Initiation of maintenance treatment with salmeterol/fluticasone propionate 50/100 microg bd versus fluticasone propionate 100 microg bd alone in patients with persistent asthma: integrated analysis of four randomised trials.

OBJECTIVES: To identify the asthma patients, on short-acting beta2-agonists alone, who would benefit from initial maintenance therapy (IMT) with salmeterol/fluticasone (SFC) propionate 50/100 microg bd compared with fluticasone propionate (FP) 100 microg bd alone. The results of an integrated analysis of data from four previous trials are presented. METHODS: The four original trials were randomised, double-blind, parallel group studies and included patients who had received IMT with SFC 50/100 microg bd or FP 100 microg bd. Patients were >or=12 years with a 6 month history of asthma and >or=15% reversibility in FEV1. Patients had either not received inhaled corticosteroids in the preceding month or were steroid naïve. Patients were assessed to determine whether any GINA-defined asthma characteristics or combination of asthma characteristics could predict those individuals who would achieve well controlled asthma status with IMT with SFC rather than with inhaled steroid alone. Patients with persistent asthma were assessed based on GINA-defined baseline asthma characteristics and well controlled asthma status in response to each treatment was investigated according to combinations of these baseline features. Subsequently, a further range of endpoints, including asthma symptoms, rescue medication use and asthma control, were analysed over weeks 1-12 for the combinations of features where the treatment difference in well controlled asthma status was greatest. RESULTS: The results of the initial analyses demonstrated that patients exhibiting two or three features of uncontrolled asthma at baseline were more likely to achieve well controlled asthma when treated with SFC than with FP alone, the most significant difference being observed in patients with three baseline features (odds ratio 2.60, 95% CI: 1.87, 3.62, p<0.001). Patients with one baseline feature showed no difference between the FP and SFC groups. Further analyses on data from patients with two or three baseline asthma features, showed that treatment with SFC resulted in significantly greater improvements in mean morning PEF, percentage symptom-free days, nights with no awakenings and rescue-free days compared with FP. In addition, asthma control was achieved earlier in patients in the SFC group. SFC and FP were well tolerated as shown previously in the four individual trials. CONCLUSIONS: Patients on short-acting beta2-agonists alone with two or three features of uncontrolled asthma (moderate to severe airflow limitation/daily symptoms/daily rescue medication use) are most likely to achieve better control, earlier, with SFC 50/100 microg bd initial maintenance treatment compared with FP 100 microg bd alone.

Admissions to intensive care units from emergency departments: a descriptive study.

OBJECTIVES: To describe the case mix, activity, and outcome for admissions to intensive care units (ICUs) from emergency departments (EDs). DESIGN: An observational study using data from a high quality clinical database, the Case Mix Programme Database, of intensive care admissions, coordinated at the Intensive Care National Audit & Research Centre (ICNARC). SETTING: 91 adult ICUs in England, Wales, and Northern Ireland, 1996-99. SUBJECTS: 46,587 intensive care admissions. MAIN OUTCOME MEASURES: Ultimate hospital mortality. RESULTS: Admissions from EDs constituted 26% of total admissions to ICU, 77% of which were direct admissions to ICU from EDs. Direct admissions from EDs, indirect admissions from EDs, and non-ED admissions presented to ICU with different conditions and severity of illness. Indirect admissions from EDs presented in the ICU with the more severe case mix (older age, more acute severity of illness, more likely to have a chronic illness) compared with direct admissions to ICU from EDs. Compared with ICU admissions not originating in EDs, unit and hospital mortality were higher for admissions from EDs, with indirect admissions experiencing the highest hospital (46.4%) mortality. For ICU survivors, indirect admissions stayed longest in the ICU. CONCLUSIONS: A large proportion of admissions to ICU (26%) originate in EDs, and differ from those not originating in EDs in terms of both case mix and outcome. Additionally, those admitted directly to ICU from EDs differ from those admitted indirectly via a ward. The observed differences in outcome between different admission routes require further investigation and explanation.

