Improving management of ARDS: uniting acute management and long-term recovery.

Acute Respiratory Distress Syndrome (ARDS) is an important global health issue with high in-hospital mortality. Importantly, the impact of ARDS extends beyond the acute phase, with increased mortality and disability for months to years after hospitalization. These findings underscore the importance of extended follow-up to assess and address the Post-Intensive Care Syndrome (PICS), characterized by persistent impairments in physical, cognitive, and/or mental health status that impair quality of life over the long-term. Persistent muscle weakness is a common physical problem for ARDS survivors, affecting mobility and activities of daily living. Critical illness and related interventions, including prolonged bed rest and overuse of sedatives and neuromuscular blocking agents during mechanical ventilation, are important risk factors for ICU-acquired weakness. Deep sedation also increases the risk of delirium in the ICU, and long-term cognitive impairment. Corticosteroids also may be used during management of ARDS, particularly in the setting of COVID-19. Corticosteroids can be associated with myopathy and muscle weakness, as well as prolonged delirium that increases the risk of long-term cognitive impairment. The optimal duration and dosage of corticosteroids remain uncertain, and there's limited long-term data on their effects on muscle weakness and cognition in ARDS survivors. In addition to physical and cognitive issues, mental health challenges, such as depression, anxiety, and post-traumatic stress disorder, are common in ARDS survivors. Strategies to address these complications emphasize the need for consistent implementation of the evidence-based ABCDEF bundle, which includes daily management of analgesia in concert with early cessation of sedatives, avoidance of benzodiazepines, daily delirium monitoring and management, early mobilization, and incorporation of family at the bedside. In conclusion, ARDS is a complex global health challenge with consequences extending beyond the acute phase. Understanding the links between critical care management and long-term consequences is vital for developing effective therapeutic strategies and improving the quality of life for ARDS survivors.

A systematic review and meta-analysis of the clinimetric properties of the core outcome measurement instruments for clinical effectiveness trials of nutritional and metabolic interventions in critical illness (CONCISE).

BACKGROUND: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE. METHODS: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted. RESULTS: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high. CONCLUSIONS: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness. TRIAL REGISTRATION: PROSPERO (CRD42023438187). Registered 21/06/2023.

Core outcome measures for clinical effectiveness trials of nutritional and metabolic interventions in critical illness: an international modified Delphi consensus study evaluation (CONCISE).

BACKGROUND: Clinical research on nutritional and metabolic interventions in critically ill patients is heterogenous regarding time points, outcomes and measurement instruments used, impeding intervention development and data syntheses, and ultimately worsening clinical outcomes. We aimed to identify and develop a set of core outcome domains and associated measurement instruments to include in all research in critically ill patients. METHODS: An updated systematic review informed a two-stage modified Delphi consensus process (domains followed by instruments). Measurement instruments for domains considered 'essential' were taken through the second stage of the Delphi and a subsequent consensus meeting. RESULTS: In total, 213 participants (41 patients/caregivers, 50 clinical researchers and 122 healthcare professionals) from 24 countries contributed. Consensus was reached on time points (30 and 90 days post-randomisation). Three domains were considered 'essential' at 30 days (survival, physical function and Infection) and five at 90 days (survival, physical function, activities of daily living, nutritional status and muscle/nerve function). Core 'essential' measurement instruments reached consensus for survival and activities of daily living, and 'recommended' measurement instruments for physical function, nutritional status and muscle/nerve function. No consensus was reached for a measurement instrument for Infection. Four further domains met criteria for 'recommended,' but not 'essential,' to measure at 30 days post-randomisation (organ dysfunction, muscle/nerve function, nutritional status and wound healing) and three at 90 days (frailty, body composition and organ dysfunction). CONCLUSION: The CONCISE core outcome set is an internationally agreed minimum set of outcomes for use at 30 and 90 days post-randomisation, in nutritional and metabolic clinical research in critically ill adults.

