bluuebunny/crossref_metadata_2025 huggingface dataset:
Supraclavicular brachial plexus block as a sole anaesthetic technique in children: an analysis of 200 cases
Authors: Pande R. , Pande M. , Bhadani U. , Pandey C. K. , Bhattacharya A.
Published: March 2003

Classical supraclavicular brachial plexus block was used as the sole anaesthetic technique in 200 children aged between 5 and 12 years undergoing closed reduction of arm fractures. The local anaesthetic used was lidocaine 1.5% with epinephrine. The block was graded as satisfactory if surgical manipulation could be performed without discomfort and unsatisfactory if general anaesthesia had to be given. In 182 children, the procedure was carried out under the block alone, whereas the remaining 18 patients required general anaesthesia. The mean (SD) time required for performing the block was 9.1 (3.7) min and the mean (SD) time to sensory blockade was 8.3 (2.3) min. The mean duration of analgesia was ≈ 3.5 h. There were few complications, with no incidence of pneumothorax in any patient. The acceptability of the block by the children and the parents was 72 and 85%, respectively. The classical supraclavicular brachial plexus block was found to be acceptable, effective and with a good success rate.
A qualitative investigation into the physical stability of polypropylene and polyethylene in liquid isoflurane and sevoflurane
Authors: Renfrew C. W. , Murray J. M. , Fee J. P. H.
Published: March 2003

The interaction between medical plastics and drugs is complex. Drug absorption into plastics may affect drug dosage and the migration of plastics' additives into a drug solution may affect drug composition. We investigated the stability of those plastics which may be used in infusion systems to inject liquid volatile anaesthetic drugs directly into an anaesthetic breathing system. Samples of two types of polypropylene from a syringe barrel and plunger and low‐ and high‐density polyethylene from extension tubing were exposed to isoflurane and sevoflurane for 1, 7 or 250 days. All samples were from the same batches. Samples of the plastics (n = 24) and the liquid volatile anaesthetics (n = 24) were subjected to Fourier transform‐infrared spectroscopy to produce series of absorption spectra. By reference to control sample absorption spectra, this allows detection of anaesthetic drug absorption into the plastics or migration of the plastics or their additives into the liquid anaesthetics. We found no evidence of migration of the plastic components or their additives into the liquid anaesthetic drugs at any of the exposure periods. Similarly, we found no evidence of absorption of isoflurane or sevoflurane by any of the plastic components during short‐term exposure of either 1 or 7 days. However, there was evidence of some absorption of the anaesthetic drugs by the polyethylene plastics after about 8 months' exposure. It would appear that low‐ and high‐density polyethylene and polypropylene are suitably safe for use in infusion systems for the direct injection of isoflurane and sevoflurane into anaesthetic breathing systems.
A randomised controlled trial of intravenous versus inhalational analgesia during outpatient oocyte recovery
Authors: Thompson N. , Murray S. , MacLennan F. , Ross J. A. S. , Tunstall M. E. , Hamilton M. P. R. , Bhattacharya S.
Published: March 2003

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.
Supplementary oxygenation with the laryngeal mask airway: a comparison of four devices
Authors: Peyton P. , Cowie D. , Howard W.
Published: March 2003

The provision of supplementary oxygen via the laryngeal mask airway used in the recovery room is important for patient safety. Several devices have been described for this purpose, but these studies have not included an accurate measurement of the most clinically important variable, the end‐tidal oxygen concentration. We constructed an artificial model of spontaneous ventilation to compare the efficacy and safety of four devices; a circuit filter, a Hudson mask, the ‘T‐bag’ device and a T‐piece. We combined the use of oximetry with a pneumotachograph to provide a continuous picture of the oxygen delivery characteristics of the devices at flow rates of 2, 4 and 8 l.min−1. The performances of the T‐bag and the T‐piece were superior to those of the filter and Hudson mask, with end‐tidal oxygen concentrations of 46.1%, 45.8% and 35.4%, 34.8%, respectively, at 8 l.min−1. Single point assessments of oxygen delivery, such as peak inspired oxygen concentration, may overestimate the efficacy of test devices.
Anti‐infective measures and Entonox® equipment: a survey
Authors: Bajekal R. R. , Turner R. , Yentis S. M.
Published: March 2003

We surveyed 102 maternity suites to investigate whether the guidelines of the Association of Anaesthetists of Great Britain and Ireland, for the use of anti‐infective filters or fully disposable anaesthetic breathing systems for each patient, were being followed with regard to Entonox® equipment on labour wards. Of 100 units giving information (98%), only seven used filters and only two replaced tubing between cases. Our survey shows that the recommended policy is not being applied to Entonox apparatus in delivery suites.
The use of central venous cannulae in neuroanaesthesia
Authors: Mills S. J. , Tomlinson A. A.
Published: March 2003

