bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential organ scoring as a measure of effectiveness of critical care
Authors: Hutchinson C. , Craig S. , Ridley S.
Published: March 2003

We performed an observational nonrandomised study in a critical care unit of a large district general hospital in England to establish whether sequential organ scoring could be used as a measure of effectiveness of intensive care. The degree of organ dysfunction of 75 consecutive patients admitted to the critical care unit whose duration of stay exceeded 48 h was measured using the Logistic Organ Dysfunction System score. The trends in organ dysfunction of survivors and non‐survivors were significantly different with function improving in survivors and remaining constant or worsening in non‐survivors. In both groups, the degree of organ dysfunction decreased over the first three days of intensive care. On an individual patient basis, we achieved no change or an improvement in organ score over this period in 80% of patients. In terms of individual organ function, intensive care consistently improved scores relating to the cardiovascular, respiratory and renal systems over the first 72 h of care, but not the neurological, hepatic or haematological systems. In conclusion, daily organ scoring usefully reflects the ability of an intensive care unit to stabilise or reverse physiological dysfunction.
The use of a target‐controlled infusion of alfentanil to provide analgesia for burn dressing changes
Authors: Gallagher G. , Rae C. P. , Kenny G. N. C. , Kinsella J.
Published: March 2003

Burn dressing changes require profound analgesia for a short duration. This study aimed to determine whether an operator‐adjusted target‐controlled infusion of alfentanil could provide effective analgesia for burn dressing changes. Ten patients with a burn of between 5 and 50% of body surface area were studied. Pain scoring was performed before, during and following the dressing change. Target and effect site concentrations of alfentanil were recorded during and for 15 min after the dressing change. Median baseline visual analogue pain score (VAS) was 22 mm. Median (range) duration of dressing change was 35 (20–75) min. Median (range) VAS during the dressing change was 30 (14–66) mm. All patients were satisfied with their pain relief. There was no respiratory depression or cardiovascular instability. No patient became sedated and there were no episodes of nausea or vomiting. Median (range) total dose of alfentanil was 2.6 (1–10.7) mg. This study supports the efficacy of an operator‐adjusted target‐controlled infusion of alfentanil to provide analgesia for burn dressing changes.
Analgesic effect of low‐dose intrathecal morphine and bupivacaine in laparoscopic cholecystectomy
Authors: Motamed C. , Bouaziz H. , Franco D. , Benhamou D.
Published: March 2003

We assessed the peri‐operative analgesic efficiency of low‐dose intrathecal morphine combined with a low dose of bupivacaine after elective laparoscopic cholecystectomy since postoperative pain in such procedures, although less than after a conventional open technique, may be significant, particularly during the first 12–24 h. After informed consent, 34 ASA I or II patients were randomly allocated to one of two groups to receive either a lumbar intrathecal injection of morphine (75 or 100 μg) combined with 5 mg of isobaric bupivacaine (spinal group) or a subcutaneous injection of a saline solution (control group). Intra‐operatively, opioid requirements, blood pressure response and heart rate changes after insufflation were recorded. Postoperatively, morphine requirements, pain scores and opioid‐related side‐effects were assessed by a physician blinded to the randomisation. Intra‐operative opioid requirements did not differ significantly between groups. Mean (SD) postoperative morphine requirements were significantly lower in the spinal group [13 (10) vs. 23 (10) mg; p = 0.04] as were postoperative pain scores (p < 0.001). Side‐effects were of comparable incidence and severity between groups. Low‐dose intrathecal morphine combined with low‐dose bupivacaine provided effective postoperative analgesia for elective laparoscopic cholecystectomy.
Effects of surgical stress and nitrous oxide anaesthesia on peri‐operative plasma levels of total homocysteineA randomised, controlled study in general surgery
Authors: Foschi D. , Rizzi A. , Zighetti M. L. , Bissi M. , Corsi F. , Trabucchi E. , Mezzetti M. , Cattaneo M.
Published: March 2003

Previous studies of patients have shown that anaesthesia with nitrous oxide (N2O) increases the plasma levels of total homocysteine. In a randomised, controlled trial we measured the plasma total homocysteine levels in patients undergoing general surgery before and after anaesthesia with and without N2O. Plasma total homocysteine levels were measured before anaesthesia and 1, 3–5 and 24 h after incision in 24 patients randomly allocated to anaesthesia with N2O (n = 12) and without N2O (n = 12). Total homocysteine levels significantly decreased from 10.4 ± 2.7 to 8.2 ± 2.9 µmol.l−1 in the non‐N2O group 24 h after incision (p < 0.02), while they tended to increase slightly in the N2O group from 10.5 ± 4.5 to 10.9 ± 4.3 µmol.l−1 (p > 0.05). Our randomised controlled study indicates that total homocysteine decreases after general surgery in patients in whom anaesthesia is maintained without N2O, but not in patients in whom anaesthesia is maintained with N2O.
Buscopan® for the treatment of pain after laparoscopic sterilisation
Authors: Habib A. , Sharpe P. , Anderson S. , Francis S. , Davidson A. C. , Smith G.
Published: March 2003