Calcium channel blockers for acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury is a major cause of death and disability. Calcium channel blockers (calcium antagonists) have been used in an attempt to prevent cerebral vasospasm after injury, maintain blood flow to the brain, and so prevent further damage. OBJECTIVES: To estimate the effects of calcium channel blockers in patients with acute traumatic brain injury, and in a subgroup of brain injury patients with traumatic subarachnoid haemorrhage. SEARCH STRATEGY: Handsearching and electronic searching for randomised controlled trials. SELECTION CRITERIA: Randomised controlled trials in patients with all levels of severity of clinically diagnosed acute traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the identified studies for eligibility and extracted data from each study. Summary odds ratios were calculated using the Mantel-Haenszel method. MAIN RESULTS: Six RCTs were identified as eligible for inclusion in the systematic review. The effect of calcium channel blockers on the risk of death was reported in five of the RCTs. The pooled odds ratio (OR) for the five studies was 0.91 (95% confidence interval [95%CI] 0.70-1.17). For the four RCTs that reported death and severe disability (unfavourable outcome), the pooled odds ratio was 0.85 (95%CI 0.68-1.07). In the two RCTs which reported the risk of death in a subgroup of traumatic subarachnoid haemorrhage patients, the pooled odds ratio was 0.59 (95%CI 0.37-0.94). Three RCTs reported death and severe disability as an outcome in this subgroup, and the pooled odds ratio was 0.67 (95%CI 0.46-0.98). REVIEWER'S CONCLUSIONS: This systematic review of randomised controlled trials of calcium channel blockers in acute traumatic head injury patients shows that considerable uncertainty remains over their effects. The effect of nimodipine in a subgroup of brain injury patients with subarachnoid haemorrhage shows a beneficial effect, though the increase in adverse reactions suffered by the intervention group may mean that the drug is harmful for some patients.

Influence of patient gender on admission to intensive care.

STUDY OBJECTIVES: To compare the case mix and outcomes of male and female patients admitted to intensive care units for a wide range of conditions. DESIGN: Cross sectional study of prospectively collected data. SETTING: The Intensive Care National Audit and Research Centre, (ICNARC) Case Mix Programme. PARTICIPANTS: 46 587 admissions to 91 units across England, Wales, and Northern Ireland. MAIN RESULTS: No gender differences were found in case mix on admission or in mortality for five conditions (cardiac arrhythmia, chronic obstructive airways disease, asthma, self poisoning, and seizures). There was some evidence of horizontal and vertical inequity for female patients with myocardial infarction and with neurological bleeding. Vertical equity was not achieved for male pneumonia and ventricular failure patients and for women with primary brain injury. CONCLUSIONS: This study demonstrated, for the first time, possible inequitable use of intensive care for patients with certain conditions. This may be secondary to gender bias and can result in either over-treatment in the favoured group, or under-treatment in the neglected group. It would therefore be pertinent to re-examine these findings using other databases, and to further investigate the causative factors, including gender bias.

Development and testing of a hierarchical method to code the reason for admission to intensive care units: the ICNARC Coding Method. Intensive Care National Audit & Research Centre.

A computer-based hierarchical method was developed to code conditions leading to admission to intensive care in the UK. The hierarchy had five tiers: surgical status, body system, anatomical site, physiological or pathological process and medical condition. The hierarchy was populated initially using the free-text descriptions of the reason for admission from 10,806 admissions recorded as part of the Intensive Care Society's UK APACHE II study. After refinement and error-checking, a prospective evaluation was undertaken on 22,059 admissions to 62 UK intensive care units. Individual units coded between 60 and 1610 (mean 356) admissions. All but 50 (0.2%) of the admissions could be coded and 38 units coded every admission. Fifty admissions (0.2%) could not be coded within 24 h of admission but were coded subsequently when more information became available. Of the admissions, 96.1% were coded at all levels of the hierarchy in the coding method. Six hundred and thirty-seven of the 741 unique conditions (85.9%) were used in one of the five reasons for admission and 564 (76.1%) in the primary reason for admission. Five conditions account for 19.4% of all primary reasons for admission. This is the first method to be developed empirically for coding the reason for intensive care admission.

