Two in one: patient-controlled epidural analgesia (PCEA) to prevent erection and control pain in adult hypospadias-surgery patients.

Following penile surgery, erections are painful and may prejudice the result, because the sutures may not withstand a rigid erection. Therefore, prevention of erection and management of pain are extremely important following hypospadias repair, especially in adult patients. In this prospective study, we aimed to achieve these goals by using an epidural block with patient-controlled analgesia. We allocated 20 adult patients scheduled for hypospadias repair randomly either to receive or not to receive epidural analgesia. Postoperative pain was scored according to a standardised scoring system, based on a 10 point visual analogue scale. In group I (n = 10), analgesia was provided by a 3 ml h(-1) continuous infusion of fentanyl (2 microg) and bupivacaine solution (0.125%) in 1 ml saline via an epidural catheter for the first 3 days. Patient-controlled epidural analgesia was administered with an additional 5 ml of the same solution when the pain score was high (> 4). After 3 days, fentanyl was excluded from the treatment protocol, and analgesia was maintained with bupivacaine (0.125%). In group II (n = 10, control group), an epidural catheter was not inserted, and analgesia was maintained with pethidine (1 mg kg(-1)). Pain management was found to be more effective in group I. No erections occurred in group I, but the erection rate in group II was mean +/- s.d. = 1.7 +/- 0.2. The differences were found to be statistically significant (P<0.05). We highly recommend the technique described here, which offers efficient analgesia and control of erection in adult hypospadias patients.

Propofol does not affect platelet aggregation.

Abnormalities of platelet haemostasis pose increased risk to patients undergoing anaesthesia and surgery. We have investigated the effect of propofol on platelet aggregation in 12 patients undergoing upper and lower abdominal surgery. Propofol 2.5 mg kg-1 was administered via a cannula in the antecubital vein. Venous blood samples were obtained before induction and 10 min after administration of propofol. Platelet aggregation measurements were made for adenosine diphosphate (ADP), collagen and adrenaline. The results show that propofol does not affect platelet aggregation in the concentrations used.

Diaphragmatic fatigue in the rat.

We studied fatigue of rat diaphragm in response to repetitive brief and prolonged electrical stimulation of the phrenic nerve, at 0.2, 1-100 Hz. Low and high frequency of stimulation produced twitch and tetanic contractions in the rat diaphragm. A mean maximum twitch tension of 1.4 +/- 0.1 g was produced at 1 Hz, and a mean maximum tetanic tension of 5.6 +/- 0.3 g was obtained at 100 Hz (means +/- S.E., n = 8). Twitch and tetanic fatigue was produced at all frequencies of stimulations, but with different time scale, or duration, and with different number of stimuli delivered to the muscle. At low rates of stimulation, e.g. 10 Hz, fewer stimuli were needed to fatigue the muscle (3000 in 5 min), whereas at high rates of stimulation, e.g. 50 Hz, more stimuli were needed to fatigue the muscle (6600 in 2.2 min). The amplitude of the tetanic tensions elicited at 10 and 50 Hz, at the end of 5 or 2 min fatiguing stimulation, was 39 +/- 2.7% and 80 +/- 3.1% of their respective control tensions (2.8 +/- 0 2 g and 5.3 +/- 0.5 g, n = 8, P 0.001). It was concluded that fatigue in the rat diaphragm depended on the frequency and duration of stimulation as well as on the number of stimuli delivered to the muscle. Various mechanisms of muscle fatigue are described in the discussion to explain the observations made in the present investigation.

Assessment of neuromuscular blockade produced by atracurium in the rat diaphragm preparation. Measurements of tetanic fade, depression and recovery profile.

The effect of atracurium, a relatively new muscle relaxant, on neuromuscular transmission, in the rat diaphragm preparation, was studied, by analysing the characteristic features of tetanic fade and recovery pattern following a blocking concentration of atracurium (10 microns). Tetanic fade (TF) and peak tetanic tension (Tp) and its depression by atracurium, were analysed and the results were interpreted in terms of atracurium action at the neuromuscular junction. Atracurium reduced the sustained tetanic tension, elicited at 50 Hz for 0.5 s duration, and produced a marked tetanic fade in 38 s. Atracurium also reduced the peak tetanic tension by 40%, of the control value, in 38 s. Maximum tetanic tension was 5.7 g tension, and the time taken to completely block the tetanus was 4.75 +/- 0.15 min (means +/- SE, n = 8). Recovery from atracurium-induced blockade occurred in 30s (tetanic fade) and in 3-4 min (peak tetanic tension). It was concluded that atracurium produces a profound tetanic fade, at a time when the peak tetanic tension is reduced by only 40%. The data presented indicate that atracurium has a rapid onset of blockade, intermediate duration and a quick recovery profile at the rat neuromuscular junction.