We investigated the effect of Buscopan® 20 mg, given at the end of surgery, on analgesic requirements in 44 ASA I and II patients presenting as day cases for laparoscopic sterilisation using Filshie clips. Patients were randomly allocated to receive either intravenous Buscopan 20 mg or saline placebo at the end of surgery. There was no significant difference in pain scores, analgesic requirements or the incidence of nausea and vomiting between the two groups. We conclude that intravenous Buscopan 20 mg was not effective for pain relief following laparoscopic sterilisation.
Survey of 1057 patients receiving postoperative patient‐controlled epidural analgesia
Authors: Wigfull J. , Welchew E.
Published: March 2003

Data were collected from 1057 consecutive patients who received patient‐controlled epidural analgesia for postoperative pain relief, using 0.1% bupivacaine with 5 µg.ml−1 fentanyl in all cases. Prescriptions were not otherwise standardised. On the first postoperative day, 741/801 patients (92.5%) had adequate analgesia and 692/719 (96.2%) were free of nausea. During a total of 3858 treatment days, two patients (0.19%) had an episode of severe respiratory depression and one patient (0.09%) became unrousable. Hypotension occurred in 45 patients (4.3%). There were no cases of epidural haematoma or abscess. We conclude that a patient‐controlled epidural analgesia service as described is both efficacious and safe for use on surgical wards.
The use of a vertical infraclavicular brachial plexus block in a patient with myasthenia gravis: effects on lung function
Authors: Sinha A. , Ahmad K. , Harrop‐Griffiths W.
Published: March 2003

A patient who was suffering an exacerbation of myasthenia gravis dislocated her elbow. She underwent closed reduction of the dislocation under vertical infraclavicular brachial plexus blockade. The technique was successful but was associated with a 29% decrease in forced vital capacity, from 1.7 l to 1.2 l. The patient did not show any symptoms of ventilatory failure. Her recovery was uncomplicated.
Tracheal intubation and cervical spine excursion: direct laryngoscopy vs. intubating laryngeal mask
Authors: Waltl B. , Melischek M. , Schuschnig C. , Kabon B. , Erlacher W. , Nasel C. , Fuchs M. , Kapral S.
Published: March 2003

Until recently, the most appropriate technique of intubating a patient with a cervical spine injury has been the subject of debate. Tracheal intubation by means of the intubating laryngeal mask (Fastrach™), a modified conventional laryngeal mask airway, seems to require less neck manipulation. The aim of this study was to compare the excursion of the upper cervical spine during tracheal intubation using direct laryngoscopy with that during intubation via the laryngeal mask (Fastrach™), by examination of lateral cervical spine radiographs in healthy young patients. The intubating laryngeal mask (Fastrach™) caused less extension (at C1−2 and C2−3) than intubation by direct laryngoscopy. Direct laryngoscopy is still the fastest method to secure an airway provided no intubating difficulties are present. However, in trauma patients requiring rapid sequence induction and in whom cervical spine movement is limited or undesirable, the intubating laryngeal mask (Fastrach™) is a safe and fast method by which to secure the airway.
Kinin‐mediated anaphylactoid reaction implicated in acute intra‐operative pulseless electrical activity
Authors: O'Sullivan S. , McElwain J. P. , Hogan T. S.
Published: March 2003

A 65‐year‐old patient undergoing total hip replacement under general anaesthesia suffered acute pulseless electrical activity with a fatal outcome. A kinin‐mediated analphylactoid reaction following administration of a polygeline plasma expander (Haemaccel®) was implicated by in vitro testing. This case report illustrates the diagnostic difficulties posed by non‐histaminoid anaphylactoid reactions and the resistance to epinephrine of kinin‐mediated hypotension.
An evaluation of the Airway Management Device
Authors: Cook T. M. , Gupta K. , Gabbott D. A. , Nolan J. P.
Published: March 2003

We have evaluated the Airway Management Device (AMD™) in 105 anaesthetised patients. We were successful in establishing a clear airway on the first attempt on 69 occasions and unable to establish a patent airway at all in 10 patients. Airway obstruction requiring removal of the device occurred during maintenance of anaesthesia in a further two cases and during emergence in three. Loss of the airway during anaesthesia occurred in eight of 95 patients and could be reversed by manipulation of the airway in six cases. Overall, a mean of 0.56 manipulations per patient were required to establish an airway and a further 0.42 per patient were required during maintenance of anaesthesia. In the 95 patients in whom an airway was established, assisted ventilation was satisfactory in 93, with a leak pressure above 20 cmH2O in 65. Intracuff pressure was measured in 12 cases and was above 100 cmH2O in eight. Minor complications occurred in 12 patients. Blood was visible on removal of the device in six cases.
Transoesophageal acoustic quantification for evaluation of cardiac function during laparoscopic surgery
Authors: Irwin M. G. , Ng J. K. F.
Published: March 2003

