A randomised controlled trial to evaluate the effect of self-administered analgesia on women's experience of outpatient treatment at colposcopy.

OBJECTIVE: To evaluate the effect of self-administered isoflurane and desflurane on women's experience of outpatient treatment at colposcopy. DESIGN: A prospective double-blinded randomised controlled trial. SETTING: A colposcopy clinic serving a regional population. POPULATION: Three hundred and ninety-six women scheduled for treatment of cervical intraepithelial neoplasia (CIN) by large loop excision of the transformation zone (LLETZ). METHODS: Self-administration of trial gas during a LLETZ procedure. One hundred and ninety-eight women were randomised to use isoflurane and desflurane and 198 to use placebo. MAIN OUTCOME MEASURES: Patient satisfaction, pain and anxiety. RESULTS: The mean pain score for cervical surgery was significantly lower for women using isoflurane and desflurane (22.4) than the placebo arm (29.6) (P= 0.003). There was no significant difference between arms in anxiety levels before or after treatment. More women using isoflurane and desflurane (78%) reported 'total helpfulness' of the trial gas than those using placebo (67%) (P= 0.012). A subgroup analysis of trial participants classified as anxious by Hospital Anxiety and Depression Scale (HADS) score at recruitment showed that using isoflurane and desflurane significantly increased total treatment acceptability, helpfulness of the gas and willingness to undergo a similar procedure at six-month follow up. CONCLUSION: Satisfaction with outpatient treatment at colposcopy is generally high. The main effect of isoflurane and desflurane evaluated in this trial was to reduce pain. It appeared to be effective for women with clinically significant anxiety and could be offered as an alternative to general anaesthesia.

Phase behaviour of premixed 0.25% isoflurane in 50% nitrous oxide and 50% oxygen.

BACKGROUND: Isoflurane (0.25%) in premixed nitrous oxide and oxygen 50/50, v/v, (IN(2)O), has been suggested for pain relief in labour. METHODS: Possible phase separation of this mixture was studied by analysis of samples from pre-filled cylinders as they were cooled. RESULTS: Condensation of isoflurane was found at 3.1 degrees C in a cylinder, which held 8.7 MPa at 15 degrees C. In a cylinder holding 13.8 MPa, which is the standard filling pressure stipulated by the National Health Service, the condensation temperature was -2.3 degrees C. At the highest cylinder filling pressure investigated (14.15 MPa) the separation temperature was even less, -3.0 degrees C. After exposure of cylinders to -40 degrees C and complete phase separation of the mixture, complete mixing was achieved by 24 h storage in the horizontal position at room temperature and, either three complete inversions of the cylinder or mechanical rolling at 30 r.p.m. CONCLUSIONS: These findings should assist the use and storage of IN(2)O.

Simulated use of premixed 0.25% isoflurane in 50% nitrous oxide and 50% oxygen.

BACKGROUND: Isoflurane (0.25%) in premixed nitrous oxide and oxygen, 50/50, v/v (IN(2)O), has been suggested for pain relief in labour. Possible phase separation of the mixture was studied during simulated administration. METHODS: A sinusoidal pump set at stroke volume of 2 litres and a rate of 20-22 bpm and cycling for 1 min in three was used to simulate breathing during the painful contractions of labour. RESULTS: The temperature inside a 10-litre capacity cylinder did not drecrease sufficiently to cause separation of the gas mixture. Temperature in the demand valve decreased to -15.5 degrees C and this caused a small amount of liquid formation within the valve. Accordingly, the inspired concentration during the first breath of mixture in a cycle could be transiently as high as 0.55%. The concentration observed at the patient connection after the first breath varied between 0.17 and 0.28%. CONCLUSIONS: The system delivered a clinically acceptable performance although further development to avoid liquid condensation is needed.

Blocking chloride channels in the rat lens: localized changes in tissue hydration support the existence of a circulating chloride flux.

