High frequency spectral components after secobarbital: the contribution of muscular origin--a study with MEG/EEG.

OBJECTIVES: Previously we found that benzodiazepines not only provoke beta-activity in the EEG, but also higher frequency activity. Knowing the origin of this high frequency activity is crucial if localisation of epileptogenic brain tissue is the query. We attempt to differentiate cerebral from muscular origin of such activity. METHODS: We postulate that EEG and MEG have similar sensitivity to brain activity, but different sensitivity to muscle activity, and compare co-recorded EEG and MEG signals in a group of five patients who had received short-lasting barbiturates to induce sleep. We performed principal components analysis over time and subtract the results for MEG from the EEG to see where the frequency spectra differ. RESULTS: The EEG showed activity in the gamma bands up to 270Hz for all patients; the MEG significantly less. We find no differences in the lower frequency bands. Topographically the differences localized over the frontotemporal regions. CONCLUSIONS: In the EEG benzodiazepines and/or barbiturates are not only associated with frequencies in the beta band, but also with wide range gamma activity. The latter seems to be of muscular origin. SIGNIFICANCE: Our study suggests that gamma activity in such measurements may not be cerebral in origin. MEG is less susceptible to contamination from muscle activity than the EEG.

Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death.

Barbiturates are widely used as anesthetics, anticonvulsants, and neuroprotective agents. However, barbiturates may also inhibit mitochondrial respiration, and mitochondrial inhibitors are known to potentiate NMDA receptor-mediated neurotoxicity. Here we used rat cortical cultures to examine the effect of barbiturates on neuronal mitochondria and responses to NMDA receptor stimulation. The barbiturates tested, secobarbital, amobarbital, and thiamylal, each potentiated NMDA-induced neuron death at barbiturate concentrations relevant to clinical and experimental use (100-300 microm). By using rhodamine-123 under quenching conditions, barbiturates in this concentration range were shown to depolarize neuronal mitochondria and greatly amplify NMDA-induced mitochondrial depolarization. Barbiturate-induced mitochondrial depolarization was increased by the ATP synthase inhibitor oligomycin, indicating that barbiturates act by inhibiting electron transport sufficiently to cause ATP synthase reversal. Barbiturates similarly amplified the effects of NMDA on cytoplasmic free calcium concentrations. The cell-impermeant barbiturate N-glucoside amobarbital did not influence mitochondrial potential or potentiate NMDA neurotoxicity or calcium responses. However, all of the barbiturates attenuated NMDA-induced calcium elevations and cell death when present at millimolar concentrations. Whole-cell patch-clamp studies showed that these effects may be attributable to actions at the cell membrane, resulting in a block of NMDA-induced current flux at millimolar barbiturate concentrations. Together, these findings reconcile previous reports of opposing effects on barbiturates on NMDA neurotoxicity and show that barbiturate effects on neuronal mitochondria can be functionally significant. Effects of barbiturates on neuronal mitochondria should be considered in experimental and clinical application of these drugs.

Barbiturates inhibit progesterone synthesis in cultured Leydig tumor cells and human granulosa cells.

Screening drugs used in obstetrical practice for effects on steroid hormone synthesis revealed that phenobarbital inhibited progesterone synthesis in MA-10 Leydig tumor cells. The inhibition was apparently a drug class effect since it could be reproduced by other barbiturates. Barbiturate blockade was reversible and could be bypassed in the MA-10 cells by using 22-hydroxycholesterol. Human granulosa cell progesterone synthesis was also inhibited in a dose dependent fashion by phenobarbital, secobarbital and barbituric acid. Significant inhibition occurred in dose ranges that would be therapeutic for treating epilepsy. From these data we conclude that barbiturates block steroidogenesis by inhibiting cholesterol transport to the cholesterol side chain cleavage enzyme.

Comparing single and cumulative dosing procedures in human triazolam discriminators.