Management of COVID-19 ICU-survivors in primary care: - a narrative review.

Many survivors of critical illness suffer from long-lasting physical, cognitive, and mental health sequelae. The number of affected patients is expected to markedly increase due to the COVID-19 pandemic. Many ICU survivors receive long-term care from a primary care physician. Hence, awareness and appropriate management of these sequelae is crucial. An interdisciplinary authorship team participated in a narrative literature review to identify key issues in managing COVID-19 ICU-survivors in primary care. The aim of this perspective paper is to synthesize important literature to understand and manage sequelae of critical illness due to COVID-19 in the primary care setting.

Versión chilena de la Functional Status Score for the Intensive Care Unit: traducción y adaptación transcultural / Chilean version of the Functional Status Score for the Intensive Care Unit: a translation and cross-cultural adaptation

INTRODUCCIÓN: La Functional Status Score for the Intensive Care Unit (FSS-ICU) es un instrumento válido y confiable para medir funcionamiento físico en unida-des de cuidados intensivos. Sin embargo, la traducción y adaptación trans-cultural de la FSS-ICU en Chile no ha sido publicada. OBJETIVO: Traducir y adaptar transculturalmente todos los documentos asociados de la FSS-ICU original para Chile. MÉTODO: Se utilizó como punto de partida la versión en español de la FSS-ICU, disponible en www.ImproveLTO.com. Esta versión se tradujo previamente junto a los desarrolladores originales de la FSS-ICU, siguiendo las recomen-daciones establecidas para este proceso. La versión de bolsillo chilena se desarrolló recientemente en base a la versión original en inglés. Se realizaron entrevistas cognitivas a kinesiólogos de la unidad de cuidados intensivos para evaluar la comprensión de la FSS-ICU y versión de bolsillo. Las adaptaciones se realizaron cuando el acuerdo entre los kinesiólogos fue inferior al 80%. RESULTADOS: Se realizaron las entrevistas cognitivas de la FSS-ICU en español (85 ítems) y versión de bolsillo (18 ítems) en 30 kinesiólogos chilenos provenientes de 18 diferentes hospitales (14 públicos y 4 privados). Durante las entrevistas se realizaron adaptaciones principalmente en las guías generales e instrucciones específicas para tres ítems de la FSS-ICU y dos ítems de la versión de bolsillo. Finalmente, se desarrollaron las preguntas frecuentes, la versión de bolsillo y la versión completa de la FSS-ICU. Todas las adaptaciones fueron aceptadas por los desarrolladores originales. CONCLUSIONES: La versión chilena de la FSS-ICU fue fácil de entender por los kinesiólogos. La FSS-ICU está disponible gratis para uso clínico e investigación no comercial en Chile.

BACKGROUND: The Functional Status Score for the Intensive Care Unit (FSS-ICU) is a valid and reliable instrument to measure physical functioning in the intensive care unit setting. Translation and cross-cultural adaptation in Chile has not been published for the FSS-ICU. AIM: To translate and cross-culturally adapt all associated documents of the original FSS-ICU for Chile. METHOD: The Spanish version of FSS-ICU, available at www.ImproveLTO.com, was used as the starting point. This version was previously translated, with the original FSS-ICU developers, following established guidelines for this process. The Chilean pocket card version was newly developed based on the English version at www.ImproveLTO.com. Cognitive interviews were conducted for the adaptation of the FSS-ICU and pocket card version to assess understanding of relevant stakeholders (i.e., Chilean intensive care unit physiotherapists). Adaptations to the translation were made when agreement among the physiotherapists was less than 80%. RESULTS: Cognitive interviews of the Chilean FSS-ICU (85 items) and pocket card version (18 items) were performed with 30 Chilean physiotherapists from 18 hospitals (14 public and 4 private). During the interviews, modest adaptations mainly made in the general guidelines and specific instructions for three items of the FSS-ICU and two items of the pocket card. Finally, the frequently asked questions, pocket card and full version of the FSS-ICU were developed. The original developers accepted all adaptations. CONCLUSIONS: The Chilean version of the FSS-ICU was easy to understand by the physiotherapists. The FSS-ICU is freely available for non-commercial clinical and research use by Chilean Spanish-speakers.

