Economic evaluations for intensive care unit randomised clinical trials in Australia and New Zealand: Practical recommendations for researchers.

OBJECTIVES: Economic evaluations of intensive care unit (ICU) interventions have specific considerations, including how to cost ICU stays and accurately measure quality of life in survivors. The aim of this article was to develop best practice recommendations for economic evaluations alongside future ICU randomised controlled trials (RCTs). REVIEW METHODS: We collated our experience based on expert consensus across several recent economic evaluations to provide best-practice, practical recommendations for researchers conducting economic evaluations alongside RCTs in the ICU. Recommendations were structured according to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Consolidated Health Economic Evaluation Reporting Standards (CHEERS) Task Force Report. RESULTS: We discuss recommendations across the components of economic evaluations, including: types of economic evaluation, the population and sample size, study perspective, comparators, time horizon, choice of health outcomes, measurement of effectiveness, measurement and valuation of quality of life, estimating resources and costs, analytical methods, and the increment cost-effectiveness ratio. We also provide future directions for research with regard to developing more robust economic evaluations for the ICU. CONCLUSION: Economic evaluations should be built alongside ICU RCTs and should be designed a priori using appropriate follow-up and data collection to capture patient-relevant outcomes. Further work is needed to improve the quality of data available for linkage in Australia as well as developing costing methods for the ICU and appropriate quality of life measurements.

Long-term costs and cost-effectiveness of adjunctive corticosteroids for patients with septic shock in New Zealand.

OBJECTIVE: The aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. DESIGN: This is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period. SETTING: The study was conducted in New Zealand. PARTICIPANTS AND INTERVENTION: Patients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial. MAIN OUTCOME MEASURES: Healthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months. RESULTS: Of 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months. CONCLUSIONS: In New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.

Hydroxyethyl starch or saline for fluid resuscitation in intensive care.

BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS: We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS: A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

Helicopter emergency medical services (HEMS) over-triage and the financial implications for major trauma centres in NSW, Australia.

BACKGROUND: In NSW Australia, a formal trauma system including the use of helicopter emergency medical services (HEMS) has existed for over 20 years. Despite providing many advantages in NSW, HEMS patients are frequently over-triaged; leading to financial implications for major trauma centres that receive HEMS patients. The aim of this study was to investigate the financial implications of HEMS over-triage from the perspective of major trauma centres in NSW. METHODS: The study sample included all trauma patients transported via HEMS to 12 major trauma centres in NSW during the period: 1 July 2008 to 30 June 2009. Clinical data were gathered from individual hospital trauma registries and merged with financial information obtained from casemix units at respective hospitals. HEMS over-triage was estimated based on the local definition of minor to moderate trauma (ISS≤12) and hospital length of stay of less than 24 hrs. The actual treatment costs were determined and compared to state-wide peer group averages to obtain estimates of potential funding discrepancies. RESULTS: A total of 707 patients transported by HEMS were identified, including 72% pre-hospital (PH; n=507) and 28% inter-hospital (IH; n=200) transports. Over-triage was estimated at 51% for PH patients and 29% for IH patients. Compared to PH patients, IH patients were more costly to treat on average (IH: $42,604; PH: $25,162), however PH patients were more costly overall ($12,329,618 [PH]; $8,265,152 [IH]). When comparing actual treatment costs to peer group averages we found potential funding discrepancies ranging between 4% and 32% across patient groups. Using a sensitivity analysis, the potential funding discrepancy increased with increasing levels of over-triage. CONCLUSIONS: HEMS patients are frequently over-triaged in NSW, leading to funding implications for major trauma centres. In general, HEMS patient treatment costs are higher than the peer group average and the potential funding discrepancy varies by injury severity and the type of transport performed. Although severely injured HEMS patients are more costly to treat, HEMS patients with minor injuries make up the majority of HEMS transports and have larger relative potential funding discrepancies. Future episode funding models need to account for the variability of trauma patients and the proportion of patients transported via HEMS.

Injury trends and mortality in adult patients with major trauma in New South Wales.