A postal questionnaire was sent to all UK consultant members of the Neuroanaesthesia Society to ascertain whether there was any consensus on indications for use and route of insertion of central venous cannulae in elective neuroanaesthetic practice. Five brief clinical scenarios were presented. Of 179 respondents, 98% indicated that they would insert a central venous cannula into patients requiring excision of an acoustic neuroma in the sitting position, 76% for clipping of an intracranial aneurysm and 75% for resection of an arteriovenous malformation. The antecubital fossa was the preferred route of insertion for 43.5% of respondents with 36.5% preferring the internal jugular approach. The subclavian (17%) and femoral (3%) routes were unpopular first‐choice approaches. A significant proportion of respondents (43.5%) do not routinely order a chest X‐ray at any stage following pre‐operative central venous cannulation. The indications for use and advantages and disadvantages of each route of insertion, with reference to neuro‐anaesthetic practice, are discussed.
Psychological problems following ICU treatment*
Authors: Scragg P. , Jones A. , Fauvel N.
Published: March 2003

Treatment in an intensive care unit can be stressful and may leave patients with persisting psychological symptoms that impair quality of life. This postal questionnaire study of patients who had previously been treated in a general adult intensive care unit showed that 38 (47%) of 80 patients who returned fully completed questionnaires reported clinically significant anxiety and depression as measured by the Hospital Anxiety and Depression Scale. Thirty (38%) reported significant symptoms of post‐traumatic stress disorder, of whom 12 (15%) reached levels consistent with a diagnosis of full post‐traumatic stress disorder as measured by the Trauma Symptom Checklist 33 and the Impact of Events Scale. We describe a new measure of psychological distress specifically related to the experience of intensive care management, the Experience after Treatment in Intensive Care 7 Item Scale, and compare it to the other scales. The Experience after Treatment in Intensive Care 7 Item Scale shows that at least a proportion of the post‐traumatic stress reported was directly attributable to the experience of treatment in the intensive care unit.
Induction with propofol target‐concentration infusion vs. 8% sevoflurane inhalation and alfentanil in hypertensive patients
Authors: Nathan N. , Vial G. , Benrhaiem M. , Peyclit A. , Feiss P.
Published: March 2003

Haemodynamic parameters during an inhalation induction with 8% sevoflurane were compared with those obtained with a target‐controlled infusion of propofol in 50 hypertensive patients in a prospective randomised study. Heart rate and arterial pressure were recorded continuously. End‐tidal sevoflurane and nitrous oxide concentration, Spo2 and bispectral index (BIS) were also collected from the beginning of anaesthesia until 8 min after tracheal intubation. Patients either received 4 mg.l−1 target‐concentration propofol or performed a vital capacity inhalation of 8% sevoflurane in a high flow of oxygen (8 l.min−1) supplemented with 50% nitrous oxide at loss of consciousness. As soon as BIS was < 60, 20 µg.kg−1 alfentanil and 0.6 mg.kg−1 rocuronium were injected and orotracheal intubation was then performed 1 min later. Thereafter, the end‐tidal concentration of sevoflurane was reduced to 1.3 minimum alveolar concentration (MAC). Hypotension was defined as a 30% decrease in arterial pressure and was treated with repeated 3‐mg boluses of ephedrine. When 12 mg ephedrine was unable to correct hypotension, the concentration of propofol was reduced by 1 mg.l−1 and that of sevoflurane by 0.5%. Hypotension occurred in 22 patients in the sevoflurane group and 21 in the propofol group, and hypertension occurred in two and three patients in each group, respectively. The maximal reduction in mean (SD) arterial pressure was similar in the sevoflurane (45 (4) mmHg) and propofol (41.3 (2.6) mmHg) groups, as were the ephedrine requirements (9.6 (1.1) vs. 9.1 (1.1) mg, sevoflurane vs. propofol, p > 0.05), the duration of hypotension (276 (37) vs. 292 (38) s, sevoflurane vs. propofol, p > 0.05), and the number of hypotensive episodes or anaesthetic changes and depth of anaesthesia. Nevertheless, heart rate was lower during the 8 min following tracheal intubation in the sevoflurane group. In both groups, the duration of hypotension was easily controlled either by ephedrine or by adjusting the anaesthetic concentrations. Overall, haemodynamic tolerance appears to be similar in the two techniques. Because hypotension occurred after alfentanil in most patients, this study questioned which is the best opioid dose, if any, to associate with propofol or sevoflurane for the induction in hypertensive patients.
A new device to reduce the consumption of a halogenated anaesthetic agent*
Authors: Enlund M. , Wiklund L. , Lambert H.
Published: March 2003

We report the first clinical application of a new anaesthetic agent‐saving device. The principles of a heat–moisture exchanger have been further developed to create a device that reduces inhalational agent consumption. Sixteen patients were randomly allocated to receive isoflurane through either a vaporiser or through the agent‐saving device. A coaxial Mapleson D system (Bain) was used in both groups. A standard ventilatory setting was used, aiming for normocapnia. Mean (SD) isoflurane consumption was 24.5 (2.8) ml.MAC‐hour−1 with the vaporiser, compared with 15.2 (3.0) ml.MAC‐hour−1 with the new device (p < 0.05). This corresponded to a 40% saving in the consumption of isoflurane. The amount of isoflurane that was scavenged to the atmosphere was reduced by an average of 55%.
Prophylaxis against thromboembolism in patients with traumatic brain injury: a survey of UK practice
Authors: Cupitt J. M.
Published: March 2003

