceramic crowns (PCC) are both accepted for restoring posterior teeth with extended lesions today. However, as esthetics in dentistry becomes increasingly important, CGPC are being progressively replaced by PCC. The aim of the present prospective split-mouth study was the comparison of the clinical performance of PCC and CGPC after 3 years of clinical service. Twenty-eight patients (11 men and 17 women) participated in the 3-year recall with a total of 56 restorations. In each patient, one CGPC (Degulor C) and one PCC (Vita Mark II ceramic/Cerec III) had been inserted at baseline. CGPC were placed using a zinc phosphate cement (Harvard); PCC were adhesively luted (Variolink II/Excite). All restorations were clinically assessed using modified US Public Health Service (USPHS) criteria at baseline, 1 year, 2 years, and 3 years after insertion. Twenty-eight CGPC and 14 PCC were placed in molars, and 14 PCC were placed in premolars. Early data were reported previously under the same study design. After 3 years, the evaluation according to USPHS criteria revealed no statistically significant differences between both types of restorations with the exception of marginal adaptation and marginal discoloration: A statistically significant difference within the PCC group (baseline/3 years) was determined for the criterion marginal adaptation. For the 3-year recall period, overall failure was 0% for CGPC and 6.9% for PCC. At 3 years, PCC meet American Dental Association Acceptance Guidelines criteria for tooth-colored restorative materials for posterior teeth.

Periodontal healing after non-surgical therapy with a new ultrasonic device: a randomized controlled clinical trial.

AIM: The aim of this study was to compare the clinical and microbiological healing outcomes following non-surgical periodontal therapy using the new Vector ultrasonic system versus scaling and root planing (S/RP) with Gracey curettes. MATERIAL AND METHODS: The study comprised 20 chronic periodontitis patients. Using a split-mouth design, both treatment modalities were randomly applied to one quadrant of the upper and the lower jaws each. Clinical and microbiological parameters were assessed at baseline, 4 weeks, and 6 months after treatment. Furthermore, post-operative hypersensitivity was assessed. The Wilcoxon signed rank test (alpha=0.05) was used for statistical analysis. RESULTS: Both therapies provided statistically significant clinical and microbiological improvements of periodontal conditions after 4 weeks and 6 months. Hypersensitive teeth were found only 4 weeks after S/RP. Besides a significantly better bleeding on probing reduction in deep S/RP sites, no other clinical and microbiological parameters revealed significant differences between the sites treated with the Vector system or S/RP. CONCLUSION: Both the Vector system and S/RP provided favourable periodontal healing results, although in deep pockets S/RP appeared to achieve a better resolution of inflammation.

Periodontal healing after non-surgical therapy with a modified sonic scaler: a controlled clinical trial.

AIM: The aim of this study was to compare the clinical and microbiological healing outcomes following non-surgical periodontal therapy using a modified sonic scaler system versus scaling and root planing (S/RP) with hand instruments. MATERIAL AND METHODS: The study comprised 20 chronic periodontitis patients. Using a split-mouth design, both treatment modalities were randomly applied to one quadrant of the upper and lower jaws. Clinical and microbiological parameters were assessed at baseline, 4 weeks, and 6 months after treatment. Furthermore, post-operative hypersensitivity was investigated. The Wilcoxon signed-rank test (alpha = 0.05) was used for statistical analysis. RESULTS: With both therapy methods, periodontal conditions showed statistically significant clinical and microbiological improvements after 4 weeks and 6 months. Hypersensitive teeth were found only 4 weeks after S/RP. Besides a significantly better bleeding on probing reduction in deep S/RP sites and less time required for root instrumentation by the sonic scaler, no other clinical and microbiological parameters revealed significant differences between sites treated with the sonic scaler or S/RP. CONCLUSION: The sonic scaler system and S/RP seem to provide similarly favourable periodontal healing results, although in deep pockets S/RP appeared to achieve a better resolution of inflammation.

Management of the paediatric patient.

Recent introduction of new fast-onset short-duration anaesthetic drugs and the use of regional anaesthesia techniques in children have resulted in good control of anaesthesia and perioperative pain with few adverse effects. Ambulatory surgery has gained popularity in paediatric practice, particularly as children are often otherwise healthy and usually undergo minor surgery.

Simple devices in differentiating the effects of buprenorphine and fentanyl in healthy volunteers.

We have tested the usefulness of the critical flicker fusion threshold-test (CFF), Maddox wing readings (MW), and visual analogue scale scores (VAS) in a double-blind, random-order study designed to evaluate the clinical effects of two different kinds of opiates, buprenorphine and fentanyl in comparison with those of placebo. The results were compared with the so-called postanaesthetic recovery score (PARS). In 7 healthy volunteers MW and VAS differentiated the effects of buprenorphine 7.5 micrograms/kg i.v. from those of fentanyl 2.5 micrograms/kg i.v. and placebo. CFF was very insensitive in this respect and PARS completely useless. Our results show that, in addition to the known usefulness of VAS, MW is also able to differentiate the effects of these opiates.

Use of simple tests to determine the residual effects of the analgesic component of balanced anaesthesia.

In order to evaluate simple means of determining the rate of recovery after general anaesthesia, the usefulness of the critical flicker fusion threshold test, the Maddox wing apparatus and the visual analogue scale were compared. The postanaesthetic recovery score was used as a reference. Two patient groups (n = 15 in each) received, in a randomized double-blind study, a similar balanced anaesthesia for Caesarean section, except that the analgesic component was either fentanyl 2.5 micrograms kg-1 i.v. or buprenorphine 7.5 micrograms kg-1 i.v. Maddox wing apparatus and visual analogue scale were sensitive enough to differentiate between the postanaesthetic residual effects of the two opioids, but critical flicker fusion threshold and, especially, postanaesthetic recovery score were insensitive in this respect. There was no difference between the two patient groups in mean arterial pressure and heart rate. Our results show that the residual effects of different kinds of opioids as an analgesic component of balanced anaesthesia can be differentiated using simple means like Maddox wing apparatus and visual analogue scales.