Tetanic fade following atracurium-induced neuromuscular blockade in the rat diaphragm preparation.

1. The effect of atracurium on neuromuscular transmission was studied in the rat diaphragm preparation, by analysing the characteristics of tetanic fade and its recovery profile after using a blocking concentration of atracurium (10 mumol.litre-1). 2. Tetanic fade (TF), peak tetanic tension (Tp), and its depression, and end tetanic tension (Te), sustained tension, were analysed and compared to their respective control values before administration of atracurium. 3. The results showed that atracurium reduced the tetanic tension, i.e., the peak and end tetanic tensions, elicited at 50 Hz for 0.5 s duration, and produced a marked tetanic fade, which was developed fully in about 38 s. On the other hand, the peak tetanic tension (Tp) was only reduced by 40% (at 38 s) of its control value (5.7 g tension). The time taken to completely block Tp was about 5 min. 4. After washing out atracurium, recovery of the peak tetanic tension occurred within 3-4 min., while tetanic fade was reversed within 30 s. 5. It was concluded that atracurium produces a profound tetanic fade, at a time when the peak tetanic tension is only depressed by about 40% of the control value. The results indicated that atracurium had a powerful neuromuscular blocking action at the rat diaphragm preparation.

Clinical assessment of neuromuscular blockade produced by vecuronium using twitch, train of four, tetanus and post-tetanic twitch responses of the adductor pollicis muscle.

In the present investigation, the phenomenon of post-tetanic twitch potentiation (PTP) has been used to provide a sensitive index for neuromuscular blockade during an intense paralysis of the adductor pollicis muscle in man. We have also used and compared PTP assessment with that of twitch, train of four and tetanus in the same muscle and in the absence and presence of vecuronium (50 micrograms.kg-1). Vecuronium had a rapid onset of blockade (5-10s) and an intermediate duration of action (22-26 min). During the onset of blockade, the PTP response was still remaining (residual) whereas all the other mechanical responses disappeared within 2.5 min (Fig. 1b, c, d). Thus, the PTP values increased (upto 300% of control value of 18%, Fig. 1a) with increasing the intensity of neuromuscular blockade. The PTP value provided a better index for assessing the degree of neuromuscular blockade than did the twitch, train of four or the tetanus. However, during the onset of blockade, the PTP technique can also delay the onset of blockade, i.e. it has a decurarizing effect (Fig. 1b, c, d). During recovery of neuromuscular blockade, the PTP is actively involved in the enhancement of spontaneous recovery process, i.e. enhancement of de-curarization with repetitive stimulation of the ulnar nerve. In this respect, the PTP response recovers first, followed by the tetanus, train of four and the twitch responses. Thus the latter may be considered as a more sensitive index for the recovery process.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of atropine and glycopyrrolate on neuromuscular transmission in the rat phrenic nerve-diaphragm preparation.

1. The effects of atropine and glycopyrrolate on neuromuscular transmission and on muscle contraction, were studied, in the rat diaphragm preparation, by analyzing their effects on the indirectly (and directly)-elicited twitch (0.2 Hz), tetanic (50 Hz for 20 sec duration), post-tetanic twitch responses (at 5 sec after the tetanus), and on the phenomenon of post-tetanic twitch potentiation (PTP), which is thought to be of a presynaptic origin, i.e. due to increased transmitter release. 2. Atropine (0.001-10 microM) increased the indirectly-elicited twitch tension by 22 +/- 2.1% (control 0.9 +/- 0.1 g, P less than 0.02), the tetanus by 15 +/- 1.1% (control 3.9 +/- 0.7 g, P less than 0.05), the post-tetanic twitch response by 33 +/- 3.1% (control 1.2 +/- 0.1 g, P less than 0.01) and the PTP value by 36 +/- 1.9% (control 33 +/- 2.3%, P less than 0.01, means +/- SEM = 6). 3. Atropine (0.001-10 microM) had little effect on the directly-elicited twitch tension, but in high concentrations (e.g. 20 microM), it blocked the twitch tension. 4. In contrast, glycopyrrolate (0.1-100 microM) had little effect on the twitch tension (direct or indirect), but it significantly reduced the tetanus (by 38 +/- 3.5%, P less than 0.01), the post-tetanic twitch response (by 17 +/- 1.2%, P less than 0.05) and the PTP values (by 24 +/- 3.1% P less than 0.02). 5. In the presence of hemicholinium (1.3 microM) the responses to atropine and glycopyrrolate were altered (decreased), indicating a possible action on presynaptic mechanism of transmission. 6. It is concluded that atropine and glycopyrrolate produce different (opposite) effects at the rat neuromuscular junction, atropine enhances whereas glycopyrrolate depresses neuromuscular transmission. The effects of these two antimuscarinic drugs may be exerted at the presynaptic nerve terminals, i.e. on presynaptic muscarinic receptors, which are involved in the feedback mechanism of transmitter release.

