An economic evaluation of planned immediate versus delayed birth for preterm prelabour rupture of membranes: findings from the PPROMT randomised controlled trial.

OBJECTIVE: This study is an economic evaluation of immediate birth compared with expectant management in women with preterm prelabour rupture of the membranes near term (PPROMT). DESIGN: A cost-effectiveness analysis alongside the PPROMT randomised controlled trial. SETTING: Obstetric departments in 65 hospitals across 11 countries. POPULATION: Women with a singleton pregnancy with ruptured membranes between 34+0 and 36+6 weeks gestation. METHODS: Women were randomly allocated to immediate birth or expectant management. Costs to the health system were identified and valued. National hospital costing data from both the UK and Australia were used. Average cost per recruit in each arm was calculated and 95% confidence intervals were estimated using bootstrap re-sampling. Averages costs during antenatal care, delivery and postnatal care, and by country were estimated. MAIN OUTCOMES MEASURES: Total mean cost difference between immediate birth and expectant management arms of the trial. RESULTS: From 11 countries 923 women were randomised to immediate birth and 912 were randomised to expectant management. Total mean costs per recruit were £8852 for immediate birth and £8740 for expectant delivery resulting in a mean difference in costs of £112 (95% CI: -431 to 662). The expectant management arm had significantly higher antenatal costs, whereas the immediate birth arm had significantly higher delivery and neonatal costs. There was large variation between total mean costs by country. CONCLUSION: This economic evaluation found no evidence that expectant management was more or less costly than immediate birth. Outpatient management may offer opportunities for cost savings for those women with delayed delivery. TWEETABLE ABSTRACT: For women with preterm prelabour rupture of the membranes, the relative benefits and harms of immediate and expectant management should inform counselling as costs are similar.

Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in CD-1 mice.

The potential toxicologic and oncogenic effects of spinosad, a natural fermentation product with insecticidal properties, were investigated. The 13-week toxicity study consisted of groups of 10 CD-1 mice/sex provided diets containing 0, 0.005, 0.015, 0.045, or 0.12% spinosad (Study 1). The 0.12% group was terminated on Test Day 44 due to mortality and overt clinical signs of toxicity. An 18-month chronic oncogenicity study consisted of groups of 50 CD-1 mice/sex provided diets containing 0, 0.0025, 0.008, or 0.036% spinosad (Study 2). Two interim groups of 10 mice/sex/group were terminated after 3 and 12 months. Females given 0.036% were terminated on Day 455 due to markedly lower body weights and feed consumption, as well as excessive mortality. Because of the early termination of the female high-dose group, additional groups of 10 male and female mice (12-month interim necrospy) and 50 male and female mice (18-month necropsy) were provided diets containing 0, 0.0008, or 0.024% spinosad (Study 3) to fully assess potential chronic toxicity and oncogenicity. Standard toxicologic parameters were evaluated consistent with existing regulatory guidelines. The primary effect in the 13-week and 18-month studies was intracellular vacuolation of histiocytic and epithelial cells in numerous tissues and organs at doses of > or = 0.015%. The histological vacuolation corresponded to ultrastructural lysosomal lamellar inclusion bodies. This alteration was consistent with phospholipidosis, a condition that results from accumulation of polar lipids in lysosomes. Lesions with no apparent direct relation to vacuolation were hyperplasia of the glandular mucosa of the stomach, skeletal muscle myopathy, bone marrow necrosis, and anemia with associated splenic hematopoiesis. The incidence of tumors in mice given spinosad was not increased relative to controls at any dose level. The no observed effect level for the 13-week study was 0.005% (6 mg/kg/day) spinosad, and for the chronic toxicity/oncogenicity study was 0.008% (11 mg/kg/day) spinosad for male and female CD-1 mice.

Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in Fischer 344 rats.