Venous thromboembolism is a major complication associated with traumatic brain injury and is responsible for significant morbidity and mortality. There has been a general reluctance over the years to use anticoagulant prophylaxis for patients with head injury who have suffered intracranial bleeding or for whom intracranial surgery is needed. We conducted a postal questionnaire survey of all neurosurgical centres in the United Kingdom, enquiring about the use of thromboprophylactic methods in the management of patients with traumatic brain injury. A diversity of practice and opinion in the use of such methods was evident from the replies received. The survey highlighted concern about the failure to implement even the most simple means of prophylaxis. The evidence for the use of the various methods of prophylaxis is reviewed.
Medical repatriation via fixed‐wing air ambulance: a review of patient characteristics and adverse events
Authors: Dewhurst A. T. , Farrar D. , Walker C. , Mason P. , Beven P. , Goldstone J. C.
Published: March 2003

Anaesthetists are often employed as medical escorts for patients undergoing international transfer by air ambulance. There is little published data on the types of patients being transferred and on the incidence of adverse events. We performed a retrospective review of the documentation of all air ambulance transfers performed by a single company over a 2‐year period followed by a prospective assessment of all high‐risk patients transferred over a 1‐year period. Of 483 transfers identified, 47% were defined as high‐risk and 20% were of patients receiving mechanical ventilation. In the prospective group, 28% of patients required pretransfer optimisation, 7% required a major therapeutic intervention during transfer and there was a major adverse event in 12% of transfers. There were two deaths during transport. These data support the recommendation that escorting personnel should be from an appropriate speciality, have reasonable seniority and be adequately trained and supervised.
Intermediate outcome of medical patients after intensive care
Authors: Trivedi M. , Ridley S. A.
Published: March 2003

Medical patients suffer a high mortality after critical illness; however, the causes of mortality after intensive care management are unclear. This study's aims were to (a) explore what factors affect outcome after intensive care and (b) identify medical patients at particularly high risk of mortality. During one year, all patients admitted with a medical cause to the Critical Care Complex were enrolled. Diagnosis on admission was recorded, and whether the reason for admission was a new clinical problem or an exacerbation of existing chronic illness. All patients were followed for a minimum of one year. A total of 186 medical patients were included in the study. Fifty‐four medical patients died on intensive care (28.4% mortality), a further 16 died on the general ward after intensive care unit discharge (hospital mortality 36.8%) and six following discharge home (1 year's mortality 40.9%). Of the 16 patients who died on the general ward, 12 had been admitted to the intensive care unit with a new, previously unrecognised problem rather than exacerbation of a chronic pre‐existing problem. However, on the general ward, ‘Do Not Resuscitate’ orders were placed on seven of these 12 patients. It would appear that some of the high post intensive care hospital mortality might be due to changes in resuscitation status in patients expected to survive following intensive care unit discharge.
Blood pressure measurement in volunteers with and without padding between the cuff and the skin
Authors: Archer L. J. , Smith A. J.
Published: March 2003

Automated non‐invasive arterial blood pressure measurements are made frequently during anaesthesia. Conscious patients often find the measurement uncomfortable. The tissues under the cuff can suffer trauma such as skin creasing, blistering, petechial haemorrhages and even nerve damage. We placed soft padding between the blood pressure measurement cuff and the skin of the upper arm of 140 healthy volunteers, and compared cuff‐related skin trauma and arterial blood pressure measurements with and without the padding. Padding was associated with a significant reduction in the frequency and intensity of skin trauma (p < 0.0001). There was no significant overall effect of the presence of padding on arterial blood pressure readings. We conclude that the benefit of padding outweighs any compromise to the reliability of arterial blood pressure measurement.
Removal of obstructing blood clot from the lower airway: an alternative suction technique
Authors: Bodenham A. R.
Published: March 2003

Clotted blood or organised thrombus in the lower airway may present clinicians with life‐threatening airway obstruction or pulmonary collapse. An alternative suction technique is described, which applies suction directly to a tracheal tube.
A survey of physicians' attitudes to transfusion practice in critically ill patients in the UK
Authors: Boralessa Harsha , Rao M. P. , Morgan C. , Soni N. , Goldhill D. R. , Brett S. J. , Boralessa Hari
Published: March 2003

Summary This study aimed to examine the attitudes of intensivists and haematologists to the use of blood and blood products using a scenario‐based postal questionnaire. One hundred and sixty‐two intensivists and 77 haematologists responded to the survey. In four scenarios, the baseline haemoglobin thresholds for red cell transfusion ranged from 6 to 12 g.dl−1. There was significant variation between scenarios (p < 0.005). Increasing age, high Acute Physiology and Chronic Health Status II score, surgery, acute respiratory distress syndrome, septic shock and lactic acidosis significantly (p < 0.005) modified the transfusion threshold. There were greater variations in the baseline threshold for platelet transfusion. The majority of respondents (72.3%) selected a baseline haemoglobin threshold between 9 and 10 g.dl−1. The thresholds for platelet transfusion were far less consistent.
Leakage and absorption of isoflurane by different types of anaesthetic circuit and monitoring tubing
Authors: Smith C. , Flynn C. , Wardall G. , Broome I. J.
Published: March 2003