Pneumoperitoneum may be poorly tolerated in patients with marginal cardiopulmonary function. Transoesophageal echocardiography is a relatively non‐invasive technique that can track changes in left ventricular cavity area using acoustic quantification and has been found to provide a reliable, real‐time estimation of left ventricular function. We evaluated mid‐papillary fractional area change during pneumoperitoneum in 17 healthy adult patients (group 1) and 17 with hypertension and/or ischaemic heart disease (group 2) undergoing laparoscopic cholecystectomy. Peritoneal insufflation led to significant (p < 0.01) decreases in fractional area change and an increase in mean blood pressure. There was no significant change in heart rate. Patients with cardiovascular disease who had a > 30% decrease in fractional area change following carbon dioxide insufflation (group 2B) were given an intravenous infusion of glyceryl trinitrate. In groups 1 and 2A, fractional area change improved slightly with head‐up tilt and continued to improve over the course of surgery. Glyceryl trinitrate led to a significant increase in fractional area change and a decrease in mean blood pressure back to baseline values. We conclude that peritoneal insufflation of carbon dioxide results in a significant increase in cardiac workload that is well tolerated in patients with no cardiovascular disease. Coexisting cardiovascular disease can result in even more pronounced impairment of cardiac function, which may not be predictable by clinical assessment or adequately determined by routine monitoring. We recommend the use of transoesophageal acoustic quantification as a monitor in these patients and the administration of glyceryl trinitrate to ameliorate myocardial stress.
Redistribution of halothane and sevoflurane under simulated conditions of acute airway obstruction
Authors: Girgis Y. , Frerk C. M. , Pigott D.
Published: March 2003

Forty patients having surgery requiring muscle paralysis and tracheal intubation were randomly allocated to receive either halothane (n = 20) or sevoflurane (n = 20). Following intravenous anaesthesia and tracheal intubation, inhalation induction of anaesthesia was simulated. After attaining an end‐tidal anaesthetic concentration of 2 MAC for the respective agent, the airway was obstructed for 3 min. The end‐tidal anaesthetic concentration was measured for the first three breaths following the period of airway obstruction. The decrease in alveolar concentration of sevoflurane following 3 min of airway obstruction was found to be significantly greater than that of halothane. We conclude that even if the airway obstructs completely during inhalational induction of general anaesthesia, awakening would be faster with sevoflurane than with halothane.
A Staphylococcus aureus paraspinal abscess associated with epidural analgesia in labour
Authors: Hill J. S. , Hughes E. W. , Robertson P. A.
Published: March 2003

A case is described in which a parturient developed a Staphylococcus aureus paraspinal abscess following epidural analgesia in labour. We compared this case with other reported cases of paraspinal abscesses in obstetric patients. The presentation, diagnosis and management of these cases were reviewed. Anaesthetists need to be aware that non‐spinal−epidural abscesses can occur in patients with an associated labour epidural.
A mixture of alfentanil and morphine for rapid postoperative loading with opioid: theoretical basis and initial clinical investigation
Authors: Ludbrook G. L. , Macintyre P. E. , Douglas H. , Ong L. , Upton R. N.
Published: March 2003

Pharmacokinetic modelling of estimated central nervous system concentrations was used to devise the optimal mixture of morphine and alfentanil for the treatment of postoperative pain. Modelling revealed that an intravenous opioid pain protocol using an alfentanil−morphine mixture in the proportions 0.75 : 10 mg would provide a profile of analgesia of rapid onset, yet slow offset. The regimen was evaluated in 58 patients in the recovery ward who were randomly allocated to receive analgesia using pain protocols with either morphine or the mixture. Groups were well matched for age, weight and initial pain scores. The mean (SD) time to patient comfort was 27.6 (20.2) min for the mixture and 41.2 (18.6) min for morphine (p = 0.01). Multiple regression analysis revealed that that initial pain score (p = 0.009) and drug group (p = 0.02), but not age, weight or gender were independent predictors of the time to comfort. Drug group was not a significant predictor of adverse effects.
THIS ARTICLE HAS BEEN RETRACTED Effects of postoperative sedation with propofol and midazolam on pancreatic function assessed by pancreatitis‐associated protein
Authors: Piper S. N. , Kumle B. , Maleck W. H. , Suttner S. W. , Fent M. T. , Boldt J.
Published: March 2003