PURPOSE: To investigate the effects of inhibitors of chloride channels on lens volume and tissue architecture under isotonic conditions. METHODS: Rat lenses were maintained in organ culture under isotonic conditions in the presence of various putative chloride channel inhibitors. The effect of an inhibitor on lens wet mass and tissue morphology was determined by weighing and histologic examination, respectively. RESULTS: Exposure to 100 microM of either 5-nitro-2- (3-phenylpropylamino) benzoic acid (NPPB) or 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) caused an increase in wet mass and severe tissue disruption in the lens equatorial region. Two distinctly different zones of tissue damage were evident: a peripheral zone of fiber cell swelling and an inner zone of extensive tissue breakdown. Extracellular space dilations caused the extensive tissue damage in the inner zone and preceded the peripheral fiber cell swellings. That the observed effects were a consequence of the inhibition of chloride channels was supported by (1) the effectiveness of NPPB at the lower dose of 10 microM, (2) the absence of any NPPB effect in chloride-free medium, and (3) an identical effect after exposure to tamoxifen, an inhibitor of the chloride channel regulator p-glycoprotein. CONCLUSIONS: Study results indicate that chloride channels are active in the lens under isotonic conditions. The spatial and temporal pattern of morphologic changes that was observed is consistent with a steady state efflux of chloride ions and water from peripheral fiber cells and a corresponding influx into fiber cells deeper in the lens. These observations may therefore represent the first visualization of the chloride flux postulated by others to be a component of the lens internal circulation system.

A randomised controlled trial of intravenous versus inhalational analgesia during outpatient oocyte recovery.

To compare the efficacy and acceptability of conventional intravenous sedation with patient-controlled inhalational isodesox, 57 women undergoing outpatient oocyte recovery were randomly allocated to receive isodesox by face mask, while 55 women were given intravenous fentanyl and midazolam. Women's satisfaction with pain relief, peroperative pain, clouding of memory and the surgeons' assessment of operating conditions were evaluated. Thirty-eight women in the inhalation group (67%) and 41 (75%) women in the intravenous group were 'very satisfied' with their analgesia (p = 0. 41). The mean (SD) pain score in women given isodesox was 46.8 (34. 7), while in the intravenous group it was 34.1 (21.3) (p = 0.02). Oxygen saturation levels < 94% were recorded in one woman using isodesox and in 16 (29%) women given intravenous analgesia. Despite higher pain scores, in comparison with the conventional analgesia, patient-controlled isodesox offers a safer method of pain relief with comparable satisfaction rates.

The use of 0.25% isoflurane premixed in 50% nitrous oxide and oxygen for pain relief in labour.

The addition of 0.25% isoflurane to 50% nitrous oxide in oxygen provides more effective pain relief in labour than 50% nitrous oxide alone. This study was carried out to determine whether self-administration by demand valve of 0.25% isoflurane in 50% nitrous oxide in oxygen premixed in cylinders at 13.7 MPa (IN2O) was practical and safe during labour. Two hundred and twenty-one mothers used IN2O in labour after 50% nitrous oxide had become inadequate for pain relief. Data on IN2O use was recorded during labour and details of the course of labour and opioid usage were taken from the clinical notes. The duration of IN2O use was 0.1-12.35 h (median 2.3). Thirty-two mothers (14.5%) required an epidural and intolerance to IN2O was seen in a maximum of 17 cases (7.7%). One hundred and twenty-six cases were primiparous and 93 parous with 151 deliveries being spontaneous and 70 interventional, of which 12 were by Caesarean section. Maternal blood loss was 20-1500 ml (median 200 ml). Apgar scores at 1 and 5 min were unaffected by IN2O use although a positive correlation was found between the use of opioids and the number of neonates with a 1-min score below 8 and the number requiring resuscitation. Six neonates had an Apgar score below 8 at 5 min, but their condition was adequately explained by factors other than the sedative technique used. Self-administered IN2O was found to be a safe and practical technique for sedation in labour when 50% nitrous oxide alone had become inadequate.

Localised fibre cell swelling characteristic of diabetic cataract can be induced in normal rat lens using the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid.