Summary Conductive rubber anaesthetic circuit tubing both absorbs volatile agents and leaks these agents through its walls. We quantified the leakage and absorption properties of the most commonly used plastic materials used to make breathing circuit tubing, relative to conductive rubber. We then compared two different types of plastic tubes used to carry gas to volatile agent monitors; one made of polyvinyl chloride, the other made of polyvinyl chloride lined internally with a thin layer of polyethylene. We found that the three commonly used plastic types used to make anaesthetic circuit tubing all leak less volatile anaesthetic through their walls than conductive rubber. Polyethylene and polypropylene tubing absorb significantly less volatile anaesthetic than conductive rubber; however, this is not the case with polyvinyl chloride tubing. Differences in the leakage and absorption properties of polyvinyl chloride monitoring tubing are not significantly changed by the addition of a thin internal layer of polyethylene. It is therefore not worthwhile incorporating this feature into production.
Effect of pre‐operative anxiolysis on postoperative pain response in patients undergoing total abdominal hysterectomy
Authors: Caumo W. , Hidalgo M. P. L. , Schmidt A. P. , Iwamoto C. W. , Adamatti L. C. , Bergmann J. , Ferreira M. B. C.
Published: March 2003

Summary In a double blind, placebo‐controlled trial, we have assessed the effects of pre‐operative anxiolysis on postoperative pain scores in 112 ASA I‐II women, aged 18–65 years, scheduled to undergo total abdominal hysterectomy. Subjects were randomly allocated to receive either oral diazepam 10 mg (n=56) or placebo (n=56) pre‐operatively. Postoperative anxiety, pain scores, analgesic consumption, and sedation were evaluated at several time points during the first 24 h following surgery. Postoperative pain scores were found to be significantly higher in the diazepam group. Trait and state anxiety showed a significant effect on pain scores, independent of the treatment group. No difference was found between the groups in morphine consumption, but there was a significant reduction in morphine consumption with time.
The Human Rights Act 1998: implications for anaesthesia and intensive care
Authors: White S. M. , Baldwin T. J.
Published: March 2003

Summary The Human Rights Act 1998 was incorporated into UK statutory law on October 2, 2000. The 18 Articles of the Act are likely to have a significant impact on the practice of medicine in the UK, particularly in reference to consent, disclosure of medical information and patient access to healthcare. This article examines the implications of the new legislation for anaesthetic and intensive care practice.
A comparison of the laryngeal mask airway and PAXpressTM for short surgical procedures
Authors: Ahmed S. M. , Maroof M. , Khan R. M. , Singhal V. , Rizvi K. A.
Published: March 2003

Summary Sixty adult patients undergoing minor peripheral surgery under general anaesthesia were randomly allocated to receive either the laryngeal mask airway (laryngeal mask airway; size 4 for females and size 5 for males) or the PAXpressTM (adult size), inserted by a single operator with experience of > 50 insertions of each device. The laryngeal mask airway was correctly placed on the first attempt in 27 patients (90%) compared with 20 patients (67%) when using the PAXpress (p < 0.01). No patient required more than two attempts at insertion and there were no failures with the laryngeal mask airway, compared with four (13%) who needed three attempts and two failures (7%) with the PAXpress (p < 0.001 and p < 0.01, respectively). Mean (SD) total placement time was shorter with the laryngeal mask airway [24.6 (3.1) s] than with the PAXpress[35.4 (2.5) s; p < 0.01]. The most common complication was sore throat, which occurred less frequently with the laryngeal mask airway (8 patients; 26%) than with the PAXpress (15 patients; 53.5%; p < 0.001).
Clinical governance and chronic pain: towards a practical solution
Authors: Griffiths D. P. G. , Mitchell Noon J. , Campbell F. A. , Price C. M.
Published: March 2003

Summary There have been many studies into the effectiveness of single interventions in pain, however, little is known of performance or outcome of pain clinics where treatment often consists of multiple, complex interventions. Many pain clinicians currently experience considerable difficulty in fulfilling the requirements of clinical governance and completing a personal portfolio. There is a clear and urgent need for a viable method of monitoring performance. This study describes a well‐developed computer‐based system – Pain Audit Collection System (PACS). PACS has been designed by pain clinicians through consensus and its success in uptake suggests that it is a viable method for outcome evaluation. An analysis is provided of outcome data in typical pain clinics. Further work is needed to investigate the utility of this data.
Cerebrovascular reactivity to carbon dioxide in sepsis syndrome*
Authors: Bowie R. A. , O'Connor P. J. , Mahajan R. P.
Published: March 2003

Summary Cerebral dysfunction in sepsis is common in critically ill adults. However, little is known of the effects of sepsis on cerebral haemodynamics. We studied 12 sedated and ventilated patients in whom sepsis had been established for > 24 h. Transcranial Doppler measurements of the middle cerebral artery flow velocity were made at normocapnia, then hypocapnia (−1 kPa) and hypercapnia (+1 kPa). From these data, cerebrovascular reactivity to carbon dioxide was calculated. Variables indicating disease severity, systemic cardiovascular status and outcome were also recorded. We found significant changes in cerebrovascular reactivity to carbon dioxide. Only three of 12 patients had a cerebrovascular reactivity to carbon dioxide in the normal range; seven patients had a reduced cerebrovascular reactivity to carbon dioxide, whereas in two patients it was raised. In this small sample, we could not find any trend of association between altered cerebrovascular reactivity to carbon dioxide and severity of illness, cardiovascular status or outcome. This study suggests that established sepsis profoundly affects the vascular tone and reactivity, not only of the systemic circulation, but also of the cerebral vasculature.
Oligocene to middle Miocene basin development in the Eastern Betic Cordilleras, SE Spain (Vélez Rubio Corridor – Espuña): reflections of West Mediterranean plate‐tectonic reorganizations
Authors: Geel  , Roep†
Published: March 2003