Research priorities in critical care medicine in the UK.

OBJECTIVES: To establish priorities for research in critical care medicine in the UK using survey and nominal group (NG) techniques. DESIGN: The senior doctor and nurse from 325 intensive care units (ICUs) in the UK were invited to contribute up to ten research questions relevant to intensive care organisation, practice or outcomes. These were then ranked twice using a Likert scale by a panel (nominal group) consisting of ten doctors (two trainees) and two nurses from university teaching and district general (community) hospitals. The first ratings were performed privately, and the second after group discussion. Thirty questions, ten each with strong, moderate or weak support, were then returned for rating by the originating ICU staff and the results compared with those of the NG. RESULTS: One hundred eighty-five respondents (35.6 % university teaching, 62.1% district general, 2.3 % not stated) provided 811 questions of which 722 were research hypotheses. The most frequently identified topics were the evaluation of high dependency care, ICU characteristics, treatments for acute lung injury and acute renal failure, nurse:patient ratios, pulmonary artery catheterisation, aspects of medical and nursing practice, protocol evaluation, and interhospital transfers. These were condensed into 100 topics for consideration by the NG. Discussion and re-rating by the group resulted in strong support being offered for 37 topics, moderate support for 48, and weak support for 21. Following circulation of ten questions from each category, nine questions achieved strong support from both ICU staff and the NG. These were the effect on outcomes from critical illness of early intervention, high dependency care, nurse:patient ratios, interhospital transfers, early enteral feeding, optimisation of perioperative care, hospital type, regionalisation of paediatric intensive care and the use of pulmonary artery catheters. The absence of any questions relating to interventions targetting mediators of the immuno-inflammatory response could be a consequence of the failure of recent studies in sepsis to demonstrate benefits in outcome. CONCLUSIONS: The intensive care community in the UK appears to prioritise research into organisational aspects of clinical practice and practical aspects of organ-system support. Health services research and the biological sciences need to develop collaborative methods for evaluating interventions and outcomes.

Calcium channel blockers for acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury is a major cause of death and disability. Calcium channel blockers have been used in an attempt to prevent cerebral vasospasm after injury, maintain blood flow to the brain and so prevent further damage. OBJECTIVES: To estimate the effects of calcium channel blockers in patients with acute traumatic brain injury and in a subgroup of brain injury patients with traumatic subarachnoid haemorrhage. SEARCH STRATEGY: Hand searching and electronic searching for randomized controlled trials available by October 1997. SELECTION CRITERIA: Randomized controlled trials in patients with all levels of severity of clinically diagnosed acute traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two reviewers (JL and CG) independently assessed the identified studies for eligibility and extracted data from each study. Summary odds ratios were calculated using the Mantel-Haenszel method. MAIN RESULTS: Four RCTs were identified as eligible for inclusion in the systematic review. The effect of calcium channel blockers on the risk of death was reported in all RCTs. The pooled odds ratio for the four studies was 0.91 (95% confidence interval 0. 70 to 1.17). For the three RCTs that reported death and severe disability the pooled odds ratio was 0.85 (95% CI 0.68 to 1.07). In the two RCTs which reported the risk of death in a sub group of traumatic subarachnoid haemorrhage patients, the pooled odds ratio was 0.59 (95% CI 0.37 to 0.94). Three RCTs reported death and severe disability as an outcome in this subgroup, and the pooled odds ratio was 0.67 (95% CI 0.46 to 0.98). REVIEWER'S CONCLUSIONS: This systematic review of randomized controlled trials of calcium channel blockers in acute traumatic head injury patients shows that considerable uncertainty remains over their effects. The effect of nimodipine in a subgroup of brain injury patients with subarachnoid haemorrhage shows a beneficial effect, though the increase in adverse reactions suffered by the intervention group may mean that the drug is harmful for some patients.

Consequences of discharges from intensive care at night.