This prospective randomised controlled study evaluated the effects of postoperative sedation with propofol and midazolam on pancreatic function. We studied 42 intensive care unit patients undergoing elective major surgery who were expected to be sedated postoperatively. Patients were randomly assigned to a propofol group (n = 21) or a midazolam group (n = 21). To assess pancreatic function, the following parameters were measured: pancreatitis‐associated protein, amylase, lipase, cholesterol and triglyceride prior to start of sedation on the intensive care unit, 4 h after the sedation was started and at the first postoperative day. Patients in the propofol group received on average (SD) 1292 (430) mg propofol and were sedated for 9.03 (4.26) h. The midazolam group received 92 (36) mg midazolam and were sedated for 8.81 (4.68) h. Plasma cholesterol concentrations did not differ significantly between groups. Triglyceride plasma levels 4 h after the start of infusion were significantly higher in the propofol group (140 (54) mg.dl−1) than the midazolam‐treated patients (81 (29) mg.dl−1), but were within normal limits. There were no significant differences between the two groups regarding amylase, lipase and pancreatitis‐associated protein plasma concentrations at any time. No markers of pancreatic dysfunction were outside the normal range. We conclude that postoperative sedation with propofol induced a significant increase of serum triglyceride levels but that pancreatic function is unchanged with standard doses of propofol.
PUMP ACTIVATED BY A FOOT SWITCH PEDAL FOR CONTROLLED ADMINISTRATION OF LOCAL ANAESTHETIC DRUGS
Authors: Ayoub C. , Lteif A. , Rizk M. , Khalily Z. , Aoude S.
Published: March 2003

Summary We describe a newly designed syringe pump which is electrically controlled by a dual foot switch pedal. The device enables the scrubbed anaesthetist performing the regional block to aspirate, ␣␣␣␣␣␣␣as well as to inject, the local anaesthetic without the need for any additional personnel.
Aseptic precautions for inserting an epidural catheter: a survey of obstetric anaesthetists
Authors: Sellors J. E. , Cyna A. M. , Simmons S. W.
Published: March 2003

Summary We performed a postal survey of Fellows of the Australian and New Zealand College of Anaesthetists with a special interest in obstetric practice, about their beliefs regarding aseptic precautions for insertion of an epidural catheter in the labour ward. Of the 435 consultant anaesthetists surveyed, 367 responded (84%), revealing a wide variation in practice. It was not thought to be essential practice to remove a watch before washing hands by 51 respondents (14%), to wear a facemask by 105 (29%) or to wear a sterile gown by 45 (12%). Three anaesthetists (1%) did not believe sterile gloves were essential. However, all respondents indicated that an antiseptic skin preparation was essential. Our results raise questions regarding an acceptable standard of aseptic practice for the insertion of an epidural catheter in labour and we propose a minimal standard of essential precautions.
The effect of a pre‐operative infusion of Ringer's solution on splanchnic perfusion in patients undergoing coronary artery bypass grafting
Authors: Klein T. F. , Osmer C. , Müller M. , Junger A. , Akintürk H. , Hempelmann G.
Published: March 2003

Summary Surgical patients develop a fluid deficit during pre‐operative starvation. This study examines the effects of pre‐operative fluid administration on haemodynamic variables, oxygenation and splanchnic perfusion in patients undergoing elective coronary artery bypass grafting. Forty‐eight patients were randomised to receive either a pre‐operative crystalloid infusion (crystalloid group, n = 24) or no infusion (control group, n = 24). Patients in the crystalloid group received a continuous infusion of Ringer's solution at 1.5 ml.kg−1.h−1 from 22:00 h until induction of anaesthesia the next morning. Immediately before induction of anaesthesia, all patients were given a colloid infusion to increase pulmonary capillary wedge pressure and central venous pressure to similar levels inboth groups. Haemodynamic and oxygenation parameters were measured using invasive cardiovascular monitoring, and splanchnic perfusion was assessed by indocyanine green clearance. Patients in the crystalloid group received a mean (SD) of 1008 (140) ml of Ringer's solution overnight. Patients in the crystalloid group had a higher splanchnic blood flow than the control group before induction of anaesthesia [mean (SD) = 1782 (573) ml.min−1 vs. 1391 (333) ml.min−1, p < 0.05]. There were no significant differences in systemic haemodynamic data and global oxygenation parameters between the two groups. Pre‐operative infusion of crystalloid appears to result in an improvement in pre‐operative splanchnic perfusion.
Efficacy of the ProSeal® laryngeal mask airway during manual in‐line stabilisation of the neck
Authors: Asai T. , Murao K. , Shingu K.
Published: March 2003