Effect of verapamil on Ca2+ influx to rat phrenic nerve-diaphragm preparation.

The effect of verapamil on contractility and on influx of calcium (Ca2+) to the rat phrenic nerve-hemidiaphragm preparation was studied in vitro, at rest and during electrical stimulation at 0.2-100 Hz. Calcium content of the bathing solution was measured using the Technicon method (SMAC, Sequential Multiple Analyser/Computer). The results showed that verapamil (a) reduced the twitch and tetanic contractions in a non-competitive manner, and (b) reduced the influx of Ca2+ to the rat hemidiaphragm preparation. Greater reductions occurred as the rate of stimulation increased.

Tetanic fade during neuromuscular blockade produced by atracurium in the rat diaphragm preparation.

In the present investigation, we studied and measured the phenomenon of tetanic fade and peak tetanic tension depression in the rat diaphragm preparation in the presence of a blocking concentration of atracurium (e.g., 10 mumol.l-1). Atracurium (10 mumol.l-1) produced a pronounced tetanic fade (i.e., 47-69% reduction of total sustained tetanic tension) at a time (15 s) when it reduced the peak tetanic tension by only 25%. The time course for total tetanic fade was 30-35 s, whereas the time taken for complete peak tetanic tension depression was 3-3.5 min, suggesting that the two effects were produced via different mechanisms, involving presynaptic and postsynaptic mechanism. It was concluded that atracurium produces a profound tetanic fade, with respect to its effect on twitch or tetanic tension, suggesting that the drug is a potent neuromuscular blocker, with rapid onset of blockade.

Atropine sulphate enhances neuromuscular transmission in the rat.

The effect of atropine (0.001-10 mumol.l-1) on neuromuscular transmission in the rat hemidiaphragm preparation was investigated by analysing its effects on directly and indirectly-elicited twitch, tetanic, post-tetanic twitch responses and on the phenomenon of post-tetanic twitch potentiation. The effect of atropine on contractions produced by endogenous acetylcholine (ACh) or exogenous ACh (added directly into organ bath containing muscle) was studied in rat ileum. The results showed that atropine in low concentrations (1 mumol.l-1 or less), enhanced the indirectly-elicited twitch, tetanic and post-tetanic twitch responses in the rat diaphragm preparation. The mean EC50 value of atropine-induced increase in twitch tension was 0.08 +/- 0.01 mumol.l-1 (mean +/- s.e. mean, n = 6). Atropine had little effect on directly-elicited twitch tension, but in high concentrations (10 mumol.l-1 or more), it reduced the directly, and indirectly-elicited twitch contractions and produced a neuromuscular block in the rat diaphragm preparation. Atropine increased the contraction produced, in rat ileum, by endogenous ACh, i.e. ACh released from the phrenic nerve stimulated at 50 Hz for 20 s duration (control contraction: 1.3 +/- 0.1 g, contraction in atropine: 1.7 +/- 0.2 g). In contrast, atropine significantly reduced the contraction produced by exogenous ACh in the same preparation (control contraction: 3.0 +/- 0.5 g, atropine: 2.0 +/- 0.1 g), suggesting that a different mechanism may be involved in the latter effect of atropine. It was concluded that atropine, in low concentration, enhanced neuromuscular transmission, possibly via a presynaptic mechanism. In high concentration, atropine may reduce and then block transmission, possibly via pre- and postsynaptic mechanisms.

A pharmacologic study on the histamine releasing effect of atracurium and other muscle relaxants in rat isolated ileum.