BACKGROUND: It is generally believed that pressure for beds on intensive-care units (ICUs) has increased in the UK. This study used discharge at night as a proxy measure to investigate pressure. METHODS: Night was defined in two ways: "out of office hours' from 2200 to 0659 h and "the early hours of the morning" from 0000 to 0459 h. The rate of discharge at night was compared for 21 295 adult admissions to 62 ICUs covering the period 1995-98 with 10806 admissions to 26 ICUs covering the period 1988-90. With data solely from 1995-98, the consequences of discharge at night and premature discharge were investigated. FINDINGS: Overall, 2269 (21.0%) admissions did not survive the ICU in 1988-90 compared with 4487 (21.1%) in 1995-98. Of ICU survivors, 2.7% were discharged at night (2200-0659 h) in 1988-90 compared with 6.0% in 1995-98. In 1995-98, night discharges (2200-0659 h) had a higher crude (odds ratio 1.46, 95% CI 1.18-1.80) and case-mix adjusted (1.33, 1.06-1.65) ultimate hospital mortality. Higher odds ratios were observed when the definition of night was 0000-0459 h. Premature discharge was commoner at night, 42.6% vs 5.0% and its importance was apparent when incorporated into the logistic-regression model (premature discharge 1.35, 1.10-1.65; night discharge 1.17, 0.92-1.49). INTERPRETATION: Night discharges from ICU are increasing in the UK. This practice is of concern because patients discharged at night fare significantly worse than those discharged during the day. Night discharges are more likely to be "premature" in the view of the clinicians involved. The implication of these results is that many hospitals have insufficient intensive-care beds. In deciding whether or not to invest more resources in intensive care we must, however, consider the cost-utility of this particular service compared with other ways that additional resources could be used.

Use of consensus development to establish national research priorities in critical care.

OBJECTIVES: To test the feasibility of using a nominal group technique to establish clinical and health services research priorities in critical care and to test the representativeness of the group's views. DESIGN: Generation of topics by means of a national survey; a nominal group technique to establish the level of consensus; a survey to test the representativeness of the results. SETTING: United Kingdom and Republic of Ireland. SUBJECTS: Nominal group composed of 10 doctors (8 consultants, 2 trainees) and 2 nurses. MAIN OUTCOME MEASURE: Level of support (median) and level of agreement (mean absolute deviation from the median) derived from a 9 point Likert scale. RESULTS: Of the 325 intensive care units approached, 187 (58%) responded, providing about 1000 suggestions for research. Of the 106 most frequently suggested topics considered by the nominal group, 37 attracted strong support, 48 moderate support and 21 weak support. There was more agreement after the group had met-overall mean of the mean absolute deviations from the median fell from 1.41 to 1.26. The group's views represented the views of the wider community of critical care staff (r=0.73, P<0.01). There was no significant difference in the views of staff from teaching or from non-teaching hospitals. Of the 37 topics that attracted the strongest support, 24 were concerned with organisational aspects of critical care and only 13 with technology assessment or clinical research. CONCLUSIONS: A nominal group technique is feasible and reliable for determining research priorities among clinicians. This approach is more democratic and transparent than the traditional methods used by research funding bodies. The results suggest that clinicians perceive research into the best ways of delivering and organising services as a high priority.

Transvaginal Doppler ultrasound of the uteroplacental circulation in the early prediction of pre-eclampsia and intrauterine growth retardation.