Summary The laryngeal mask airway has a potential role during cardiopulmonary resuscitation, but its placement becomes more difficult during manual in‐line stabilisation of the neck, and the device cannot reliably prevent pulmonary aspiration. The ProSeal® laryngeal mask airway has a theoretical advantage of reducing aspiration because of its drainage tube, but its ease of placement during stabilisation of the neck is unknown. We studied 20 patients to compare ease of placement and the sealing effect between the standard and ProSeal® laryngeal mask airways. In a randomised cross‐over fashion, after induction of anaesthesia and neuromuscular blockade, the standard and ProSeal® laryngeal mask airways were placed in turn. Placement was significantly easier for the ProSeal® laryngeal mask airway (successful at the first attempt in 16 patients and at the second attempt in the remaining four patients) than for the laryngeal mask airway (successful at the first attempt in 12 of 20 patients and at the second attempt in three patients, and failed (> two attempts) in the remaining five patients; p = 0.04). The airway pressure at which gas leaked around the device was greater forthe ProSeal® than the laryngeal mask airway (mean difference 5.8 cmH2O; 95% CI 2.9–8.7 cmH2O; p = 0.0008).
A comparison of cerebral oxygenation as measured by the NIRO 300 and the INVOS 5100 Near‐Infrared Spectrophotometers
Authors: Thavasothy M. , Broadhead M. , Elwell C. , Peters M. , Smith M.
Published: March 2003

In this study cerebral oxygenation was measured using the NIRO 300 and the INVOS 5100 spectrophotometers in 10 healthy adult volunteers, exposed to varying degrees of hyperoxia and hypoxia. The results showed similar baseline values for tissue oxygenation index and regional cerebral oxygen saturation with mean (SD) values being 64.9% (5.1) and 62.3% (6.0), respectively. The overall bias was –2.1%, with the INVOS 5100 under‐reading cerebral oxygenation compared to the NIRO 300, with limits of agreement of ±14.7%. Both monitors demonstrated similar changes in response to hyperoxia and hypocapnia (coefficient of variance for FIo2 0.45 = 10.0%, FIo2 1.0 = 10.1%, hypocapnia = 14.5%). The reasons for the bias and variability may relate to differences in the methodological approaches of the two monitors. The correlation between the monitors in response to changes in cerebral oxygenation implies that they may be useful as trend monitors in clinical practice.
The long Bain breathing system: an investigation into the implications of remote ventilation
Authors: Sweeting C. J. , Thomas P. W. , Sanders D. J.
Published: March 2003

A long version of the Bain breathing system is commonly used when remote anaesthesia is required, such as during magnetic resonance imaging or radiotherapy. We compared the static compliance and distal pressures over a range of flows in a 1.6 and 9.6 m Bain system. We examined the effect on ventilation of increasing the length of the Bain system in lung models for 10, 20 and 70 kg patients. We found that static compliance was increased in the long Bain system. We found that with matched peak inspiratory ventilator pressures there was a reduction in peak inspiratory pressures at the patient end with the longer system (p < 0.001). A reduction in tidal volume was found with the 9.6 m Bain (p < 0.001), and positive end‐expiratory pressure was increased (p = 0.01). Although the effect on tidal volume was proportionally small in the 70 kg simulation (660 and 617 ml in 1.6 and 9.6 m systems, respectively) it increases in significance in children, with a 23% reduction in tidal volume in the 10 kg mock lung (95 and 73 ml in 1.6 and 9.6 m systems, respectively). Anaesthetists should be aware of the reduction in tidal volume and increased positive end‐expiratory pressure. During remote anaesthesia with a long Bain system, the ventilator should be adjusted to compensate.
The champagne angle
Authors: Pemberton P. L. , Calder I. , O'Sullivan C. , Crockard H A.
Published: March 2003

A patient's observation led us to investigate whether drinking from a champagne flute required more cranio‐cervical extension than drinking from other types of wine glasses. We measured the cranio‐cervical extension required by normal volunteers to drink from four different types of glass. The mean [95% confidence intervals] extension from the neutral position required to drain each glass was: narrow flute 40°[35–44]; wide flute 22°[19‐25]; wine glass 26°[24‐29]; champagne saucer 0°[‐1‐2]. Drinking from the narrow rimmed champagne flute required significantly more extension than the other types of glass (p < 0.001), and 73% of the total available cranio‐cervical extension.
A study of the impact of long‐term tobacco smoking on postoperative intensive care admission
Authors: Møller A. M. , Pedersen T. , Villebro N. , Schnaberich A. , Haas M. , Tønnesen R.
Published: March 2003