OBJECTIVE: To examine trends in mechanism and outcome of major traumatic injury in adults since the implementation of the New South Wales trauma monitoring program, and to identify factors associated with mortality. DESIGN AND SETTING: Retrospective review of NSW Trauma Registry data from 1 January 2003 to 31 December 2007, including patient demographics, year of injury, and level of trauma centre where definitive treatment was provided. PARTICIPANTS: 9769 people aged ≥ 15 years hospitalised for trauma, with an injury severity score (ISS) > 15. MAIN OUTCOME MEASURES: The NSW Trauma Registry outcome measures included were overall hospital length of stay, length of stay in an intensive care unit and in ospital mortality. RESULTS: There was a decreasing trend in severe trauma presentations in the age group 16-34 years, and an increasing trend in presentations of older people, particularly those aged ≥ 75 years. Road trauma and falls were consistently the commonest injury mechanisms. There were 1328 inhospital deaths (13.6%). Year of injury, level of trauma centre, ISS, head/neck injury and age were all independent predictors of mortality. The odds of mortality was significantly higher among patients receiving definitive care at regional trauma centres compared with Level I centres (odds ratio, 1.34; 95% CI, 1.10-1.63). CONCLUSIONS: Deaths from major trauma in NSW trauma centres have declined since 2003, and definitive care at a Level 1 trauma centre was associated with a survival benefit. More comprehensive trauma data collection with timely analysis will improve injury surveillance and better inform health policy in NSW.

Primary scene responses by Helicopter Emergency Medical Services in New South Wales Australia 2008-2009.

BACKGROUND: Despite numerous studies evaluating the benefits of Helicopter Emergency Medical Services (HEMS) in primary scene responses, little information exists on the scope of HEMS activities in Australia. We describe HEMS primary scene responses with respect to the time taken, the distances travelled relative to the closest designated trauma hospital and the receiving hospital; as well as the clinical characteristics of patients attended. METHODS: Clinical service data were retrospectively obtained from three HEMS in New South Wales between July 2008 and June 2009. All available primary scene response data were extracted and examined. Geographic Information System (GIS) based network analysis was used to estimate hypothetical ground transport distances from the locality of each primary scene response to firstly the closest designated trauma hospital and secondly the receiving hospital. Predictors of bypassing the closest designated trauma hospital were analysed using logistic regression. RESULTS: Analyses included 596 primary missions. Overall the HEMS had a median return trip time of 94min including a median of 9min for activation, 34min travelling to the scene, 30min on-scene and 25min transporting patients to the receiving hospital. 72% of missions were within 100km of the receiving hospital and 87% of missions were in areas classified as 'major cities' or 'inner regional'. The majority of incidents attended by HEMS were trauma-related, with road trauma the predominant cause (44%). The majority of trauma patients (81%) had normal physiology at HEMS arrival (RTS = 7.84). We found 62% of missions bypassed the closest designated trauma hospital. Multivariate predictors of bypass included: age; presence of spinal or burns trauma; the level of the closest designated trauma hospital; the transporting HEMS. CONCLUSION: Our results document the large distances travelled by HEMS in NSW, especially in rural areas. The high proportion of HEMS missions that bypass the closest designated trauma hospital is a seldom mentioned benefit of HEMS transport. These results along with the characteristics of patients attended and the time HEMS take to complete primary scene responses are useful in understanding the benefit HEMS provides and the services it replaces.

The cost-effectiveness of adjunctive corticosteroids for patients with septic shock.

OBJECTIVE: To determine whether hydrocortisone is a cost-effective treatment for patients with septic shock. DESIGN: Data linkage-based cost-effectiveness analysis. SETTING: New South Wales and Queensland intensive care units. PARTICIPANTS AND INTERVENTION: Patients with septic shock randomly assigned to treatment with hydrocortisone or placebo in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. MAIN OUTCOME MEASURES: Health-related quality of life at 6 months using the EuroQoL 5-dimension 5-level questionnaire. Data on hospital resource use and costs were obtained by linking the ADRENAL dataset to government administrative health databases. Clinical outcomes included mortality, health-related quality of life, and quality-adjusted life-years gained; economic outcomes included hospital resource use, costs and cost-effectiveness from the health care payer perspective. We also assessed cost-effectiveness by sex. To increase the precision of cost-effectiveness estimates, we conducted unrestricted bootstrapping. RESULTS: Of 3800 patients in the ADRENAL trial, 1772 (46.6%) were eligible and 1513 (85.4% of those eligible) were included. There was no difference between hydrocortisone or placebo groups in regards to mortality (218/742 [29.4%] v 227/759 [29.9%]; HR, 0.93; 95% CI, 0.78-1.12; P = 0.47), mean number of QALYs gained (0.10 ± 0.09 v 0.10 ± 0.09; P = 0.52), or total hospital costs (A$73 515 ± 61 376 v A$69 748 ± 61 793; mean difference, A$3767; 95% CI, -A$2891 to A$10 425; P = 0.27). The incremental cost of hydrocortisone was A$1 254 078 per quality-adjusted life-year gained. In females, hydrocortisone was cost-effective in 46.2% of bootstrapped replications and in males it was cost-effective in 2.7% of bootstrapped replications. CONCLUSIONS: Adjunctive hydrocortisone did not significantly affect longer term mortality, health-related quality of life, health care resource use or costs, and is unlikely to be cost-effective.