Chloride channels are known to be involved in the regulated volume decrease that occurs when the rat lens is exposed to hypotonic challenge. We now report that chloride channel blockage makes the rat lens gain water under isotonic conditions, suggesting that chloride and water fluxes may also play an important role under resting conditions. Histological comparison of hypotonically and isotonically swollen rat lenses revealed a significant difference: in the former, fibre cells were swollen from the periphery inwards, while in the latter, swollen fibre cells were confined to a discrete cortical zone which was located 150-200 micron from the lens surface with cells on either side of this zone appearing unaffected. This localised fibre cell swelling is remarkable because of its similarity to the situation in the diabetic rat lens.

Connexins in the lens: are they to blame in diabetic cataractogenesis?

The pathohistology of the diabetic lens is an enigma. Under normal conditions the lens behaves as a functional syncitium, whereas the diabetic lens exhibits a localized zone of fibre cell swelling and rupture that is confined to the lens outer cortex. Because the lens fibre cells are extensively coupled by gap junction channels, it is believed that the abnormal closure of these channels is responsible for this phenomenon. New evidence concerning regional differences in gap junction gating supports this contention, and it is used to propose a new hypothesis that may explain the cellular changes observed in the diabetic lens.

Expression profiles of P2-receptor isoforms P2Y1 and P2Y2 in the rat lens.

PURPOSE: To verify at the molecular level that P2 receptors are expressed in the lens and to determine their expression profiles. METHODS: The reverse transcription-polymerase chain reaction (RT-PCR) was used to screen rat lens epithelial and fiber cells for the expression of the ionotropic P2X2 receptor and the G-protein-linked receptor isoforms P2Y1 and P2Y2. Northern blot analysis was used to confirm the level of expression of P2Y1 and P2Y2. The profile of P2-receptor isoform expression in the lens was identified using an indirect RT-PCR in situ hybridization procedure on paraffin sections of whole rat eyes. RESULTS: P2X2-receptor transcripts could not be detected in lens epithelial or fiber cells. P2Y1- and P2Y2-receptor transcripts were detected in lens fiber cells but not in the epithelial cells. Their expression profiles were maximal in the lens cortex and mostly overlapped each other, except that transcripts for the P2Y2-receptor isoform appeared earlier in the not yet fully elongated fiber cells in the lens bow region. CONCLUSIONS: The molecular data support physiological evidence previously reported by others that P2Y receptors are expressed in the lens and identifies cortical fiber cells as the principal site of expression.

Isoflurane for removal of chest drains after cardiac surgery.

Thirty-five patients who had undergone uncomplicated cardiac surgery were randomly allocated to receive either Entonox or isoflurane 0.25% in Entonox as inhalational analgesia for the removal of their two chest drains. The gases were presented premixed in high-pressure cylinders and were self-administered by means of a demand valve. The removal of the second drain was more painful than the first but that pain was better controlled by isoflurane 0.25% in Entonox than by Entonox alone.

Serious complications associated with epidural/spinal blockade in obstetrics: a two-year prospective study.

A prospective study of complications associated with epidural and spinal blockade in obstetrics was carried out during the years 1990 and 1991. 79 obstetric units in the United Kingdom took part. These units had a total of 467 491 deliveries during the two years. 108 133 mothers received epidural blockade and 14856 received spinal blockade. 22% of all mothers received epidural analgesia in labour, and 50% of caesarean sections were performed under either epidural or spinal anaesthesia. 128 complications (not including post dural puncture headache) were reported. Of these, 46 were neuropathies involving a single spinal or peripheral nerve. 26 unexpectedly high blockades were encountered. Backache was reported in 21 mothers and urinary retention in 8. Cardiac arrest occurred twice. Although resuscitation restored normal cardiac function in both cases, one patient was decerebrate and died some days later. Postmortem examination revealed evidence of amniotic fluid embolus. 20 reports were classified as 'miscellaneous' and presented individual clinical diagnoses. The overall complication rate (excluding post dural puncture headache) was approximately 1 per thousand.