This study evaluated a cumulative dosing procedure for drug discrimination with human participants. Four participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. A crossover design was used to compare the results under a single dosing procedure with results obtained under a cumulative dosing procedure. Under the single dosing procedure, a dose of triazolam (0, 0.05, 0.15, or 0.35 mg/70 kg) or secobarbital (0, 25, 75, or 175 mg/70 kg) was administered 45 min before assessment. Determining each dose-effect curve thus required four sessions. Under the cumulative dosing procedure, four doses of triazolam (0, 0.05, 0.10, and 0.20 mg/70 kg) or secobarbital (0, 25, 50, and 100 mg/70 kg) were administered approximately 55 min apart, producing a complete dose-effect curve in one four-trial session. Regardless of procedure, triazolam and secobarbital produced discriminative stimulus and self-reported effects similar to previous single dosing studies in humans. Shifts to the right in cumulative dose-effect curves compared to single dose-effect curves occurred on several self-report measures. When qualitative stimulus functions rather than quantitative functions are of interest, application of cumulative dosing may increase efficiency in human drug discrimination.

Parallel nature of hippocampal synaptic plasticity.

This study demonstrates that the mechanisms involved in the production of long-term potentiation (LTP) in the hippocampus appear to be independent of those which generate shorter-lasting plasticity, but that both processes are activated concurrently following an LTP-inducing stimulus. Adult male Sprague-Dawley rats were anesthetized using either pentobarbital or secobarbital to record extracellular field potentials from the hippocampal CA1 pyramidal cell layer in response to stimulation of commissural afferents. Plasticity was generated by the delivery of a five-pulse patterned stimulus train, consisting of one priming pulse followed 170 milliseconds later by a burst of four pulses at 200 Hz. While similar LTP was observed in both groups, short-term plasticity was absent in the secobarbital-anesthetized animals. This result suggests that different plasticity mechanisms in the hippocampus are activated in parallel by the triggering stimulus.

Melatonin for sleep EEG.

Melatonin 3 mg and secobarbital 100 mg assigned randomly were given to 40 psychiatric patients for sleep induction during EEG recording. Nine patients who did sleep naturally comprised a comparison group. EEGs were read blind; most were interpreted as mildly abnormal or within normal limits. No statistically significant differences between the three groups were observed in response to photic stimulation, hyperventilation or in frequency of paroxysmal variants. The electroencephalographer was able to identify the melatonin patients significantly more accurately than those who received secobarbital on the basis of lack of EEG manifestations of fast frequencies typical of barbiturate effects. Self-assessments of drowsiness, anxiety and performance on a perceptual-motor task were similar in the melatonin and secobarbital patients. However, the secobarbital group showed more impairment on a locomotion test than those who received melatonin or slept spontaneously. The results suggest that melatonin is a plausible alternative for EEG sleep sedation, especially for ambulatory patients.

Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation.

In previous publications [English, Hughes and Wolf (1994) J. Biol. Chem. 269, 26836-26841; English, Hughes and Wolf (1996) Biochem. J. 316, 279-283], we have demonstrated that peroxisome proliferators and non-steroidal anti-inflammatory drugs are inducers of the cytochrome P-450BM-3 gene in Bacillus megaterium ATCC14581. Their mechanism of action involves binding to and subsequent displacement of the transcriptional repressor, Bm3R1, from its operator site, which results in the activation of cytochrome P-450BM-3 gene transcription. We now present evidence that the branched-chain fatty acid, phytanic acid, is a potent inducer of cytochrome P-450BM-3. We have also observed that phytanic acid and peroxisome proliferators are inducers of Bm3R1 protein accumulation and associated DNA-binding activity. In contrast, several barbiturates, although capable of inducing cytochrome P-450BM-3 and Bm3R1 gene transcription, were unable to induce the Bm3R1 protein. We also demonstrate that cytochrome P-450BM-3 readily oxidizes phytanic acid, and provide evidence that, although the omega-1 hydroxy acid derivatives of phytanic acid can associate with Bm3R1, they do so with an affinity two orders of magnitude lower than the unmodified fatty acid. As a consequence, the ability of the hydroxylated product to induce cytochrome P-450BM-3 gene expression in vivo is markedly reduced. These data collectively suggest that metabolism of fatty acids by cytochrome P-450BM-3 leads to an attenuation of their ability to activate the transcription of the BM-3 operon. This work places the action of bacterial fatty acid hydroxylases in an autoregulatory loop where they may be responsible for the inactivation or clearance of the inducing fatty acid signal.