Drivers of choice of resuscitation fluid in the intensive care unit: a discrete choice experiment.

OBJECTIVE: To understand the fundamental drivers, and their relative importance, of doctors' and nurses' choice of resuscitation fluid in critically ill patients in Australia and New Zealand. DESIGN: A discrete choice experiment (DCE) administered via an online survey. Respondents were presented with one of four randomly selected DCE choice sets, each including five patient scenarios. The respondent chose between two types of hypothetical resuscitation fluid. The fluid type was characterised by several attributes and each attribute had pre-specified levels. PARTICIPANTS: Convenience sample of 367 Australian and New Zealand intensive care unit doctors and nurses. MAIN OUTCOME MEASURES: The dependent variable was fluid choice, and a regression equation was used to estimate the effect of each fluid attribute on the probability of observing the sequence of choices made over the five patient scenarios. The relative importance of each of the respective fluid attributes was calculated based on the percentage contribution to overall utility (ie, fluid preference). RESULTS: For doctors, safety concerns, patient type and fluid type were collectively responsible for almost three-quarters of decision-making utility (71%). The volume of intravenous fluid administered was the only clinical parameter not reaching statistical significance as a driver of fluid choice (P = 0.06). For nurses, decision making was influenced to a greater extent by the same three attributes (90%), although other unmeasured attributes may have been driving choice. CONCLUSIONS: Doctors and nurses rely on different information when choosing resuscitation fluids, although both cohorts are heavily influenced by safety concerns, patient type and fluid type. This information can be used to modify prescribing behaviour.

Induction of CO2 and Bicarbonate Transport in the Green Alga Chlorella ellipsoidea (I. Time Course of Induction of the Two Systems).

Changes in the physiological properties of the green alga Chlorella ellipsoidea (UTEX 20) were determined during adaptation from high CO2 to air. Cells of C. ellipsoidea, grown in high CO2, had an extremely low affinity for dissolved inorganic carbon (DIC). However, high-affinity DIC transport was induced rapidly after switching to air, which caused a massive decrease in the DIC concentration in the medium. Rates of O2 evolution without added carbonic anhydrase (CA) were compared with calculated rates of uncatalyzed CO2 formation in the medium as a measure of active HCO3-uptake. Cells were found to be able to use HCO3- after 5 h of adaptation and this capacity increased during the next 17 h. The stimulation of O2 evolution upon CA addition was used as a measurement of active CO2 transport: such stimulation occurred 2 h after transfer and increased during the next 5 h. Increases in O2 evolution rates were correlated closely with an increasing capacity to accumulate intracellular pools of acid-labile DIC and with decreases in K1/2(CO2) and CO2-compensation point of the cells. Treatment of cells with cycloheximide (5 [mu]g mL-1) during adaptation completely inhibited DIC transport induction, whereas treatment with chloramphenicol (400 [mu]g mL-1) had no effect, indicating the requirement for cytoplasmic protein synthesis in the induction. These results suggest that both CO2 and HCO3- transport are induced upon transfer of cells from high CO2 to air and that there is a temporal separation between the induction of the two systems.

Induction of CO2 and Bicarbonate Transport in the Green Alga Chlorella ellipsoidea (II. Evidence for Induction in Response to External CO2 Concentration).