Surviving critical illness: what is next? An expert consensus statement on physical rehabilitation after hospital discharge.

BACKGROUND: The study objective was to obtain consensus on physical therapy (PT) in the rehabilitation of critical illness survivors after hospital discharge. Research questions were: what are PT goals, what are recommended measurement tools, and what constitutes an optimal PT intervention for survivors of critical illness? METHODS: A Delphi consensus study was conducted. Panelists were included based on relevant fields of expertise, years of clinical experience, and publication record. A literature review determined five themes, forming the basis for Delphi round one, which was aimed at generating ideas. Statements were drafted and ranked on a 5-point Likert scale in two additional rounds with the objective to reach consensus. Results were expressed as median and semi-interquartile range, with the consensus threshold set at ≤0.5. RESULTS: Ten internationally established researchers and clinicians participated in this Delphi panel, with a response rate of 80 %, 100 %, and 100 % across three rounds. Consensus was reached on 88.5 % of the statements, resulting in a framework for PT after hospital discharge. Essential handover information should include information on 15 parameters. A core set of outcomes should test exercise capacity, skeletal muscle strength, function in activities of daily living, mobility, quality of life, and pain. PT interventions should include functional exercises, circuit and endurance training, strengthening exercises for limb and respiratory muscles, education on recovery, and a nutritional component. Screening tools to identify impairments in other health domains and referral to specialists are proposed. CONCLUSIONS: A consensus-based framework for optimal PT after hospital discharge is proposed. Future research should focus on feasibility testing of this framework, developing risk stratification tools and validating core outcome measures for ICU survivors.

The effect of augmenting early nutritional energy delivery on quality of life and employment status one year after ICU admission.

Augmenting energy delivery during the acute phase of critical illness may reduce mortality and improve functional outcomes. The objective of this sub-study was to evaluate the effect of early augmented enteral nutrition (EN) during critical illness, on outcomes one year later. We performed prospective longitudinal evaluation of study participants, initially enrolled in The Augmented versus Routine approach to Giving Energy Trial (TARGET), a feasibility study that randomised critically ill patients to 1.5 kcal/ml (augmented) or 1.0 kcal/ml (routine) EN administered at the same rate for up to ten days, who were alive at one year. One year after randomisation Short Form-36 version 2 (SF-36v2) and EuroQol-5D-5L quality of life surveys, and employment status were assessed via telephone survey. At one year there were 71 survivors (1.5 kcal/ml 38 versus 1.0 kcal/ml 33; P=0.55). Thirty-nine (55%) patients consented to this follow-up study and completed the surveys (n = 23 and 16, respectively). The SF-36v2 physical and mental component summary scores were below normal population means but were similar in 1.5 kcal/ml and 1.0 kcal/ml groups (P=0.90 and P=0.71). EuroQol-5D-5L data were also comparable between groups (P=0.70). However, at one-year follow-up, more patients who received 1.5 kcal/ml were employed (7 versus 2; P=0.022). The delivery of 1.5 kcal/ml for a maximum of ten days did not affect self-rated quality of life one year later.

Well-posedness and qualitative behaviour of a semi-linear parabolic Cauchy problem arising from a generic model for fractional-order autocatalysis.