Biological determinants of P300: the effects of a barbiturate on latency and amplitude.

Polich & Kok (1995) (Biological Psychology, 41, 103-146) have recently argued that P300 is not only sensitive to specific 'cognitive' variables, but also to non-specific biological processes such as arousal. Fluctuations in arousal are said to be indexed by an inverse relationship between latency and amplitude. We tested this hypothesis with a drug that decreases arousal-the barbiturate secobarbital sodium. Twelve subjects performed a visual 80-20% oddball task at two levels of stimulus quality and after ingesting the drug (2.9 mg/kg body weight) or a placebo. Reaction time (RT) and P300 were collected simultaneously and the latter was analyzed on both a single trial and average basis. The RT results confirmed that secobarbital interacts with stimulus quality. Secobarbital slowed single trial P300 by about half as much as RT, and this slowing was additive with stimulus quality. Thus the two measures dissociated. Secobarbital did not influence P300 amplitude. Average P300 revealed the same pattern of results, although the size of the latency effects was somewhat attenuated. RT and P300 latency were more strongly correlated than P300 latency and amplitude. We propose that P300 latency reflected the slowing of stimulus evaluation produced by the depressant properties of the drug, and that fluctuations in arousal are not necessarily associated with a simple inverse relationship between P300 latency and amplitude.

Secobarbital in humans discriminating triazolam under two-response and novel-response procedures.

Humans were trained to discriminate the benzodiazepine triazolam (0.32 mg/70 kg) from placebo under a two-response (drug vs. placebo) drug discrimination procedure. Dose-effect curves for several drugs were then determined in a crossover design using the two-response procedure and a 'novel-response procedure' that provided a novel-appropriate response for drugs unlike triazolam or placebo. Three subjects were tested with triazolam (0.1-0.32 mg/70 kg), the barbiturate secobarbital (56-177 mg/70 kg), and caffeine (320 and 560 mg/70 kg). Triazolam dose dependently increased triazolam-appropriate responding under both procedures and generally did not occasion novel-appropriate responding under the novel-response procedure. Secobarbital substituted for triazolam in the two-response procedure and dose-dependently increased novel-appropriate responding as well as occasioned some triazolam-appropriate responding in the novel-response procedure. Caffeine generally occasioned placebo-appropriate responding under the two-response procedure and a mix of novel- and placebo-appropriate responding under the novel-response procedure. Triazolam and secobarbital produced qualitatively similar self-reported drug effects. These results suggest that the novel-response procedure for human drug discrimination may enhance the pharmacological selectivity of triazolam- and placebo-appropriate responding.

Barbiturate inhibition of GLUT-1 mediated hexose transport in human erythrocytes exhibits substrate dependence for equilibrium exchange but not unidirectional sugar flux.