The critical species and concentrations of dissolved inorganic carbon (DIC) required for the induction of DIC transport during adaptation to low CO2 were determined for the green alga Chlorella ellipsoidea. The concentration of dissolved CO2 needed for the induction of both CO2 and HCO3- transport was independent of pH during adaptation, whereas the total DIC concentration required increased at alkaline pH. At pH 7.5, the minimum equilibrium DIC concentration at which high CO2 characteristics were maintained, i.e. transport was repressed, was 2100 [mu]M, whereas the maximum equilibrium DIC concentration below which DIC transport was fully induced (DICIND) was 500 [mu]M. Intracellular DIC concentration during adaptation to DICIND decreased temporarily after 2 h to 60% of the maximum level but recovered after 3 h of adaptation. After 3 h of adaptation to DICIND, cells exhibited maximum O2 evolution rate at DICIND. When cells partially adapted to DICIND were returned to high CO2, there was an immediate halt to the induction of transport and a gradual decrease in transport capacity over 23 h. The capacity for the induction of transport was unaffected by the absence of light. These results indicate that changes in the internal DIC pool during adaptation to low CO2 do not trigger the induction of DIC transport and that the induction is not light dependent. Induction of DIC transport in C. ellipsoidea appears to occur in response to the continuous exposure of cells to a critical CO2 concentration in the external medium.

A New Screening Method for Algal Photosynthetic Mutants (CO2-Insensitive Mutants of the Green Alga Chlorella ellipsoidea).

A new method has been developed for screening algal photosynthetic mutants. This method uses autoradiography to assess gross photosynthetic 14C fixation by green algal colonies on agar plates and allows the identification of clones that differ in photosynthetic characteristics from wild-type cells. Three wild-type cells, high-CO2-grown Chlorella ellipsoidea, air-grown C. ellipsoidea, and air-grown Chlorella saccharophila, had K0.5 values for dissolved inorganic carbon (DIC) of 1083, 250, and 50 [mu]M, respectively, and as plaques on agar plates at Chl densities greater than 25 [mu]g cm-2 exhibited relative amounts of 14C fixation of 15, 55, and 100%, respectively. Cells of C. ellipsoidea were mutagenized with x-rays and screened by this method. Growth of C. ellipsoidea in high CO2 represses DIC transport and thus lowers its affinity for DIC. Five of the mutants detected by this method showed high-affinity photosynthesis similar to air-grown wild-type cells even when grown in high CO2. Seven other mutants when grown in high CO2 showed affinities for DIC intermediate between air-grown and high-CO2-grown wild-type cells. The affinities of high-CO2-grown mutants were reflected precisely in their capacities to accumulate DIC intracellularly. These results indicate that the mutants are fully or partially insensitive to the repressive effect of ambient CO2 concentration on DIC transport.

Identification of Distinct Internal and External Isozymes of Carbonic Anhydrase in Chlorella saccharophila.

External carbonic anhydrase (CA) was detected in whole cells of alkaline-grown Chlorella saccharophila but was suppressed by growth at acid pH or growth on elevated levels of CO2. Internal CA activity was measured potentiometrically as an increase in activity in cell extracts over that of intact cells. Cells grown under all conditions had equal levels of internal CA activity. Two isozymes were identified after electrophoretic separation of soluble proteins on cellulose acetate plates. The fast isozyme was found in cells grown under all conditions, whereas the slow isozyme was found only in cells grown at alkaline pH. Western blot analysis following sodium dodecyl sulfate-polyacrylamide gel electrophoresis using antibodies produced against the periplasmic form of CA from Chlamydomonas reinhardtii revealed a single band at 39 kD, which did not change in intensity between growth conditions and was associated only with proteins eluted from the fast band. The slow isozyme was inactivated by incubation of cell extract at 30[deg]C and by incubation in 10 mM dithiothreitol, whereas the internal form was unaffected. These results indicate that external and internal forms of CA differ in structure and their activities respond differently to environmental conditions.

Quantification of the Contribution of CO2, HCO3-, and External Carbonic Anhydrase to Photosynthesis at Low Dissolved Inorganic Carbon in Chlorella saccharophila.