In this study, the effects of histamine, antihistamines (terfenadine and mepyramine), 5-hydroxytryptamine, and muscle relaxants, atracurium, vecuronium and gallamine, on the tone and contractility of rat ileum were studied and compared in vitro. The aim of the present investigation was to measure, pharmacologically, the histamine releasing effect of muscle relaxants, e.g atracurium, vecuronium and gallamine, by comparing their contractile response in the absence and presence of antihistamines and comparing their mechanical responses with those produced by histamine and 5-hydroxytryptamine (5-HT). The results showed that the antihistamines, triludan(terfenadine) and mepyramine produced opposite effects in rat ileum. Terfenadine (0.1-20 microM) produced concentration-dependent contractions in the rat ileum, whereas mepyramine (0.1-10 microM) relaxed the muscle, e.g. by 1.2 g tension. Atracurium (0.5-500 microM), vecuronium (0.2-200 microM), and gallamine (0.1-7.0 microM) produced marked contractions (1.5-4.0 g tension) in rat ileum, and these contractions were markedly reduced by mepyramine (1.3 microM) or terfenadine (5 microM), implicating histamine release in the generation of these contractions. However, there was some residual contraction which was not blocked by mepyramine, but by 5-HT antagonist, methysergide (1 microM), indicating that a mechanism other than histamine release may be responsible for the residual contraction, i.e. release of other mediators such as 5-HT, prostaglandins, or calcium. 5-HT (0.5-500 microM) and histamine (0.5-500 microM) produced contractions in the rat ileum, but 5-HT was more effective than histamine in producing these contractions. Similarly, gall amine was more effective than atracurium and vecuronium in contracting the rat ileum.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of atropine and oxotremorine on neuromuscular transmission at the rat hemidiaphragm preparation.

The effects of atropine (0.001-10 microM) and oxotremorine (0.51-51.3 microM) on neuromuscular transmission and muscle contraction were studied by analysing their effects on the twitch, tetanic and post-tetanic twitch responses and on the phenomenon of post-tetanic twitch potentiation (PTP) in a rat phrenic nerve-diaphragm preparation. In addition, the effects of atropine (0.1 microM) and oxotremorine (0.6 microM) were studied on the contractions produced in rat ileum by superfusate from repetitively stimulated phrenic nerve diaphragm preparation. The results showed that atropine had a dual action at the neuromuscular junction; at low concentrations (0.001-1.0 microM) enhanced, whereas at high concentration (greater than 1.0 microM) decreased the twitch, tetanic and post-tetanic twitch responses in the rat diaphragm preparation. Oxotremorine, on the other hand, always reduced these responses and also reduced the contractions produced by diaphragm perfusate and by exogenous acetylcholine (ACh) in the rat ileum. Since atropine enhanced the contractions, in rat diaphragm, to electrical stimulation, and those in rat ileum, to superfusate of stimulated diaphragm preparation, the results may suggest that atropine has a presynaptic action at the rat neuromuscular junction. The presence of more than one type of presynaptic muscarinic autoreceptors is discussed in relation to the results obtained.

The effect of ethanol on spontaneous contractions and on the contraction produced by periarterial nerve stimulation and by acetylcholine in the rat isolated ileum.

1. The effect of ethanol (0.01-1000 mg.ml-1) on tone, contractility, and the contractions produced by periarterial nerve stimulation and by acetylcholine was studied in the rat isolated ileum. 2. In low concentrations, ethanol reduced the spontaneous contractions by 60 +/- 1.5% and in high concentrations, it produced a marked contraction in the muscle (3.2 +/- 0.3 g, mean +/- SE, n = 6). 3. In the presence of adrenergic, histaminergic, serotonin and prostaglandin antagonists, ethanol (1.8 mg.ml-1) reduced the contractions produced by periarterial nerve stimulation, at 1-100 Hz with 20 V and 0.2 msec pulse duration, by 80 +/- 3.4%. Ethanol also reduced the contractions produced by acetylcholine (0.001-1 microgram.ml-1), the mean EC50 values were 0.1 +/- 0.01 microgram.ml-1, control, and 0.96 +/- 0.1 microgram.ml-1, in ethanol, respectively. 4. Although the mechanism of action of ethanol at the gut smooth muscle is not clear, it is known that it may block conduction, depolarize the cell membrane and cause release of intracellular calcium, which is, in part, responsible for the contraction produced by ethanol in the rat ileum.

Local anaesthetics inhibit influx of calcium, sodium and potassium into rat ileum, diaphragm and human isolated saphenous vein.