Spinosad is an insecticide derived from a naturally occurring bacterium via fermentation. The toxicity of spinosad was characterized in subchronic and chronic toxicity/oncogenicity studies conducted according to standard toxicology regulatory guidelines. Subchronic toxicity was evaluated in groups of 10 Fischer 344 rats/sex given feed containing 0, 0.05, 0.1, 0.2, or 0.4% spinosad (Study 1) or 0, 0.003, 0.006, 0.012, or 0.06% spinosad (Study 2) for 13 weeks. Lower body weights and increased mortality occurred in rats given 0.4% spinosad. Microscopic effects were observed in the adrenal glands, liver, lymphoid cells, reproductive tissues, kidney, thyroid, stomach, lung, and skeletal muscle of rats given > or = 0.05% spinosad, and consisted primarily of vacuolation of cells; however, degenerative, regenerative, and/or inflammatory changes were also noted in some tissues. Vacuolation within a number of tissues was ultrastructurally characterized by an increase in size and number of lysosomes that contained extensive membranous whorls consistent with phospholipidosis. The no observed effect level (NOEL) in the 13-week studies was 0.012% (24 mg/kg/day) spinosad. Chronic toxicity and oncogenicity were evaluated in groups of 60 Fischer 344 rats/sex given feed containing 0, 0.005, 0.02, 0.05, or 0.1% spinosad for up to 2 years. Rats given 0.1% spinosad for 1 year had microscopic effects similar to those observed in the subchronic studies. Vacuolation and inflammation of the thyroid gland also occurred in rats given 0.05% spinosad for 1 year. Excessive mortality occurred in rats from the oncogenicity study given 0.1% spinosad by 21 months, and surviving rats were euthanized because the maximum tolerated dose had been exceeded. Rats given 0.05% spinosad for 2 years had vacuolation and/or inflammation involving the thyroid, lymphoid tissue, and lung. Rats given 0.05% spinosad had similar numbers of neoplasms as control rats, indicating that spinosad was not carcinogenic at dose levels up to 0.05%. The NOEL at 2 years was 0.005% (2.4 mg/kg/day) spinosad.

Pre-anesthetic assessment clinics in Ontario.

PURPOSE: To survey the provision of pre-anesthetic assessment clinics in hospitals in Ontario during the summer of 1997. METHODS: Mail survey questionnaire of all 300 hospitals in Ontario. RESULTS: Replies were received from 260 hospitals (86.7%) of which 131 provide anesthesia. Of these, 86% are community and 14% teaching hospitals. Regular clinics are held in 63% of these hospitals, most commonly daily. As to location, 73% are held in the outpatient department. Written guidelines detailing which patients should be referred are issued by 77% of departments. The attending surgeon is the most common source of referral (64%). Referred patients are most commonly seen by a nurse (52%) who decides on onward referral to an anesthesiologist. Services generating the most referrals are general surgery (83%), orthopedics (64%) and obstetrics/gynecology (49%). In 47% of hospitals 10-50 patients are seen per month and they travel most commonly up to 100 km. The average "no show" rate is 6.2%. Only 36% of departments assess patients the same day as seen by the surgeon. On attending the clinic, 51% can see an internist the same day in contrast to 30% being able to see a cardiologist. Pre-admission testing is available to 97% on the same day. Direct funding is available for the nurse (87%), physician (1%) and secretarial help (43%). Remuneration of the anesthesiologist is fee for service (99%) and sessional (1%). CONCLUSION: Pre-anesthetic assessment clinics are common in Ontario. More development is required to enable patients to receive all aspects of their preoperative assessment during one visit.

Chronic dietary toxicity/oncogenicity studies on 2,4-dichlorophenoxyacetic acid in rodents.

Forms of 2,4-dichlorophenoxyacetic acid (collectively known as 2,4-D) are herbicides used to control a wide variety of broadleaf and woody plants. Doses in the 2-year chronic/oncogenicity rat study were 0, 5, 75, and 150 mg/kg/day. The chronic toxicity paralleled subchronic findings, and a NOEL of 5 mg/kg/day was established. A slight increase in astrocytomas observed (in males only) at 45 mg/kg/day in a previously conducted chronic rat study was not confirmed in the present study at the high dose of 150 mg/kg/ day. Doses in the 2-year mouse oncogenicity studies were 0, 5, 150, and 300 mg/kg/day for females and 0, 5, 62.5, and 125 mg/ kg/day for males. No oncogenic effect was noted in the study. In summary, the findings of these studies indicate low chronic toxicity of 2,4-D and the lack of oncogenic response to 2,4-D following chronic dietary exposure of 2,4-D in the rat and mouse.

Single-dose and 13-week repeated-dose neurotoxicity screening studies of chlorpyrifos insecticide.