An equation has been developed incorporating whole-cell rate constants for CO2 and HCO3- that describes accurately photosynthesis (Phs) in suspensions of unicellular algae at low dissolved inorganic carbon. At pH 8.0 the concentration of CO2 available to the algal cells depends on the rate of supply from, and the loss to, HCO3- and the rate of use by the cells. At elevated cell densities (>30 mg chlorophyll [Chl] L-1), at which CO2 use by the cells is high, the slope of a graph of absolute Phs versus Chl concentration approaches the rate of Phs on a milligram of Chl basis because of HCO3- use alone. The slope of a graph of Phs versus HCO3- will be the rate constant for HCO3-, and for Chlorella saccharophila it was 0.16 L mg-1 Chl h-1. The difference between the constants for dissolved inorganic carbon (measured in cells with external carbonic anhydrase) and HCO3-1 is the constant for CO2, which was 26 L mg-1 Chl h-1. This difference causes the half-saturation constant for Phs to increase 5- to 6-fold at high cell densities. The increase in CO2 use as a result of external carbonic anhydrase is described mathematically as a function of cell density.

Paraganglioma of the temporal bone in infancy. A congenital lesion?

Jugulotympanic glomus tumors have been called many things, but "paraganglioma of the temporal bone" is perhaps a more suitable term. This tumor is generally described as benign with a predilection for middle-aged women. Herein we report the case of an 11-month-old female infant with this condition. The extensiveness of the tumor with intracranial involvement at presentation suggests that the lesion might have been present for some time and raises the question of it being congenital in origin. We emphasize the overall importance of including paraganglioma of the temporal bone in the differential diagnosis of a "bleeding polyp" of the ear.

Meniére's disease. Electron microscopy of the vestibular ganglion and end organs after ultrasound.

Material for electron microscopy study was obtained from a patient previously suffering from Meniere's disease and treated by ultrasound. It consisted of parts of the membranous labyrinth as well as the vestibular ganglion. The neuro-epithelium of the macula showed degenerative changes and there was marked vacuolation of the cytoplasm. The endothelial cells lining the semicircular canal showed gross vacuoles contained degenerating mitochondria and some debris which may reach the endolymph. The wall of the semi circular canal was oedematous and the basement membrane lifted off by oedematous fluid. There was obvious change in nerves and neurones. The nerves showed loosening of the myelin sheath and ballooning. The neurones contained lipoid inclusions and multicystic lysosomes. Similar inclusions were also noted in some myelinated nerves.

Uptake and release of alcohol by homograft tissues in tympanoplasty.

Alcohol is known to produce severe cochlear damage and it is possible that deafness as a complication of tympanoplasty can be caused by alcohol which remains in homograft materials after inadequate washing. An investigation was made in which the quantity of alcohol taken up by ossicles, cartilage, temporalis fascia, dura and ear-drum was estimated. The rate of release of alcohol from such materials into saline during washing was also measured. The amount absorbed was found to depend upon the nature of the material, its weight and its surface area. The rate of release of alcohol from these materials differed significantly for each material.

Chemodectoma of the larynx.

Two cases of laryngeal chemodectoma are presented. They illustrate the differences between benign and malignant varieties of this tumour. The problem of differentiating between these two types at an early stage is discussed and a possible treatment policy is presented.

Nasal aspects of cystic fibrosis in children.

Despite the extraordinary prevalence of upper respiratory allergy and infection in children nasal polyposis is an extremely rare condition. Seven cases of cystic fibrosis are presented in order to demonstrate the nasal aspects of the disease. All but one had nasal polyposis. The literature has been reviewed with particular reference to clinical, radiological and histo-pathological features. Conservative treatment is stressed.

Massive acquired cholesteatoma of the temporal bone.

Nine patients with massive acquired cholesteatoma of the temporal bone were treated by radical mastoidectomy, facial nerve decompression, and excision of the inner ear. The commonest presenting symptoms were otorrhea and deafness, but otalgia, vertigo, external swelling and facial nerve palsies were also seen. Polytomography was helpful in assessing the degree of bone erosion preoperatively. The large cavity present following cholesteatoma excision was partially obliterated by a superiorly based temporalis muscle pedicle which helped to seal the internal auditory meatus and prevented the development of a cerebral hernia. Those patients with preoperative facial nerve palsies showed evidence of nerve degeneration and had incomplete recovery at a one year follow-up.