The suture between two West Mediterranean crustal blocks once situated several hundreds of kilometres apart can be studied in the Vélez Rubio Corridor – Espuña area of the Eastern Betic Cordilleras. This suture, or Internal–External Zone Boundary, separates the former passive southern margin of Iberia (the External Zone) from a stack of allochthonous nappe complexes (the Internal Zone), of which the highest unit is formed by the weakly or nonmetamorphosed Malaguide Complex. Analysis of the Oligocene to middle Miocene sediments of the Vélez Rubio Corridor and the Espuña, and comparison with coeval deposits elsewhere in the Western Mediterranean shows that (a) up to the middle Miocene, the southern part of the External Zone (Southern Subbetic) was positioned some 100 km more eastward; (b) up to the early Aquitanian, the Malaguide Complex, forming part of the South Sardinian block (the southern section of a West Mediterranean continental segment) was juxtaposed to the North Sardinian block (the northern part of that continental fragment), some 400 km more eastward; (c) West European extensional rifting during the late Oligocene to earliest Aquitanian resulted in deposition of rift valley sediments (Ciudad Granada and Pliego Formations) in the Malaguide realm; (d) during the Aquitanian, the West Mediterranean segment disintegrated and the West Mediterranean oceanic basins opened, resulting in, for example, the south‐westward drift of the Internal Zone, with concomitant thrusting and thinning and deposition of submarine fans (Solana‐Algeciras Formation) along the margin; (e) in the early Burdigalian, the allochthonous Internal Zone collided with the Iberian margin, causing the disruption of the platform‐slope configuration of the External Zone; (f) after the collision a deep basin was formed upon the suture filled in with erosional products from both Internal and External Zones (Espejos–Viñuelas–Millanas Formations); (g) a strong compressive event in the late Burdigalian caused the southward thrusting of the Subbetic over the Espejos Formation, thus double‐sealing the collisional contact; (h) in the latest Burdigalian to Langhian, new strongly subsiding basins were formed in the Western Mediterranean, e.g. along the Internal–External Zone Boundary; (i) dextral strike‐slip faulting in the Serravallian resulted in a westward displacement of over 100 km of the southern Subbetic plus Internal Zone; (j) onset of a new pattern of strike‐slip faulting induced the formation of a new suite of basins in the Tortonian.
Apatite fission track thermochronology: an overview of its potential and limitations in geomorphology
Authors: Gunnell
Published: March 2003

The specific time window of apatite fission track thermochronology (AFTT) places it in a unique position to offer continuous time–temperature baseline histories for relatively stable shield, rift and passive margin environments, spanning several geological eras. Fission tracks anneal partially at temperatures between ≈110 °C and ≈60 °C and thereby provide information on residence times within specific levels of the crust. Most samples collected from these terrains, however, are usually found to have cooled out of the apatite partial annealing zone (APAZ) by the mid‐Cenozoic at the latest. Owing to the stability, at geological timescales, of tracks at temperatures <60 °C (i.e. within depths of 0–2.5 km at normal geothermal gradients), a significant loss of resolution must therefore be reckoned with at shallow, although geomorphologically crucial, crustal depths. Indeed, the Neogene and Quaternary are understood to have been most influential in generating the scenery of today, and a use of radiometric and stratigraphic techniques in a nested, multisystem approach can assist in bridging the resolution gap. This paper examines and illustrates, mostly with original examples, the uses and limitations of AFTT in addressing the response of Earth surface systems to event patterns in global tectonics, the controls of lithology and structure on denudation rates, the origin and evolution of passive margin escarpments, the mass‐balanced reconstruction of palaeoelief, the use of apatites as tracers for understanding provenance in sediment routing systems, and the tempo (or episodicity) of denudation as postulated by W. M. Davis’ canons of the ‘geographical cycle’. Alongside efforts towards standardizing the supply of analytically robust AFT results in the laboratory, a more standardized geoscientific interpretation of AFT data is also desirable in order to build a consistent world base of geomorphic rates which can be made available to – and used with confidence by – non‐AFTT specialists.
Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers
Authors: Peck R. W. , Wootton R. , Wiggs R. , Layton G. , Posner J.
Published: March 2003

Aims
 The potential effects of food and gender on the pharmacokinetics of tucaresol were investigated in healthy volunteers.

Methods
 Ten males (mean weight 76.5 kg, age 27–42 years) and eight females (mean weight 58.9 kg, age 18–44 years) received a single oral dose of 200 mg tucaresol on two occasions in random order. On one occasion, tucaresol was given after an overnight fast and on the other, immediately after ingestion of a standard breakfast.

Results
 There were no significant differences in standard pharmacokinetic parameters between the two occasions but the rate of tucaresol absorption was faster after food intake. Female subjects had higher Cmax (ratio 1.25 with 95% CI 1.10–1.44) and AUC (ratio 1.25 with 95% CI 1.05–1.49) values than males but the differences were due to the higher body weights of the males; weight‐adjusted apparent total clearance values (CL/F ) were not different between genders (ratio 1.03 with 95% CI 0.87–1.21).