Barbiturates inhibit GLUT-1 mediated hexose transport both in vivo [Gjedde & Rasmussen (1980) J. Neurochem. 35, 1382-1387; Otsuka et al. (1991) Am. J. Physiol. 261, R265-R275] and in vitro [Honkanen et al. (1995) Biochemistry 34, 535-544]. In the present study, the mechanism by which barbiturates inhibit GLUT-1 mediated hexose transport was examined by measuring both unidirectional zero trans and equilibrium exchange fluxes of hexoses in the functionally well-characterized, GLUT-1 rich human erythrocyte system. Unidirectional influx were both inhibited (> 80%) by 10 mM pentobarbital (PB). This symmetrical inhibition of unidirectional flux by PB was virtually independent of cis sugar concentration (2-130 mM) and exhibited an IC50 of approximately 2 mM. In contrast to unidirectional sugar flux, PB inhibition of equilibrium exchange sugar flux is attenuated by increased substrate concentration (e.g., 88% inhibition at 1 mM Glc versus 40% inhibition at 130 mM Glc in the presence of 10 mM PB) and exhibits an IC50 of approximately 10 mM at 100 mM Glc. Other barbiturates were found to inhibit sugar flux in human erythrocytes in this differential manner. These findings, when viewed with kinetic models proposed for GLUT-1 mediated transport [Carruthers (1990) Physiol. Rev. 70, 1135-1176], are consistent with barbiturates being noncompetitive inhibitors of Glc translocation and preferentially inhibiting the unoccupied form of the carrier protein. We propose, therefore, that barbiturates may prevent or alter the conformational changes associated with the reorientation of the carrier protein within the membrane. Overall, these results imply that barbiturates may more strongly inhibit GLUT-1 mediated Glc flux in vivo when the trans Glc is near zero as a result of either metabolism or another transport process.

Secobarbital-mediated inactivation of cytochrome P450 2B1 and its active site mutants. Partitioning between heme and protein alkylation and epoxidation.

Secobarbital (SB) is a relatively selective mechanism-based inactivator of cytochrome P450 2B1, that partitions between epoxidation and heme and protein modification during its enzyme inactivation. The SB-2B1 heme adduct formed in situ in a functionally reconstituted system has been spectrally documented and structurally characterized as N-(5-(2-hydroxypropyl)-5-(1-methylbutyl)barbituric acid)protoporphyrin IX. The SB-protein modification has been localized to 2B1 peptide 277-323 corresponding to the active site helix I of cytochrome P450 101. The targeting of heme and this active site peptide suggests that the 2B1 active site topology could influence the course of its inactivation. To explore this possibility, the individual SB epoxidation, heme and protein modification, and corresponding molar partition ratios of the wild type and seven structural 2B1 mutants, site-directed at specific substrate recognition sites, and known to influence 2B1 catalysis were examined after Escherichia coli expression. These studies reveal that Thr-302 is critical for SB-mediated heme N-alkylation, whereas Val-367 is a critical determinant of 2B1 protein modification, and Val-363 is important for SB epoxidation. SB docking into a refined 2B1 homology model coupled with molecular dynamics analyses provide a logical rationale for these findings.

Thiobarbiturates suppress depolarization-induced contraction of vascular smooth muscle without suppression of calcium influx.

We have studied the effects of barbiturates on vascular smooth muscle tension and cytosolic calcium concentrations ([Ca2+]i) in endothelium-denuded rat aortic rings, preloaded with fluo-3. Changes in [Ca2+]i were estimated by the fluorescence intensity of the calcium-bound form of fluo-3. In aortic rings under basal conditions, thiobarbiturates (thiopentone and thiamylal 100-300 mumol litre-1) increased [Ca2+]i, concomitantly with an increase in tension, although oxybarbiturates (pentobarbitone and secobarbitone up to 300 mumol litre-1) had no effect. Thiopentone (300 mumol litre-1)-induced increases in tension and fluorescence intensity were mean 25.1 (SD 3.2)% and 55.0 (6.0)%, respectively, of those induced by KCl 30 mmol litre-1 (n = 8, each). In KCl (30 mmol litre-1)-precontracted aortic rings, thiopentone decreased tension without reduction of [Ca2+]i, whereas pentobarbitone decreased tension and [Ca2+]i, KCl (30 mmol litre-1)-induced contraction was suppressed by pretreatment with all barbiturates (100-300 mumol litre-1); thiopentone 300 mumol litre-1 suppressed contraction to 64.8 (2.5)% (n = 6) and pentobarbitone 300 mumol litre-1 to 57.5 (2.2)% (n = 9). However, the increase in [Ca2+]i was suppressed by oxybarbiturates (pentobarbitone 300 mumol litre-1 to 77.9 (5.2) %; n = 9), but not altered by thiobarbiturates. These results suggest that thiobarbiturates and oxybarbiturates affect vascular smooth muscle differently and that the affected site in thiobarbiturate-induced vasodilatation is distal to regulation of [Ca2+]i.