In this paper, we examine a semi-linear parabolic Cauchy problem with non-Lipschitz nonlinearity which arises as a generic form in a significant number of applications. Specifically, we obtain a well-posedness result and examine the qualitative structure of the solution in detail. The standard classical approach to establishing well-posedness is precluded owing to the lack of Lipschitz continuity for the nonlinearity. Here, existence and uniqueness of solutions is established via the recently developed generic approach to this class of problem (Meyer & Needham 2015 The Cauchy problem for non-Lipschitz semi-linear parabolic partial differential equations. London Mathematical Society Lecture Note Series, vol. 419) which examines the difference of the maximal and minimal solutions to the problem. From this uniqueness result, the approach of Meyer & Needham allows for development of a comparison result which is then used to exhibit global continuous dependence of solutions to the problem on a suitable initial dataset. The comparison and continuous dependence results obtained here are novel to this class of problem. This class of problem arises specifically in the study of a one-step autocatalytic reaction, which is schematically given by A→B at rate apbq (where a and b are the concentrations of A and B, respectively, with 0

An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults

RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.(AU)

Evaluation of two delirium screening tools for detecting post-operative delirium in the elderly.

BACKGROUND: Postoperative delirium in the elderly is common and associated with poor outcomes, but often goes unrecognized. Delirium screening tools, validated in postoperative settings are lacking. This study compares two screening tools [Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Nursing Delirium Symptom Checklist (NuDESC)] with a DSM-IV-based diagnosis of delirium, conducted by neuropsychiatric examination in postoperative settings. METHODS: Consecutive English-speaking patients, ≥70 yr, undergoing surgery with general anaesthesia and capable of providing informed consent, were recruited. Diagnostic test characteristics were compared for each screening tool vs neuropsychiatric examination, both in the Post-Anaesthesia Care Unit (PACU), and daily during inpatient hospitalization, adjusting for repeated measures. RESULTS: Neuropsychiatric examination identified delirium in 45% of 91 patients evaluated in the PACU and in 32% of 166 subsequent delirium assessments on the ward in the 58 admitted patients. The sensitivity [95% confidence interval (CI)] of delirium detection of the CAM-ICU in the PACU, and in all repeated assessments was 28% (16-45%) and 28% (17-42%), respectively; for the NuDESC (scoring threshold ≥2), 32% (19-48%) and 29% (19-42%), respectively, and the NuDESC (threshold ≥1), 80% (65-91%) and 72% (60-82%), respectively. Specificity was >90% for both the CAM-ICU and the NuDESC (threshold ≥2); specificity for the NuDESC (threshold ≥1), in the PACU was 69% (54-80%) and 80% (73-85%) for all assessments. CONCLUSIONS: While highly specific, neither CAM-ICU nor NuDESC (threshold ≥2) are adequately sensitive to identify delirium post-operatively; NuDESC (threshold ≥1) increases sensitivity, but reduces specificity.

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

BACKGROUND AND PURPOSE: Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity. EXPERIMENTAL APPROACH: The pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling. KEY RESULTS: GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, GW870086 showed comparable anti-inflammatory efficacy to FP. CONCLUSION AND IMPLICATIONS: GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

Post-traumatic stress disorder symptoms after acute lung injury: a 2-year prospective longitudinal study.

BACKGROUND: Survivors of critical illnesses often have clinically significant post-traumatic stress disorder (PTSD) symptoms. This study describes the 2-year prevalence and duration of PTSD symptoms after acute lung injury (ALI), and examines patient baseline and critical illness/intensive care-related risk factors. METHOD: This prospective, longitudinal cohort study recruited patients from 13 intensive care units (ICUs) in four hospitals, with follow-up 3, 6, 12 and 24 months after ALI onset. The outcome of interest was an Impact of Events Scale - Revised (IES-R) mean score ≥1.6 ('PTSD symptoms'). RESULTS: During the 2-year follow-up, 66/186 patients (35%) had PTSD symptoms, with the greatest prevalence by the 3-month follow-up. Fifty-six patients with post-ALI PTSD symptoms survived to the 24-month follow-up, and 35 (62%) of these had PTSD symptoms at the 24-month follow-up; 50% had taken psychiatric medications and 40% had seen a psychiatrist since hospital discharge. Risk/protective factors for PTSD symptoms were pre-ALI depression [hazard odds ratio (OR) 1.96, 95% confidence interval (CI) 1.06-3.64], ICU length of stay (for a doubling of days, OR 1.39, 95% CI 1.06-1.83), proportion of ICU days with sepsis (per decile, OR 1.08, 95% CI 1.00-1.16), high ICU opiate doses (mean morphine equivalent ≥100 mg/day, OR 2.13, 95% CI 1.02-4.42) and proportion of ICU days on opiates (per decile, OR 0.83, 95% CI 0.74-0.94) or corticosteroids (per decile, OR 0.91, 95% CI 0.84-0.99). CONCLUSIONS: PTSD symptoms are common, long-lasting and associated with psychiatric treatment during the first 2 years after ALI. Risk factors include pre-ALI depression, durations of stay and sepsis in the ICU, and administration of high-dose opiates in the ICU. Protective factors include durations of opiate and corticosteroid administration in the ICU.