Conclusions
 Food intake and gender have no significant effect on the exposure to orally administered tucaresol.
Lung delivery of non‐CFC salbutamol via small volume metal spacer and large volume plastic spacer devices compared with an open vent jet nebulizer
Authors: Lipworth B. J. , Clark D. J.
Published: March 2003

Aims
 To compare the lung delivery of salbutamol from a commonly used constant output open vent jet nebuliser (Sidestream) with use of both a conventional large volume plastic spacer (Volumatic) and a novel small volume metal spacer (NebuChamber). This was assessed using the early lung absorption profile of salbutamol over the first 20 min after inhalation.

Methods
 Twelve healthy volunteers were studied in a randomized single (investigator) blind crossover design. Single 1200 μg nominal doses salbutamol from a CFC‐free metered‐dose inhaler (12 sequential 100 μg puffs of Airomir) were delivered via the Volumatic and NebuChamber spacers. A single 1200 μg nominal dose of salbutamol was given as a 4ml fill volume from a Sidestream nebuliser with mouthpiece. Mouth rinsing was performed after each drug sequence. Plasma salbutamol was measured at 5, 10, 15 and 20 min after the last dose of each inhalation sequence, with calculation of maximal concentration (Cmax ) and average concentration over 20 min (Cav ). Systemic β2‐responses were measured as plasma potassium, tremor and heart rate.

Results
 Both the Volumatic and the NebuChamber spacers produced significantly greater salbutamol concentration than the Sidestream nebuliser. For Cav this amounted to a 7.34‐fold difference (95%CI 5.31 to 9.38) between Volumatic vs Sidestream, and a 7.04‐fold difference (95%CI 4.91 to 9.17) for NebuChamber vs Sidestream. Similar differences were found for the extrapulmonary β2‐responses. There were no significant differences in either salbutamol concentration or extrapulmonary β2‐responses between the Volumatic and NebuChamber spacers.

Conclusions
 We found that, in vivo, both the Volumatic and the NebuChamber spacers produced seven‐fold greater lung delivery of salbutamol than the Sidestream nebuliser when comparing microgram equivalent nominal doses, in terms of the early lung absorption profile.
Increases in metabolism of valproate and excretion of 6β‐hydroxycortisol in patients with traumatic brain injury
Authors: Anderson Gail D. , Awan Asaad B. , Adams Carlyn A. , Temkin Nancy R. , Winn H. Richard
Published: March 2003

Aims
 The objectives of this study were to determine the effect of brain trauma on the multiple pathways of metabolism of valproate and to evaluate the use of the urinary 6β‐hydroxycortisol to cortisol ratio in predicting changes in hepatic metabolism induced by brain injury.

Methods
 Fourteen patients with severe head injuries received a 15 mg kg−1 loading dose and a maintenance dose of valproate to maintain therapeutic plasma concentrations. A minimum of one steady state trough blood sample and one dosage interval urine were collected during days 3–6 and during days 7–14 post‐injury. Total and unbound valproate plasma concentrations were determined by gas chromatography‐flame ionization detection (GC‐FID) with and without ultrafiltration. Urinary valproate metabolites were measured by gas chromatography|mass spectrometry (GC‐MS) (n=10). Urinary 6β‐hydroxycortisol and cortisol concentrations were determined by high performance liquid chromatography (h.p.l.c.) (n=14). Total intrinsic clearance (CLint ) for valproate and individual formation clearances (CLf ) to its major metabolites were calculated. Data obtained during baseline (days 3–6) were averaged for each patient and were compared with averaged data obtained from days 7 to 14 using a paired t‐test.

Results
 Statistically significant increases in the CLint, CLf of VPA glucuronide, 2‐ene‐VPA, and 4‐OH‐VPA pathways and the 6β‐hydroxycortisol to cortisol ratio were found. The percent change in the 6β‐hydroxycortisol to cortisol ratio correlated significantly with the changes in the CLint of valproate.

Conclusions
 Brain trauma results in induction of multiple pathways of valproate metabolism and increases in the 6β‐hydroxycortisol to cortisol ratio, suggesting a non‐specific enzyme induction in response to head injury.
Loratadine‐pseudoephedrine in children with allergic rhinitis, a controlled double‐blind trial
Authors: Serra Héctor Alejandro , Alves Oscar , Rizzo Leonardo Francisco Luis , Devoto Flavio Marcelo , Ascierto Héctor
Published: March 2003

Aims
 To conduct a randomized placebo controlled double‐blind crossover trial in order to evaluate a loratadine‐pseudoephedrine combination (L+PS) in children with seasonal allergic rhinitis.

Methods
Forty children (15 males; 25 females), aged 3–15 years, were included in this study. They were randomized to receive L+PS (0.2 mg kg−1 body weight–2.4 mg kg−1 body weight respectively) or placebo (PLA) for 14 days. After 7 days of washout, patients were shifted to the other treatment for a further 14 days. Nasal symptoms (sneezing/itching, congestion, nasal dripping) and signs (turbinal swelling, retronasal drainage), rated on a scale ranging from: 1. absent to 5. very intense, and their sum or mean total symptom score (MTSS) were used as efficacy measurement.