Secobarbital attenuates excitotoxicity but potentiates oxygen-glucose deprivation neuronal injury in cortical cell culture.

We examined the effects of secobarbital and other sedative-hypnotic barbiturates on the neuronal death induced by exposure to excitatory amino acids or deprivation of oxygen or glucose in mouse cortical cell cultures. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate, and kainate toxicities were attenuated in a concentration-dependent fashion by high concentrations of secobarbital or thiopental. Antagonism of NMDA toxicity was not overcome by increasing NMDA concentration and not mimicked by gamma-aminobutyrate. Despite these antiexcitotoxic actions, secobarbital exacerbated the neuronal death induced by deprivation of either glucose alone or oxygen and glucose together; death induced by oxygen deprivation alone was little affected. Thiopental and methohexital also increased oxygen-glucose deprivation injury. A possible explanation for this injury potentiation was provided by the observation that secobarbital enhanced the cellular ATP depletion induced by combined oxygen-glucose deprivation. Deleterious effects on ATP production may counterbalance the protective effects of barbiturates under some conditions.

Effect of secobarbital and morphine on arterial blood gases in healthy human volunteers.

Secobarbital is still widely used as a hypnotic and morphine as an analgesic perioperatively in surgical patients. Their combination is often used as a preanesthetic medication. Although their ventilatory depressant effect is recognized, the resulting blood gas changes have not been studied as yet adequately in a sufficiently large population of healthy volunteers. Therefore this study was undertaken. Thirty healthy volunteers who gave valid written consent were studied. Secobarbital 2.0 mg/kg intravenously caused a significant (P < .05) decrease in arterial oxygen pressure (PaO2), peaking at 10 minutes (n = 10; mean age, 23.4 years). Morphine, 0.2 mg/kg intravenously also caused a significant decrease in PaO2 at 5 minutes (n = 10; mean age, 26.3 years). The combination of the same doses of morphine and secobarbital caused a significantly (P < .01) greater decrease in PaO2 at 5 and 10 minutes than the sole administration of either drug (n = 10; mean age, 23.5 years). Arterial oxygen pressure remained significantly (P < .05) reduced for 30 minutes. Although the PaCO2 increases after secobarbital and morphine did not reach statistical significance, their combination caused a significant (P < .05) increase in PaCO2. Both secobarbital and morphine alone caused significant (P < .05) decrease in pHa at 30 minutes. Their combination caused a significant (P < .01) reduction in pHa from 5 minutes until 60 minutes. In conclusion, both secobarbital and morphine alone caused ventilatory depression. The duration of ventilatory depression was greater with the intravenous combination than with either drug alone.

Acute, chronic and differential effects of several anesthetic barbiturates on glutamate receptor activation in neuronal culture.