Chlorpyrifos (CPF), a widely used organophosphate insecticide, was screened for neurotoxic effects in Fischer 344 rats using United States Environmental Protection Agency 1991 guidelines for single-dose and 13-wk repeated dose studies. The studies emphasized a functional observational battery (which included grip performance and hindlimb splay tests), automated motor activity testing and comprehensive neurohistopathology of perfused tissues. Doses of up to 100 mg/kg body weight in corn oil by gavage in the single-dose study and up to 15 mg/kg body weight/day in diet for 13 wk in the repeated dose study were administered. It is known that CPF and other phosphorothionates can be activated to the oxon in local (extrahepatic) tissues. Local activation could possibly cause different effects in different tissues with cholinergic innervation, and thereby create syndromes unique to each phosphorothionate according to their structure. Consequently, the conduct of CPF neurotoxicity screening studies by contemporary guidelines offered opportunity to characterize the CPF over-exposure syndrome in rats. Single-dose high levels of oral exposure to CPF caused a range of clinical signs characteristic of cholinergic overstimulation. Although there was no clinical evidence of wide differences in sensitivity of one cholinergic response versus another, motor dysfunction (incoordination etc.) was more prominent than other signs, for example soiling. Effects were much more apparent in females and regressed over several days. Effects were minimal in the 13-wk study, and there was no evidence of accumulation of toxicity during the 13 wk of daily dietary exposure. Motor activity was decreased at the high dose in males and females at wk 4, but was not significantly different from controls in subsequent weeks. The 'normalization' of motor activity later in the study was interpreted as tolerance to repeated administration of CPF. Comprehensive neuropathological examination revealed no treatment-related lesions in either study.

Sustained inflations improve respiratory compliance during high-frequency oscillatory ventilation but not during large tidal volume positive-pressure ventilation in rabbits.

OBJECTIVE: To determine whether volume recruitment maneuvers that induce significant lung reexpansion during high-frequency oscillatory ventilation are also of value during conventional positive-pressure ventilation. DESIGN: Crossover comparison of volume recruitment maneuvers administered during high-frequency oscillatory ventilation and positive-pressure ventilation in normal and surfactant-deficient adult rabbits. SETTING: Laboratory. SUBJECTS: Nineteen adult New Zealand white rabbits (weight 2.3 to 3.3 kg). METHODS: Respiratory system compliance was measured plethysmographically before and after sustained inflations in six normal and five saline-lavaged anesthetized rabbits, using both ventilators over a range of mean and end-expiratory pressures. RESULTS: Under conditions where sustained inflations during high-frequency oscillatory ventilation at 15 Hz increased respiratory system compliance 50 +/- 28%, sustained inflations during conventional positive-pressure ventilation at a rate of 30 to 40 breaths/min and tidal volumes of 14 to 17 mL/kg did not change respiratory system compliance (mean change 3 +/- 9%). Sustained inflations during conventional positive-pressure ventilation could not be made effective by increasing the positive end-expiratory pressure level to equal the mean pressure during high-frequency oscillatory ventilation. Sustained inflations on conventional positive-pressure ventilation remained ineffective up to positive end-expiratory pressure levels of 17.5 cm H2O. In lavaged rabbits, sustained inflations increased respiratory system compliance 49 +/- 14% during high-frequency oscillatory ventilation and 0 +/- 3% during conventional positive-pressure ventilation. Sustained inflations increased compliance significantly during conventional positive-pressure ventilation only when ventilating with tidal volumes of 7 mL/kg and low end-expiratory pressure. CONCLUSIONS: Active recruitment of lung volume during high-frequency oscillatory ventilation appears necessary, because small pressure/volume cycles adequate to support high-frequency gas transport are not able to reexpand atelectatic lung units without the aid of a sustained inflation. We conclude that volume recruitment maneuvers improve respiratory system compliance substantially during high-frequency oscillatory ventilation at 15 Hz, but these maneuvers offer potential risk and no benefit during conventional positive-pressure ventilation with large tidal volumes or when using smaller tidal volumes and high levels of positive end-expiratory pressure.

Volume recruitment maneuvers are less deleterious than persistent low lung volumes in the atelectasis-prone rabbit lung during high-frequency oscillation.