Action of salicylate on membrane capacitance of outer hair cells from the guinea-pig cochlea.

1. The effect of salicylate on membrane capacitance and intracellular pH has been measured in isolated outer hair cells (OHCs) during whole cell recording. Cell membrane capacitance was measured using a lock-in amplifier technique. 2. Salicylate applied in the bath reduced the fast charge movement, equivalent to a voltage-dependent membrane capacitance, present in OHCs. Simultaneous measurement of membrane capacitance and voltage-driven cell length changes showed that salicylate reduced both together. 3. A small effect of salicylate on outward currents at 0 mV was observed. Sodium salicylate (5 mM) reduced the currents by 19% and another weak acid, sodium butyrate (10 mM), reduced outward currents in OHCs by 15%. 4. The ratiometric dye 2,7-bis(2-carboxymethyl)-5,6-carboxyfluorescein (BCECF) was used to measure pHi changes in OHCs during weak acid exposure. Membrane capacitance and pHi were measured simultaneously in OHCs exposed first to 10 mM sodium butyrate and then to 5 mM sodium salicylate. Although both compounds produced a similar reduction in pHi, butyrate decreased the resting capacitance from a mean resting capacitance of 35 pF (at -30 mV) by 5.4 +/- 2.1 pF, whereas salicylate decreased it by 15.7 +/- 2.3 pF (n = 4). 5. Exposure of OHCs to 10 mM sodium benzoate, an amphiphilic anion, reduced resting membrane capacitance at -30 mV by 9.2 +/- 3.2 pF (n = 3). Outward currents, measured at 0 mV, were reduced by 0.25 +/- 0.05 nA during benzoate application, comparable with the effect of salicylate. 6. Capacitance was measured during slow bath application of salicylate. The resulting dose-capacitance curve had a Hill coefficient of 3.40 +/- 0.85 (n = 4) and a half-maximal dose of 3.95 +/- 0.34 mM. The dose-capacitance curve was not significantly voltage dependent. 7. Salicylate had no detectable effect on the resting capacitance of Deiters' cells, a non-sensory cell type of the organ of Corti. 8. It is concluded that many of the described effects of salicylate on hearing may arise from the partitioning of the salicylate molecule into the membrane of the OHC and consequent inhibition of OHC motility.

Properties of networks controlling locomotion and significance of voltage dependency of NMDA channels: stimulation study of rhythm generation sustained by positive feedback.

1. We have built a realistic 24-neuron model based on data from the spinal pattern generator for swimming in Xenopus embryos with the use of the SWIM programs. The neurons have dendrite, soma, and axon compartments with voltage-gated Na+ and K+ channels. Dendritic synapses were modeled as modulated ionic conductances with currents that have different reversal levels. One of these conductances was voltage dependent to model N-methyl-D-aspartate ("NMDA") synapses in the presence of Mg2+. 2. In this model, rhythm generation is initiated by a brief excitation, depends on rebound from reciprocal inhibition, and is sustained by long-duration "NMDA-dependent" feedback excitation. 3. Without NMDA voltage dependency, rhythmic activity is stable over a wide range of synaptic conductances. Its frequency decreases with more inhibition and increases with more excitation. The introduction of normally distributed variation in soma size or excitatory synaptic conductance extends the lower stable frequency range. Without such variation the frequency of the 24-neuron model is the same as a 4-neuron model provided that the synaptic conductances for each neuron are the same. 4. The effect of introducing NMDA voltage dependency on rebound after negative current injections or synaptic inhibition was investigated in single depolarized model neurons. With NMDA voltage dependency, hyperpolarizations and rebound spike responses were increased. 5. Network activity with NMDA voltage dependency was similar to that without it, but inhibitory postsynaptic potentials (IPSPs) and spikes were larger, and frequencies were lower and more sensitive to changes in excitatory and inhibitory conductance. 6. We conclude that in the model, mutual reexcitation among excitatory spinal interneurons can sustain rhythm generation by positive feedback and that NMDA voltage dependency can enhance postinhibitory rebound, stabilize swimming activity and extend its lower frequency range, and steepen the dependency of frequency on synaptic drive.