The acute and chronic effects of several anesthetic barbiturates, in therapeutic concentrations, on the excitatory amino acid (EAA)-induced elevation of intracellular calcium levels ([Ca2+]i) were examined in neuronal tissue culture. The ultrashort-acting barbiturate, thiamylal, was effective in blocking elevations of [Ca2+]i induced by kainate, N-methyl-D-aspartate (NMDA), and quisqualate or by membrane depolarization with 40 mM KCl. The structurally similar barbiturate, secobarbital which differs from thiamylal only by having an oxygen in place of a sulfur, was able to block elevations induced by the above EAAs but was less effective than thiamylal and did not significantly reduce [Ca2+]i that resulted from membrane depolarization with KCl. Pentobarbital, while differing from secobarbital by only a methyl group, was without effect on either the NMDA- or 40 mM KCl-induced elevations of [Ca2+]i. By contrast, cyproheptadine, a compound that has been shown to block Ca2+ channels, has a different profile from the above barbiturates in that cyproheptadine is more effective in blocking elevation of [Ca2+]i induced by membrane depolarization with KCl while the barbiturates are more effective in reducing [Ca2+]i induced by EAAs. An anticonvulsant barbiturate, phenobarbital, did not reduced elevations of [Ca2+]i induced by any EAA tested or by membrane depolarization with KCl. When cells were treated chronically with thiamylal for 4 days, 2-6 h after the abrupt drug withdrawal there was a hyperresponsiveness to the elevations of [Ca2+]i induced by both kainate and NMDA but not by quisqualate. A similar hyperresponsiveness was not seen after the chronic treatment with phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of the nicotinic acetylcholine receptor by barbiturates and by procaine: do they act at different sites?

1. The effects of three barbiturates and the local anesthetic procaine on the ion channel function of mouse nicotinic acetylcholine receptor (nAChR) muscle subtype expressed in Xenopus laevis oocytes were examined by whole-cell voltage-clamp technique. 2. A concentration-response curve for the specific nicotinic agonist dimethylphenylpiperazinium iodide (DMPP) was first determined. This agonist produced increasing whole-cell currents up to a concentration of 100 microM (EC50 = 13 microM), then decreased responses at higher concentrations. 3. The barbiturates (amobarbital, secobarbital, pentobarbital) and procaine produced reversible inhibition of DMPP-induced currents at clinically used concentrations. The two classes of drugs differed in the voltage dependence of the inhibition: procaine-induced inhibition was increased at more negative transmembrane holding potentials (-90 vs. -45 mV); whereas amobarbital-induced inhibition did not vary at different transmembrane potentials. 4. Mutant forms of the nAChR, containing single amino acid changes in the M2 regions of alpha and beta subunits, showed increased sensitivity to procaine but no change in sensitivity to amobarbital-induced inhibition. 5. These electrophysiologic studies provide further evidence that barbiturates and local anesthetics produce inhibition of the nAChR at different sites.

Differential sensitivity of diabetic rat papillary muscles to negative inotropic effects of oxybarbiturates versus thiobarbiturates.

The negative inotropic effects of oxybarbiturates and thiobarbiturates were examined in papillary muscles isolated from streptozotocin-induced diabetic rats and in papillary muscles from age-matched control rats. The muscles from diabetic rats exhibited less negative inotropic responses to pentobarbital and secobarbital than the muscles from control rats. Conversely, the negative inotropic responses to thiopental and thiamylal were significantly enhanced in diabetic muscles. Differences in sensitivity to pentobarbital between control and diabetic muscles became less marked by treatment with ouabain or by lowering [Na+]o. Enhancement of the negative inotropic effect of thiamylal observed in diabetic muscles remained unchanged with these treatments. In both control and diabetic muscles, the negative inotropic effect of pentobarbital was completely reversed by increasing [Ca2+]o, but the effect of thiamylal was only partially reversed. These results suggest a difference in mechanism of action involved in establishment of the negative inotropic effects of oxybarbiturates vs thiobarbiturates. Oxybarbiturates appear to exclusively reduce the influx of extracellular Ca2+, whereas thiobarbiturates appear to affect Ca2+ movements at the Ca2+ storage sites in addition to the Ca2+ influx inhibition.

Correlation of sedative effects with brain levels of barbiturates in LS and SS mice.