Results
 Significant relief was observed; post‐treatment MTSS difference and its percent change were respectively; L+PS=−4.29; 95% CI: −3.64 and −4.94 (27.8%), and PLA=−1.63; 95% CI: −0.95 and −2.31 (10.7%) (P<0.001 baseline vs endpoint and between treatments). Furthermore, L+PS and PLA significantly modified symptoms, but only L+PS significantly modified signs. No clinical changes were observed during the trial; only one patient showed slight transient insomnia when receiving L+PS.

Conclusions
It is concluded that L+PS is useful and well tolerated in children with seasonal allergic rhinitis. However, elements such as placebo effect must be taken into account for planning future trials.
Role of lipoproteins in the plasma binding of SDZ PSC 833, a novel multidrug resistance‐reversing cyclosporin
Authors: Simon Nicolas , Dailly Eric , Combes Olivier , Malaurie Emmanuelle , Lemaire Michel , Tillement Jean‐Paul , Urien Saïk
Published: March 2003

Aims
 The plasma binding of the cyclosporin D analogue SDZ PSC 833 was investigated in vitro.

Methods
 The plasma total binding constant (corresponding to the bound‐to‐free concentration or binding ratio) was determined at 37° C by the erythrocyte partitioning technique on plasma samples from three healthy volunteers and three cancer patients. Lipoproteins were also removed from plasma samples from three healthy volunteers by a standard ultracentrifugal technique.

Results
 SDZ PSC 833 plasma binding was 97.8±1.1% and 97.3±0.2% in samples from three healthy volunteers and three cancer patients respectively. More than 95% of blood SDZ PSC 833 was distributed in plasma. When the original plasma samples of three individuals were delipidated, SDZ PSC 833 binding was strongly decreased (58% bound to plasma proteins) and when lipoproteins were resuspended in the delipidated plasma samples to produce varying lipoprotein plasma concentrations, the binding increased continuously with the fraction of added lipoproteins. When lipoproteins were resuspended to restore the original lipoprotein plasma content, the % plasma‐bound SDZ PSC 833 increased to 98.2%, close to the value observed with the original plasma (98.7%).

Conclusions
 These results clearly indicate that SDZ PSC 833 plasma binding is mainly determined by lipoproteins and that in blood, most of SDZ PSC 833 is distributed in plasma.
Non‐linear fluvoxamine disposition
Authors: Spigset Olav , Granberg Kerstin , Hägg Staffan , Söderström Emma , Dahlqvist Rune
Published: March 2003

Aims
 To study the pharmacokinetics of fluvoxamine when given in increasing doses to healthy volunteers.

Methods
 Ten healthy, non‐smoking men were given maintenance treatment with fluvoxamine for 4 weeks. Eight subjects were CYP2D6 extensive metabolisers (EMs) and two were CYP2D6 poor metabolisers (PMs). As a measure of the CYP1A2 phenotype, the paraxanthine/caffeine ratio in saliva after intake of caffeine was studied. The fluvoxamine doses given were 25 mg day−1 the first week, 50 mg day−1 the second week, 100 mg day−1 the third week and 200 mg day−1 the fourth week, divided in two daily doses. On the seventh day every week, serum concentrations of fluvoxamine were followed for a dose interval of 12 h. After discontinuation of treatment, fluvoxamine concentrations were followed for 1 week.

Results
 For each of the three two‐fold increases in given dose, the mean AUC increased 3.25‐fold, 3.17‐fold and 3.14‐fold, respectively (P<0.0001), indicating a decrease in oral clearance with increasing dose. The elimination half‐life based upon the serum concentrations 12–48 h after discontinuation of fluvoxamine was 32.1±11.0 h whereas the half‐life based upon the concentrations 3–7 days after discontinuation was significantly shorter, 15.8±4.2 h (means±s.d.; P<0.001). There were no significant correlations between the CYP1A2 phenotype and fluvoxamine AUCs at different doses (r=−0.56; P=0.095 for the correlation between the paraxanthine/caffeine ratio in saliva and fluvoxamine AUC at a dose of 50 mg day−1 ). The two CYP2D6 PMs had AUC values in the same range as the EMs.

Conclusions
 The present study conclusively demonstrates that fluvoxamine exhibits non‐linear kinetics within the therapeutic dose interval. The reason for non‐linearity is not Michaelis‐Menten saturation kinetics of a single metabolic pathway, but rather a complex involvement of multiple parallel pathways.
Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man
Authors: Kiely David G. , Lee Alison F. C. , Struthers Allan D. , Lipworth Brian J.
Published: March 2003

Aims
 The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using NG‐monomethyl‐l‐arginine (l‐NMMA) on systemic and pulmonary haemodynamics.

Methods
Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double‐blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l‐NMMA (4 mg kg−1 h−1 ) with a front loaded bolus (4 mg kg−1 ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t0 ) and after 4, 8, and 12 min (t1, t2 and t3 ).

Results
 Infusion of l‐NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t1 and persisted during the entire infusion period.

Conclusions
 These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.
Effect of age and gender on the pharmacokinetics of eprosartan
Authors: Tenero David M. , Martin David E. , Miller Ann K. , Ilson Bernard , Boike Steven C. , Zariffa Névine , Jorkasky Diane K.
Published: March 2003

Aims
 To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).