OBJECTIVE: To evaluate the predictive value of transvaginal Doppler ultrasound studies of the uterine and umbilical arteries in early pregnancy, in identifying pregnant women at risk of subsequently developing pre-eclampsia, or the delivery of a small for gestational age infant. DESIGN: A multivariate logistic regression of Z scores of Doppler indices obtained from the uterine and umbilical arteries of 652 women with singleton pregnancies at 12 to 16 weeks of gestation. Measurements included the presence or absence of a notch, bilateral (right and left waveform) notching, vessel diameter, the resistance index, the pulsatility index, time averaged mean velocity (cm/s), maximum systolic velocity (cm/s), and volume flow (mL/min). Stepwise logistic regression and multivariate analysis of all the parameters measured was used to construct several scoring systems. MAIN OUTCOME MEASURES: Pre-eclampsia, birthweight, preterm delivery. RESULTS: In women that developed complications, there was a trend towards increased resistance and reduced velocity and volume flow. If bilateral notches were present there was an increased risk of pre-eclampsia (odds ratio [OR] 21.99, 95% CI 6.55-73.79), premature delivery (OR 2.38, 95% CI 1.19-4.75), and the delivery of a small for gestational age baby (OR 8.63, 95% CI 3.95-18.84). Using multivariate analysis, a seven parameter model was selected (after removal of vessel diameter, uterine and umbilical resistance index). This model produces a scoring system with a sensitivity of 92.9% and a specificity of 85.1% for the prediction of pre-eclampsia. A three parameter model (bilateral notches, uterine resistance index, umbilical pulsatility index) provides similar sensitivities, but lower specificities, when compared with the seven parameter model. CONCLUSION: These data indicate that there are differences in uterine and umbilical artery Doppler blood flow indices at 12 to 16 weeks, in pregnancies with a normal or complicated outcome. Scoring systems derived from multivariate analysis of Doppler indices demonstrate the potential of being able to identify, in early pregnancy, a group of women at increased risk of the subsequent development of pre-eclampsia, premature delivery, or the birth of a small for gestational age baby.

Transvaginal uterine and umbilical artery Doppler examination of 12-16 weeks and the subsequent development of pre-eclampsia and intrauterine growth retardation.

We aimed to determine whether Doppler measurements obtained from the uterine and umbilical arteries in early pregnancy correlate with the subsequent development of pre-eclampsia, or the delivery of a small-for-gestational-age (SGA) baby. A follow-up study was carried out in 652 women with singleton pregnancies who had transvaginal uterine and umbilical artery Doppler examinations performed at 12-16 weeks' gestation. Measurements included: the presence or absence of an early diastolic notch, vessel diameter, resistance index (RI), pulsatility index (PI), time-averaged mean velocity (TAV), maximum systolic velocity and volume flow in the right and left uterine arteries and RI and PI in the umbilical arteries. The main outcome measures were: intrauterine death, birth weight, pre-eclampsia (proteinuric pregnancy-induced hypertension, PPIH) and antepartum hemorrhage. Twelve pregnancies terminated in the second trimester, and in 14 the outcome is unknown. In the remaining 626 women, 44 (7.0%) pregnancies ended in a premature delivery, 30 (4.7%) women developed PPIH, 60 (9.6%) infants were SGA (< 10th centile), of which 19 were < 5th centile and five were < 3rd centile, and 23 (3.7%) women suffered an antepartum hemorrhage. At 12-16 weeks, 205 (32.7%) women had bilateral (right and left) notching of the uterine artery waveforms. When compared to values from women with a normal pregnancy outcome, women who subsequently developed PPIH demonstrated a significant difference in mean uterine artery TAV (24.6 cm/s for PPIH vs. 33.25 cm/s for normal outcome, p < 0.003), volume flow (120.5 ml/min vs. 184.5 ml/min, p < 0.001) and elevated resistance (mean RI = 0.80 vs. 0.695, p < 0.001). In women with bilateral notching, there were significant differences between values for pregnancies with PPIH (odds ratio (OR) 42.02, 95% confidence interval (CI) 5.66, 311.99), being SGA at birth (OR 8.61, 95% CI 4.0, 20.0) or delivering prematurely (OR 2.38, 95% CI 1.19, 4.75), compared with pregnancies with a normal outcome. We conclude that abnormal Doppler values, indicative of a failure to modify the uterine circulation in early pregnancy, are associated with premature delivery, the development of PPIH and the delivery of an SGA baby. This information may be of value in increasing our understanding of the pathophysiological events that lead to the subsequent development of uteroplacental complications such as pre-eclampsia.