Long-sleep (LS) and short-sleep (SS) mice, genetically selected for their differential CNS sensitivity to ethanol, have also been shown to differ in their response to other sedative-hypnotics, including the barbiturates. We have applied a gas-chromatographic method of analysis of brain barbiturate concentrations following IP administration of either the water-soluble barbiturate diethylbarbital (DB) or the lipid-soluble barbiturate secobarbital (SB). Brain barbiturate levels were assessed at loss of righting response, and at regaining righting response (waking). In addition, latency to loss of righting response and duration of loss of righting response were measured following IP barbiturate administration. We have observed a differential sensitivity of LS and SS mice to the sedative effects of DB, with LS mice having greater sensitivity compared to SS. This differential sensitivity to DB, as measured by a lower concentration of DB which caused loss of righting in LS, was accompanied by an equal rate of water-soluble barbiturate brain distribution and elimination in the two lines. With the lipid-soluble barbiturate SB, LS and SS mice did not differ in brain SB concentration at loss of righting response or at waking. However, sleep time was much longer in SS mice than LS due to slower brain clearance of the barbiturate in SS. Therefore, duration of loss of righting (sleep time) did not adequately reflect central sensitivity to the lipid-soluble barbiturate. These data suggest the importance of quantifying brain concentrations at loss of righting reflex when assessing central sensitivity to sedative-hypnotic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Barbiturates inhibit intracellular Ca2+ rise induced by thrombin in rat platelets.

The effects of a number of barbiturates (anesthetic as well as anticonvulsant) on thrombin-induced calcium mobilization were tested in rat platelets using the fluorescent Ca2+ probe Fura-2. All drugs, except barbituric acid and Na-barbital, inhibited the thrombin-induced intracellular Ca2+ rise. Both the uptake of extracellular Ca2+ and the release of calcium from intracellular organelles were affected but influx was inhibited more strongly and at lower concentrations of the drugs (e.g. IC50 of thiopental was 0.83 mM for influx and 1.2 mM for intracellular release). Inhibitory potencies of the various barbiturates were markedly different. Thiopental was the most and barbital the least potent inhibitor. The order of inhibitory potency of the drugs appeared generally to follow their lipid solubility and the order of their hypnotic efficiency, with hexobarbital as the most conspicuous exception. Therefore, barbiturate treatment of cells perturbs agonist-induced calcium mobilization. This effect may be partially linked to their previously reported inhibitory action on two kinases, protein kinase C and phosphatidylinositol 4-phosphate kinase [1, 2].

Analgesia versus sedation during Broviac catheter placement.

Premature infants are capable of mounting physiologic and metabolic responses to pain. Systemic and local anesthesia reduce stress responses to major and minor surgical procedures. We evaluated the effects of local anesthesia (5 mg/kg lidocaine) preceded by either 1 mg/kg secobarbital (S) intravenously or by 2 micrograms/kg fentanyl (F) intravenously on the stress response to Broviac catheter placement. Twenty-nine premature infants ages 5 to 30 days, weighing between 650 and 1350 gm, were randomly assigned to either S or F groups. Age, birthweight, sex, race, and severity of illness were similar among S and F groups. Heart rate and blood pressure remained unchanged throughout the procedure. Oxygen saturation (O2sat) declined significantly in both groups during skin preparation and wound closure, but not during incision, dissection, or tunneling. In spite of fractional inspired oxygen adjustments made in 13 of 14 S- and 3 of 15 F-treated patients, decline in O2sat was more common and more pronounced (p less than 0.01) in S-treated babies. Hyperglycemic responses occurred in all S- and in none of the F-treated patients (p less than 0.001). Norepinephrine plasma concentrations did not change during Broviac catheter placement in either F or S group. Epinephrine concentrations were more elevated in S- than in F-treated patients, although these differences were not statistically significant. Low-dose fentanyl analgesia effectively complements local lidocaine anesthesia during Broviac catheter placement. Sedatives neither abolish metabolic responses to surgical stress nor prevent profound and persistent oxygen desaturation.