Summary Smoking is a risk factor for intra‐operative pulmonary complications and a wide range of postoperative pulmonary, cardiovascular, infection and wound‐related complications. These may all lead to unplanned postoperative intensive care admission. We tested the hypothesis that smokers have an increased incidence of postoperative intensive care admission and more postoperative complications than nonsmokers in a general and orthopaedic surgical population. The following information was assessed in 6026 surgical patients: age, sex and smoking status (pack‐years), history of heart and lung disease, American Society of Anesthesiologists (ASA) physical classification, intensive care admission and postoperative complications. Two thousand five hundred and twenty‐six (46%) were smokers but for 620 patients (10.3%) smoking status was not confirmed. Postoperative intensive care admission was required by 319 patients (5.3%). Patients with > 50 pack‐years were admitted to the intensive care more frequently than were smokers with ≤50 pack‐years history and nonsmokers (p < 0.001). Ex‐smokers with > 50 pack‐years history had the same risk of postoperative admission to intensive care as smokers with > 50 pack‐years history. Smokers admitted to intensive care with > 50 pack‐years history had a higher incidence of chronic lung disease (p < 0.005) and heavy alcohol consumption (p < 0.001). These smokers also had a higher incidence of postoperative pulmonary complications (odds ratio = 3.91, p < 0.01). The mortality rate was 37% in smokers with > 50 pack‐years history and 24% in nonsmokers (odds ratio = 2.02, p = 0.08). We conclude long‐term tobacco smoking (> 50 pack‐years) carries a higher risk of postoperative admission to intensive care, and there seems to be a dose relationship between the amount of tobacco consumed and the risk of postoperative intensive care admission.
Effect of the Confidential Enquiries into Maternal Deaths on the use of Syntocinon® at Caesarean section in the UK*
Authors: Bolton T. J. , Randall K. , Yentis S. M.
Published: March 2003

Summary The recommended dose of Syntocinon® used for uterine contraction at Caesarean section is 5 units intravenously, given slowly. We conducted a survey of the use of Syntocinon at Caesarean section among 240 lead obstetric anaesthetists in the UK in 2001 and found that 155 (87%) of the 179 (75%) respondents gave 10 units, 77 of them (50%) by rapid bolus. The risks of Syntocinon, especially given by rapid injection, were highlighted in the report of the Confidential Enquiries into Maternal Deaths in the UK (1997–99), which was published at the end of 2001, and so the survey was repeated in 2002. Of the 256 forms sent, 198 completed replies were returned (77%); these indicated a dramatic change of practice: only 30 (15%) now gave 10 units and only 7 of these (23%) by a rapid injection. One hundred and sixty‐seven respondents to the second survey (84%) stated they had changed their practice and 159 of these (95%) gave the Confidential Enquiries report as the main reason for change. These results highlight the importance of the Confidential Enquiries as a means of improving practice.
Development of mountainous topography in the Basin Ranges, USA
Authors: Ellis  , Densmore  , Anderson
Published: March 2003

We use the landcape evolution modelZscapeto explore quantitatively the development of mountainous topography in the Basin and Range province (formerly the Basin Ranges), USA, as a function of faulting, surface processes and microclimate. Many of the classic morphologies of mountains in the Basin and Range were described in the late part of the 19th century. The varied topography coupled with differing experiences led to a similarly diverse set of explanations. We are able to demonstrate through a variety of numerical experiments that a diverse landscape is easily obtained by the simple, steady combination of tectonic and surface processes. Numerical landscapes reveal the same features observed in the field, including facets, spur benches, piedmonts, and relatively linear and regularly spaced drainages. In all cases, a steady‐state landscape is generated on the order of 106years, so that there remains little information in the landscape that can tell us about processes or conditions prior to 1 million years ago. The fundamental form of the steady‐state landscape (including the facet and spur bench morphology) is governed by the spacing of rivers and bedrock strength and the resulting relief is for the most part strength‐limited. Neither hillslope nor facet relief is dependent on the rate of fault slip or channel incision. Relief is incision‐limited, however, nearer the headwaters of rivers where stream power is relatively low. Topographically asymmetric ranges may be generated over tectonically symmetric horsts by allowing precipitation to be driven by orographic processes, but the asymmetry is likely to be dependent on the ability to remove eroded material from the adjacent basins. The value of the experiments presented here is to demonstrate that the astute and impressive observations made by the likes of Gilbert, Davis and Dutton are reproducible using a relatively simple description of the relevant physics and that we can recognize and explain various landscape morphologies that have in the past been the subject of necessarily qualtitative reasoning.
Tectono‐climatic evolution of a Neogene intramontane basin (Late Miocene Carboneras subbasin, southeast Spain): revelations from basin mapping and biofacies analysis
Authors: Brachert T. C. , Krautworst U. M. R. , Stueckrad O. M.
Published: March 2003