Methods
 Twenty‐four subjects (eight subjects/group) received a single 200 mg eprosartan oral dose followed by serial blood sampling over 24 h.

Results
 Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and Cmax values were ≈2‐fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and Cmax values were, on average, ≈2‐fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h).

Conclusions
 No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈ two fold higher AUC and Cmax values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.
L‐arginine‐induced vasodilation in healthy humans:pharmacokinetic–pharmacodynamic relationship
Authors: Bode‐Böger Stefanie M. , Böger Rainer H. , Galland Andrea , Tsikas Dimitrios , Frölich Jürgen C.
Published: March 2003

Aims Administration of l‐arginine by intravenous infusion or via oral absorption has been shown to induce peripheral vasodilation in humans, and to improve endothelium‐dependent vasodilation. We investigated the pharmacokinetics and pharmacokinetic‐pharmacodynamic relationship of l‐arginine after a single intravenous infusion of 30 g or 6 g, or after a single oral application of 6 g, as compared with the respective placebo, in eight healthy male human subjects.

Methods l‐arginine levels were determined by h.p.l.c. The vasodilator effects of l‐arginine were assessed non‐invasively by blood pressure monitoring and impedance cardiography. Urinary nitrate and cyclic GMP excretion rates were measured as non‐invasive indicators of endogenous NO production.

Results Plasma l‐arginine levels increased to (mean±s.e.mean) 6223±407 (range, 5100–7680) and 822±59 (527–955) μmol l−1 after intravenous infusion of 30 g and 6 g l‐arginine, respectively, and to 310±152 (118–1219) μmol l−1 after oral ingestion of 6 g l‐arginine. Oral bioavailability of l‐arginine was 68±9 (51–87)%. Clearance was 544±24 (440–620), 894±164 (470–1190), and 1018±230 (710–2130) ml min−1, and elimination half‐life was calculated as 41.6±2.3 (34–55), 59.6±9.1 (24–98), and 79.5±9.3 (50–121) min, respectively, for 30 g i.v., 6 g i.v., and 6 g p.o. of l‐arginine. Blood pressure and total peripheral resistance were significantly decreased after intravenous infusion of 30 g l‐arginine by 4.4±1.4% and 10.4±3.6%, respectively, but were not significantly changed after oral or intravenous administration of 6 g l‐arginine. l‐arginine (30 g) also significantly increased urinary nitrate and cyclic GMP excretion rates by 97±28 and 66±20%, respectively. After infusion of 6 g l‐arginine, urinary nitrate excretion also significantly increased, (nitrate by 47±12% [P<0.05], cyclic GMP by 67±47% [P=ns]), although to a lesser and more variable extent than after 30 g of l‐arginine. The onset and the duration of the vasodilator effect of l‐arginine and its effects on endogenous NO production closely corresponded to the plasma concentration half‐life of l‐arginine, as indicated by an equilibration half‐life of 6±2 (3.7–8.4) min between plasma concentration and effect in pharmacokinetic‐pharmacodynamic analysis, and the lack of hysteresis in the plasma concentration‐versus‐effect plot.

Conclusions The vascular effects of l‐arginine are closely correlated with its plasma concentrations. These data may provide a basis for the utilization of l‐arginine in cardiovascular diseases.
Frusemide inhibits angiotensin II‐induced contraction on human vascular smooth muscle
Authors: Stanke Françoise , Devillier Philippe , Bréant Didier , Chavanon Olivier , Sessa Carmine , Bricca Giampierro> , Bessard Germain
Published: March 2003

Aims Frusemide is widely used in the treatment of acute pulmonary oedema, chronic congestive heart failure and, to a lesser degree, in the treatment of hypertension. Evidence suggests that frusemide exerts an anti‐vasoconstrictor effect independent of its diuretic properties. Since angiotensin II is a highly potent vasoconstrictor involved in the pathophysiology of these diseases, we have investigated the effect of frusemide on the contraction elicited by angiotensin II on human internal mammary artery (IMA) and saphenous vein (SV).

Methods Rings of IMA and SV were suspended for isometric tension recording in organ baths. Concentration‐response curves to angiotensin II were performed in the absence (control) or in the presence of frusemide (10−6 to 10−3 m ). In addition, the effect of frusemide was evaluated after cyclooxygenase inhibition by indomethacin (10−6 m ) and was compared with those of the other loop diuretic bumetanide (10−4 m ).

Results Frusemide induced a concentration‐dependent decrease of the contraction elicited by angiotensin II on IMA and SV. On both vessels, the inhibitory effect on the maximal contraction to angiotensin II was significant with concentrations of frusemide from 10−5 to 10−3 m. Angiotensin II potency (pD2 ) was only reduced by 10−3 m frusemide. The effect of frusemide was not altered in the presence of indomethacin. Bumetanide was less potent than frusemide in inhibiting angiotensin II‐induced contractions in both IMA and SV.

Conclusions Frusemide, at concentrations in the therapeutic range (10−5 m ), inhibits angiotensin II‐induced contraction on human isolated IMA and SV. This inhibitory effect is cyclooxygenase independent and appears mediated, at least in part, by inhibition of Na+/K+/2Cl− symport. Reduction in the vasoconstrictor effect of angiotensin II may be involved in the therapeutic efficacy of frusemide.