The south-east Scotland dermatology workload study: 30 years' analysis.

BACKGROUND: Dermatological activity data have been collected for the same region of south-east Scotland (population 1·24 million), approximately every 5 years, since 1981. This has allowed assessment of trends in demand from primary and secondary care, and activity within secondary care dermatology services, assisting planning of dermatological services. OBJECTIVES: To quantify dermatology outpatient workload across the same population to allow comparison with previous studies for trends in practice. METHODS: During November 2010, a standardized proforma was completed for all National Health Service and private practice dermatology outpatient consultations. Demographic data, source and reason for referral, diagnoses, investigations, treatments and disposal were recorded, and comparisons made with five previous studies. RESULTS: A total of 5470 consultations were recorded: 2882 new and 2588 review patients (new to review ratio 1 : 0·9, male to female 1 : 1·3, mean age 49 years, range 1 month to 101 years). Ninety-one per cent of referrals came from primary care and 9% from secondary care. Fifty-eight per cent of referrals were for diagnosis and 32% for hospital management. Diagnostic concordance between referrer and dermatologist ranged from 94% for acne to 14% for melanoma. Benign tumours accounted for 30% of referrals, malignant tumours 13%, dermatitis 13·3%, psoriasis 6·2% and acne/rosacea 5%. The referral rate rose to 23·2/1000 population per annum, with the increase coming mainly from primary care. CONCLUSIONS: Demand for dermatology continues to increase: new referrals have risen by 134% in 30 years, with a 36% increase in the last 5 years, despite corresponding population increases of 5·3% and 3%, respectively.

Metabolism and excretion of piperonyl butoxide in the rat.

[14C]-piperonyl butoxide (PBO) was administered to male and female rats by gavage at a dose rate of 50 or 500 mg kg-1 body weight. In all cases, the radioactivity was rapidly excreted with 87-99% being found in the 0-48-h excreta and the majority of the dose (64.1-85.0%) being eliminated in faeces. The metabolism of PBO was complex with over 25 peaks of radioactivity being seen by radio-high-performance liquid chromatography (HPLC). Using HPLC/tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR), 12 urine metabolites were assigned structures together with four plus PBO in faeces. Metabolism occurred at two sites: the methylenedioxy ring, which opened to form a catechol that could then undergo methylation, and the 2-(2-butoxyethoxy)ethoxymethyl side-chain, which underwent sequential oxidation to a series of alcohols and acids. The identified metabolites accounted for approximately 60% of the administered dose.

Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog.

1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5 mg kg(-1) day(-1) and in dog is 1 mg kg(-1) day(-1). The maximum tolerated dose (MTD) in rat is 150 and 75 kg(-1) day(-1) for male and females, respectively. The MTD in dog is 7.5 mg kg(-1) day(-1) for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50 mg kg(-1) 14C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t(1/2) were 1.3-3.4 h for rat and 99-134 h for dog following a 5 or 50 mg kg(-1) dose, respectively. This led to large differences in the calculated AUC(0-infinity) 21-57 microg eq. h g(-1) for rat and 4889-5298 microg eq. h g(-1) for dog at 5 mg kg(-1), and 122-2358 microg eq. h g(-1) for rat and 34,110-44,296 microg eq. h g(-1) for dog at 50 mg kg(-1)). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24 h for the low dose and after 48 h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120 h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.