Exceptional 3‐D exposures of fault blocks forming a 5 km × 10 km clastic sediment‐starved, marine basin (Carboneras subbasin, southeast Spain) allow a test of the response of carbonate sequence stratigraphic architectures to climatic and tectonic forcing. Temperate and tropical climatic periods recorded in biofacies serve as a chronostratigraphic framework to reconstruct the status of the basin within three time‐slices (late Tortonian–early Messinian, late Messinian, Pliocene). Structural maps and isopach maps trace out the distribution of fault blocks, faults, and over time, their relative motions, propagational patterns and life times, which demonstrate a changing layout of the basin because of a rotation of the regional transtensional stress field. Progradation of early Messinian reefal systems was perpendicular to the master faults of the blocks, which were draped by condensed fore‐slope sediments. The hangingwall basins coincided with the toe‐of‐slope of the reef systems. The main phase of block faulting during the late Tortonian and earliest Messinian influenced the palaeogeography until the late Pliocene (cumulative throw < 150–240 m), whereas displacements along block bounding faults, which moved into the hangingwall, died out over time. An associated shift of the depocentres of calciturbidites, slump masses and fault scarp degradation breccias reflects 500–700 m of fault propagation into the hangingwall. The shallow‐water systems of the footwall areas were repeatedly subject to emergence and deep peripheral erosion, which imply slow net relative uplift of the footwall. In the dip‐slope settings, erosional truncations of tilted proximal deposits prevail, which indicate rotational relative uplift. Block movements were on the order of magnitude of third order sea‐level fluctuations during the late Tortonian and earliest Messinian. We suggest that this might be the reason for the common presence of offlapping geometries in early Messinian reef systems of the Betic Cordilleras. During the late Pliocene, uplift rates fell below third order rates of sea‐level variations. However, at this stage, the basin was uplifted too far to be inundated by the sea again. The evolution of the basin may serve as a model for many other extensional basins around the world.
Perindopril postmarketing surveillance: a 12 month study in 47 351 hypertensive patients
Authors: Speirs C. , Wagniart F. , Poggi L.
Published: March 2003

Aims
 To gain information on serious adverse events in a large number of patients exposed to perindopril.

Methods
 Four thousand sevenhundred and eighty‐eight general practitioners throughout France collaborated in the recruitment of 47 351 patients for a 12 month postmarketing study. Data collection was undertaken by company representatives under the supervision of nine regional medical officers. Computerised data entry was performed by six pharmaceutical officers. Serious adverse events were later individually reviewed medically.

Results
 Withdrawals due to adverse events occurred in 6.1% of female and 3.2% of males patients. The ascertainment of adverse events in this study approved satisfactory, as shown by the reported incidence of cough, which was 11.3% in women and 7.8% in men, this being compatible with the best estimates of the true incidence of cough during ACE‐inhibitor therapy. Serious adverse reactions—anaphylaxis and blood dyscrasias—were rare.

Conclusions
 This study successfully followed a large cohort of patients treated with perindopril and failed to demonstrate any unexpected hazards.
Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin
Authors: Kivistö K. T. , Kantola T. , Neuvonen P. J.
Published: March 2003

Aims
 The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG‐CoA reductase with different pharmacokinetic properties, were studied.

Methods
 Two separate randomized, placebo‐controlled, cross‐over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h.

Results
 Itraconazole had no significant effect on the Cmax (190±124 ng ml−1vs 197±189 ng ml−1 (mean±s.d.)) or total AUC (368±153 ng ml−1 h vs 324±155 ng ml−1 h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8±0.49 h vs 2.4±0.51 h; P<0.05). The Cmax of lovastatin was increased about 15‐fold (P<0.01) and the total AUC more than 15‐fold (P<0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12‐fold (95% CI, 5.3 to 17.7‐fold; P<0.01) and 15‐fold (95% CI, 4.6 to 26.2‐fold; P<0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7±3.8 h and that of lovastatin acid 4.7±4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase.

Conclusions
 Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.
Topical penetration of commercial salicylate esters and salts using human isolated skin and clinical microdialysis studies
Authors: Cross Sheree E. , Anderson Chris , Roberts Michael S.
Published: March 2003

Aims
 The penetration of active ingredients from topically applied anti‐inflammatory pharmaceutical products into tissues below the skin is the basis of their therapeutic efficacy. There is still controversy as to whether these agents are capable of direct penetration by diffusion through the tissues or whether redistribution in the systemic circulation is responsible for their tissue deposition below the application site.

Methods
 The extent of direct penetration of salicylate from commercial ester and salt formulations into the dermal and subcutaneous tissue of human volunteers was determined using the technique of cutaneous microdialysis. We also examined differences in the extent of hydrolysis of the methylester of salicylate applied topically in human volunteers and in vitro skin diffusion cells using full‐thickness skin and epidermal membranes.

Results
 The present study showed that whilst significant levels of salicylate could be detected in the dermis and subcutaneous tissue of volunteers treated with the methylsalicylate formulation, negligible levels of salicylate were seen following application of the triethanolamine salicylate formulation. The tissue levels of salicylate from the methylsalicylate formulation were approx. 30‐fold higher than the plasma concentrations.

Conclusion
 The absorption and tissue concentration profiles for the commercial methylsalicylate formulation are indicative of direct tissue penetration and not solely redistribution by the systemic blood supply.
The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross‐over study with extensive and quinidine‐induced poor metabolizers
Authors: Wilder‐Smith Clive H. , Hufschmid Edith , Thormann Wolfgang
Published: March 2003

Aims
 Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic and visceral pain thresholds in extensive and quinidine‐induced poor metabolizers.

Methods
 Eleven healthy subjects participated in a double‐blind, randomized, placebo‐controlled, four‐way cross‐over study comparing the effects of single doses of placebo and slow‐release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured.