Longitudinal gradients in the spinal cord of Xenopus embryos and their possible role in coordination of swimming.

We consider the hypothesis that the normal rostrocaudal spread of motor activity during swimming in Xenopus embryos depends on a longitudinal, rostrocaudal gradient in synaptic drive received by the pattern generating neurons in the spinal cord. Anatomical evidence shows that there is a rostrocaudal gradient in excitatory and inhibitory premotor interneuron numbers. Intracellular recordings were therefore made from neurons at different longitudinal positions to seek direct evidence for a gradient in synaptic drive. The main finding was that during fictive swimming the amplitude of the tonic excitatory synaptic input and the mid-cycle inhibition declined in a rostrocaudal direction and caudal to the twelfth postotic segment inhibition was absent altogether. Experimental manipulation of the gradients by the caudal application of pharmacological agents lead to changes or even reversal of the normal direction of spread of motor activity. To test whether a gradient in synaptic drive could organize a rostrocaudal spread of activity we have used a 48 neuron, 12 segment model of the spinal pattern generating network. This has shown that the gradient hypothesis can provide a sufficient explanation for much of the embryo's motor coordination. A gradient in synaptic drive provides a flexible mechanism to control sequences of motor activity.

A longitudinal gradient of synaptic drive in the spinal cord of Xenopus embryos and its role in co-ordination of swimming.

1. Intersegmental co-ordination in Xenopus embryos could be influenced by longitudinal gradients in neuronal properties or synaptic drive. To determine if such gradients exist intracellular recordings were made from putative motoneurones at different spinal levels. 2. No evidence was found of a longitudinal gradient in neuronal resting potentials. In a rostrocaudal direction the duration of current-evoked spikes increased and the amplitude of the spike after-hyperpolarization (AHP) decreased. 3. During fictive swimming the amplitude of the tonic excitatory synaptic input and the mid-cycle IPSPs declined in a rostrocaudal direction. The rise-time and fall-time of mid-cycle IPSPs increased in a rostrocaudal direction. 4. Rostral to the eighth post-otic segment mid-cycle IPSPs occurred on all cycles of fictive swimming episodes. More caudally IPSPs became irregular in occurrence and caudal to the twelfth post-otic segment no mid-cycle IPSPs could be detected, even during the injection of depolarizing current or when recording with KCl-filled electrodes. 5. The duration of spikes occurring during fictive swimming increased and the amplitude of spike AHP decreased in a rostrocaudal direction. A spike AHP was absent during fictive swimming activity in neurones caudal to the ninth post-otic segment even though it was present in current-evoked spikes in the same neurones. 6. On-cycle IPSPs (occurring shortly after the spike at phase values less than 0.4) were observed predominantly at the beginning of swimming episodes in neurones recorded rostral to the eighth segment, but were not detected at all in more caudal neurones. 7. If the rostrocaudal gradients in synaptic excitatory and inhibitory drive to putative motoneurones during fictive swimming are also present in premotor spinal interneurones they would be expected to have a strong influence on rostrocaudal delays. Such gradients could therefore be important components of the mechanism underlying intersegmental co-ordination.

Self-administered mixture of Entonox and isoflurane in labour.

Entonox (50% nitrous oxide premixed in oxygen) was compared with a mixture of Entonox and approximately 0.25% isoflurane (Entonox-isoflurane) for pain relief in the first stage of labour in 39 mothers. An Oxford Miniature Vaporizer was incorporated as the draw-over vaporizer for adding isoflurane to Entonox. The mixture was self-administered via the Entonox on-demand valve. The two mixtures were given in random sequence for five consecutive contractions of labour to each patient. Linear analogue pain relief scores were significantly higher (P=0.001) with Entonox-isoflurane. Fourteen patients continued using Entonox-isoflurane until delivery. No adverse effect from prolonged use was noted. Entonox-isoflurane is considered worthy of further investigation.