OBJECTIVES: To test whether the pulmonary risk of repeated volume recruitment is greater or less than the risk associated with unreversed atelectasis during 6 hrs of high-frequency oscillatory ventilation in the atelectasis-prone rabbit lung. DESIGN: Prospective, controlled, randomized comparison over 6 hrs of ventilator management. SETTING: Laboratory. SUBJECTS: Twenty-eight adult New Zealand white male rabbits (weight 2.3 to 2.8 kg). BACKGROUND: Controversy exists over whether high-frequency oscillatory ventilation should be used with volume recruitment maneuvers in the atelectasis-prone lung, or be used at low mean and peak pressures without volume recruitment to avoid the risks of even transient pulmonary overdistention. Potential risks and benefits accompany both alternatives. INTERVENTIONS: We evaluated the pulmonary effects of three high-frequency oscillatory ventilation protocols in anesthetized rabbits made surfactant deficient by saline lavage, using animals ventilated with conventional positive-pressure ventilation with positive end-expiratory pressure as a reference group; n = 5 in each group. The three high-frequency oscillatory ventilation groups were ventilated for 6 hrs at 15 Hz (900 breaths/min), FIO2 = 1.0. The repeated stretch group received 15-sec sustained inflations at 30 cm H2O mean airway pressure every 20 mins, with maintenance mean airway pressure sufficient to keep PaO2 > 350 torr (46.7 kPa). The repeated deflation group was maintained at levels that produced PaO2 70 to 120 torr (9.3 to 16 kPa), with the endotracheal tube opened to atmospheric pressure for 15 secs every 20 mins. Animals in the repeated stretch after deflations group were managed as in the repeated stretch protocol but each sustained inflation was preceded by a 15-sec deflation to functional residual capacity. The conventional positive-pressure ventilation group was ventilated at rates of 30 to 100 breaths/min, keeping PaO2 70 to 120 torr (9.3 to 16 kPa). End-points included terminal functional residual capacity and a compliance index computed from respiratory system pressure-volume curves. MEASUREMENTS AND MAIN RESULTS: After 6 hrs of ventilation, respiratory system compliance in the repeated stretch group had returned to control values (1.35 +/- 0.18 [SD] mL/kg/cm H2O). Respiratory system compliance was significantly less than this number in both the repeated deflation (0.89 +/- 0.08) and repeated stretch after deflations (1.24 +/- 0.22) groups (p < .05). Respiratory system compliance after 3 hrs of conventional positive-pressure ventilation decreased to 0.34 +/- 0.10 mL/kg/cm H2O. Functional residual capacity changes paralleled these changes of respiratory system compliance. CONCLUSIONS: These data demonstrate that the potential pulmonary risk of repeated lung stretch during volume recruitment is significantly less than the damage arising from the avoidance of such maneuvers in lungs in which alveolar recruitment is possible. We conclude that sustained inflations during high-frequency oscillatory ventilation produce the benefits of increased oxygenation for a given mean airway pressure plus decreased progression of lung injury.

Cardiac tamponade complicating anaesthetic induction for repair of ascending aorta dissection.

A case is described of a 69-year-old woman with dissection of the ascending aorta who developed cardiac tamponade during induction of anaesthesia. The tamponade was diagnosed by a haemodynamic profile showing approximation of the central venous, pulmonary wedge and pulmonary arterial diastolic pressures, and was treated with rapid surgical intervention and drainage of the haemopericardium. Cardiac tamponade and dissecting aneurysms of the ascending aorta are conditions with contrasting anaesthetic considerations and the problems encountered are discussed.

Hydrolysis of benzo[a]pyrene diol epoxide and its covalent binding to DNA proceed through similar rate-determining steps.

The mutagenic and carcinogenic metabolite of benzo[a]pyrene, (7R,8S)-dihydroxy-(9R,10R)-epoxy-7,8, 9,10-tetrahydrobenzo[a]pyrene, undergoes two major reactions in the presence of DNA: (i) hydrolysis and (ii) covalent binding. We report that hydrolysis and covalent binding are specific and general acid-catalyzed reactions with the same or similar rate-determining steps. To account for the similarity of rate-determining steps in covalent binding and hydrolysis we propose and test two models. In each model, the rate-determining step results in formation of a carbonium ion, which serves as a precursor for both tetrol and adduct. In model A the carbonium ion is partitioned between two domains (1 and 2), while in model B there is only one domain. Measurements of pseudo-first-order rate constants, product ratios, and rate ratios support model A, while kinetic results are inconsistent with model B. Domain 1 most likely represents activated benzo[a]pyrenes that are intercalated into DNA, while domain 2 hydrocarbons are physically bound to the outside of the DNA helix.