Results
 In quinidine‐induced poor metabolizers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P<0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased from 0.91% to 0.28% of the dihydrocodeine dose (P<0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, P<0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P<0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P<0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P<0.05).

Conclusions
 In quinidine‐induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.
Grapefruit juice–drug interactions
Authors: Bailey David G. , Malcolm J. , Arnold O. , David Spence J.
Published: March 2003

The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post‐translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration‐related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6′,7′‐dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice‐drug interactions in humans.
Best practice in therapeutic drug monitoring
Authors: Gross Annette S.
Published: March 2003

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regimen and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring. This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process—the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management—are discussed.
The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers
Authors: Seaber Emma J. , Peck Richard W. , Smith Deborah A. , Allanson John , Hefting Nanco R. , Van Lier Jan J. , Sollie Frans A. E. , Wemer Johan , Jonkman Jan H. G.
Published: March 2003

Aims Zolmitriptan (Zomig (formerly 311C90)) is a novel 5‐HT1B/1D receptor agonist developed for the acute oral treatment of migraine. A highly sensitive LCMS‐MS assay has been developed which allows quantification of plasma concentrations of zolmitriptan and its active metabolite, 183C91, after therapeutic doses. Two studies using this assay method were conducted to investigate the pharmacokinetics, including absolute bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men and women, the dose‐proportionality of 2.5, 5 and 10 mg doses and the effect of food on the pharmacokinetics of a 5 mg oral dose.

Methods Two randomized, balanced, open‐label, 4‐period crossover studies were conducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan and compared the pharmacokinetics in men and women. The second study examined the dose‐proportionality in pharmacokinetics after fasting doses of 2.5, 5 and 10 mg, and the effect of food on a 5 mg dose. Blood pressure, heart rate, ECG, clinical chemistry, haematology and adverse events were also monitored.

Results The mean (s.d.) absolute oral bioavailability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48±0.14 and 0.36±0.07 after 5 mg in women and men, respectively. Without adjustment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (±s.d.) AUC was 32.7±10.1 and 60.2±26.8 ng ml−1 h after 5 mg in men and women, respectively (95% CI for ratio 0.43–0.77). After 2.5 mg mean (±s.d.) AUC was 18.4±5.4 and 23.1±9.9 ng ml−1 h in men and women, respectively (95% CI for ratio 0.61–1.09). However, these differences were of no clinical significance. Cmax and AUC of oral zolmitriptan were dose‐proportional and there was a 13 and 16% fall in mean zolmitriptan Cmax and AUC, respectively, when administered after food. Adverse effects were minor, predominantly mild and transient, and there were no clinically significant effects on ECG, blood pressure, or laboratory parameters.

Conclusions At therapeutic doses zolmitriptan has good oral bioavailability in healthy volunteers and has dose‐proportional pharmacokinetics that are not affected by food to any clinically relevant extent.
Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients
Authors: Fogari Roberto , Zoppi Annalisa , Corradi Luca , Lazzari Pierangelo , Mugellini Amedeo , Lusardi Paola
Published: March 2003

Aims The aim of this study was to compare the effects of the ACE‐inhibitor lisinopril and the angiotensin II receptor antagonist losartan on insulin sensitivity in the treatment of non diabetic hypertensives.

Methods Twenty‐five non diabetic subjects with mild to moderate hypertension, 11 females and 14 males, aged 44–63 years, after a 4‐week wash‐out period on placebo, were randomized to receive lisinopril 20 mg once daily or losartan 50 mg once daily for 6 weeks. Following another 4‐week wash‐out period, patients were crossed to the alternative regimen for further 6 weeks. At the end of the placebo and of the active treatment periods, blood pressure (BP) was measured (by standard mercury sphygmomanometer, Korotkoff I and V) and insulin sensitivity was assessed by the euglycaemic hyperinsulinaemic clamp technique. Glucose infusion rate (GIR) during the last 30 min of clamp and total glucose requirement (TGR) were evaluated.

Results Both lisinopril and losartan significantly reduced SBP (by a mean of 20.2 and 17.2 mmHg, respectively) and DBP (by a mean of 15.2 and 12.3 mmHg, respectively), with no difference between the two treatments. GIR, used as an indicator of insulin sensitivity, was significantly increased by lisinopril (+1.5 mg min−1 kg−1, P<0.05 vs baseline) but not by losartan (+0.42 mg min−1 kig−1, NS), the difference between the two drugs being statistically significant (P<0.05). TGR was increased by lisinopril (+7.3 g, P<0.05 vs baseline), whereas losartan did not significantly modify it (+1.9 g, NS).

Conclusions In conclusion, with all cautions due to an absence in this study of a randomized placebo phase, our findings suggest that lisinopril improved insulin sensitivity whereas losartan did not affect it.