The effects of 5 different local anaesthetics, lignocaine, prilocaine, etidocaine, mepivacaine, bupivacaine, on uptake of Ca2+, Na+ and K+ were studied, using a Kone Microlyte Analyzer, into 3 different types of muscle fibres, the rat ileum, rat diaphragm and human isolated saphenous vein. The aim of the present experiments was to see if local anaesthetics had a calcium antagonistic activity, like that produced by calcium antagonists, e.g. verapamil. The results showed that local anaesthetics in moderate and high concentrations (more than 100 microM) depressed uptake of Ca2+, as well as the Na+ and K+, although the depression of the uptake of Ca2+ was 7 and 2 times less than those of Na+ and K+. In low concentrations (1-10 microM), the local anaesthetics had no or little effect on Ca2+ uptake, although they still significantly reduced Na+ and K+ uptake. It was concluded that the effect of local anaesthetics on uptake of Ca2+, Na+ and K+ into rat ileum, diaphragm and human saphenous vein, is concentration-dependent, and that only at high concentrations do they have a calcium antagonistic activity in muscle. Furthermore, there was no clear evidence that the effect of local anaesthetics was species-dependent, since the uptake of Ca2+ was depressed by only about 17% more in smooth muscle than in skeletal muscle.

Atropine enhances neuromuscular transmission in humans.

The effect of atropine (1-10 micrograms . kg-1) on neuromuscular transmission in humans was studied by analysing its effects on the amplitude of indirectly-elicited twitch (0.2 Hz) and tetanic (50 and 100 Hz for 1 s duration) contractions. Six patients, free from any neuromuscular disorders, undergoing orthopaedic surgery, were included in the present study. The patients received either no premedication or the oral benzodiazepine, temazepam, 30 mg 1-2 h pre-operatively. Anaesthesia was induced with propofol (1-2 mg . kg-1, i.v., over 20 s). The patients breathed no less than 30% oxygen in nitrous oxide, halothane (1%) or enflurane (1-2%). Incremental doses of fentanyl (50-100 micrograms) were given to provide additional analgesia. The ulnar nerve was stimulated, supramaximally, at the wrist, and control mechanical responses of the adductor pollicis muscle, to nerve stimulation at 50 and 100 Hz for 1 s duration, were recorded. Theses responses were repeated at 2, 5 and 10 min intervals, after injection of atropine (1-10 micrograms . kg-1). At the same time, heart rate and blood pressures (systolic and diastolic) were recorded. The results showed that atropine enhanced the tetanic contractions, elicited at 50 and 100 Hz for 1 s duration, by 27 +/- 1.2% (50 Hz and atropine, control 220 +/- 13 g tension), and by 43 +/- 7% (100 Hz and atropine, control 333 +/- 26 g tension) at the 5 min intervals (mean +/- S.E., n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of atracurium on twitch, tetanic and post-tetanic twitch responses at the rat neuromuscular junction.

The effect of atracurium on the phenomenon of post-tetanic potentiation, which is believed to be of a presynaptic origin, i.e. due to endogenous transmitter release, was investigated to see if atracurium had a presynaptic inhibitory mechanism at the rat neuromuscular junction. The results showed that atracurium (0.8-80 microM) reduced the indirectly elicited twitch, tetanic and post-tetanic twitch tensions, in a dose-dependent manner. Atracurium (1 microM) produced a tetanic fade in the preparations stimulated at 20 Hz and above. The acetylcholine (ACh) released at high frequencies of nerve stimulation was collected, in the presence of physostigmine (0.77 microM), added to a rat ileum preparation, in which it produced a small contraction which was blocked by atracurium (1 microM), which in turn blocked the contracture produced by ACh (1 microM) added directly to the organ bath. It was concluded that, in addition to its well-known competitive blockade of postsynaptic ACh receptors, atracurium may also have a presynaptic inhibitory effect at the neuromuscular junction.

Verapamil, diltiazem and nifedipine inhibit vascular responses to noradrenaline, acetylcholine and 5-hydroxytryptamine in human saphenous vein.

Verapamil (0.02-2 microM), diltiazem (0.22-8.14 microM) and nifedipine (0.29-8.96 microM) produced concentration-dependent relaxation of human isolated saphenous vein. Based on the EC50 values of the calcium entry blockers, verapamil (relative potency = 1) was 7 and 5 times as potent as nifedipine and diltiazem, respectively, in producing relaxation of the human saphenous vein. In addition, verapamil, diltiazem and nifedipine inhibited the vascular responses (i.e. contractions) produced by noradrenaline (0.03-36 microM), acetylcholine (0.05-55 microM) and 5-hydroxytryptamine (0.02-25 microM) and to KCl (10-100 mM). It was concluded that verapamil, diltiazem and nifedipine relaxed the human isolated saphenous vein, verapamil being more potent than diltiazem or nifedipine, and modified the vascular response to vasoconstrictor agents, e.g. noradrenaline, acetylcholine, 5-hydroxytryptamine and KCl. Thus verapamil, diltiazem and nifedipine may inhibit calcium influx through both potential and receptor-operated calcium ion channels.