Evaluation of the effectiveness of UK community pharmacists' interventions in community palliative care.

INTRODUCTION: In 1997, the Royal Pharmaceutical Society of Great Britain Working Party reported that UK community pharmacists had a crucial role in effective medicines management and effective symptom control for those receiving palliative care in the community. However, prior to the integration of community pharmacists into the community palliative team, it is necessary to evaluate the effectiveness of their pharmaceutical interventions. AIM: To assess the effectiveness of community pharmacists' clinical interventions in supporting palliative care patients in primary care using an independent multidisciplinary panel review. METHODS: Patients with a life expectancy of less than 12 months were each registered with a single pharmacy and their consent was obtained for the community pharmacists to access their general practitioner (GP) case records. The community pharmacists received training in palliative pharmaceutical care and documenting interventions. The trained community pharmacists provided palliative pharmaceutical care to the recruited patients. At the end of a 10-month period, the clinical interventions were reviewed by an independent multidisciplinary expert panel consisting of a palliative care consultant, a Macmillan nurse (community palliative care nurse) and a hospital pharmacist with special interest in palliative care. RESULTS: Fourteen community palliative care teams (including community pharmacists, GPs and community nurses) took part in the study and 25 patients were recruited over the 10-month recording period. All but one patient had a diagnosis of cancer; the other patient had chronic obstructive pulmonary disease. By the end of the project, 14 patients had died. Community pharmacists recorded a total of 130 clinical interventions. Thirty interventions were excluded as insufficient information had been documented to allow review by the panel. Eighty-one per cent of the interventions were judged by the expert panel likely to be beneficial. However, 3% were judged likely to be detrimental to the patients' well-being. CONCLUSIONS: Most of the clinical interventions made by the community pharmacists for palliative pharmaceutical care were judged by the expert panel as being likely to be beneficial. The result supports the view that when community pharmacists are appropriately trained and included as integrated members of the team, they can intervene effectively to improve pharmaceutical care for palliative care patients.

The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors.

Our laboratories have been working together in close collaboration for over 10 years concerning the design and performance of lipid-based drug delivery systems. Over the past 3 years we have conceived of, developed, and tested pre-clinically, a new liposome-based temperature-sensitive drug delivery system for the treatment of solid tumors. This work is reported in a series of four publications: "J. Liposome Res. 9 (1999) 491; Cancer Res. Adv. Brief 60(5) (2000) 1197; Cancer Res. 6(9) (2000) 748; and Cancer Res. 60 (2000) 6950". Following a brief introduction concerning the motivations behind the work, this article will review these studies, including some of our earlier work that led to these ideas, and will present the rational design of the new liposome formulation from a materials engineering perspective.

Toronto Critical Care Medicine Symposium, 18-20 October 2001, Canada: research breakthroughs are not enough.

At the 2001 Toronto Critical Care Medicine Symposium, exciting new research results were presented, including a randomized trial of peri-operative pulmonary-artery catheter use and evidence-based guidelines for the prevention of ventilator-acquired pneumonia. Presenters reviewed other important recent critical care developments such as (1) activated protein C and low-dose steroids in sepsis, (2) prone positioning and long-term outcomes in patients with adult respiratory distress syndrome, and (3) medical errors in the critical care unit. Along with these new findings, another theme emerged during the symposium. This theme emphasized that research breakthroughs are not sufficient in themselves: outcome studies are needed to learn how new research is applied on a large-scale basis within actual clinical practice. Furthermore, additional study is needed for an understanding of how physicians implement new research findings. Successful methods of enhancing the widespread adoption of new research require further study.