Search

Background Frailty is common among acute hospital patients and might adversely affect recovery from inpatient cardiac arrest. Aim To assess the relationship between hospital admission characteristics, including frailty, and discharge outcome after in-hospital cardiac arrest. Methods Prospectively collected data were retrospectively analysed for all separations from a tertiary hospital during 2008-2017 that involved rapid response team attendance for cardiac arrest. Hospital Frailty Risk Score (HFRS) and Charlson index of comorbidity were calculated from 'primary' and 'associated' International Classification of Diseases, 10th revision, Australian Modification diagnoses. HFRS ≥5 was taken to signify frailty. Discharge home from hospital and death in hospital were modelled using logistic regression. Results There were 388 in-hospital arrest patients: 91% were aged ≥50 years, 34% were previously discharged in the past 6 months, 66% were unplanned admissions, 63% were non-cardiology-cardiothoracic admissions, 45% had a Charlson comorbidity index ≥2 and 19% were identified as frail. Discharge home occurred in 22%, discharge to another hospital 17% and death 62%. Of the frail patients, only 3 (4%) were discharged home, 12 (17%) were discharged to another hospital and 57 (79%) died in hospital. Fewer frail patients were discharged home compared with non-frail patients (4 vs 26%; odds ratio (OR) 0.13, P = 0.001). On multivariable analysis, patients were less likely to be discharged home if they had frailty (OR 0.24, P = 0.02), age ≥ 50 years (OR 0.36, P = 0.01), non-cardiology-cardiothoracic unit admission (OR 0.40, P = 0.001) and unplanned admission (OR 0.57, P = 0.04). Frail patients discharged to another hospital spent a median of 15 days (interquartile range 11-23) in the hospital post-arrest before leaving to continue inpatient care elsewhere. Frailty was associated with death in hospital on univariate analysis (79 vs 58%; OR 2.80, P = 0.001) but not after controlling for other factors. Conclusion Frail patients are unlikely to make a good recovery after in-hospital arrest. This should be taken into account when planning care with patients and their families.

Summary Background Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. Methods The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . Findings Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI −4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference −0·14 [–0·26 to −0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). Interpretation In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. Funding Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.

Aims: inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID‐19. UFH has antiviral effects and prevents the SARS‐CoV‐2 virus' entry into mammalian cells. In addition, UFH has significant anti‐inflammatory and anticoagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis.Methods: the INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID‐19 (INHALE‐HEP) metatrial is a prospective individual patient data analysis of on‐going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS‐CoV‐2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the metatrial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time‐to‐event analyses. Individual studies may have additional outcomes.Analysis: we use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention‐to‐treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow‐up or withdrawn.Trial registration, ethics and dissemination: the metatrial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board. Results of this study will be shared with the World Health Organisation, published in scientific journals and presented at scientific meetings.

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

IntroductionCOVID-19 is associated with the development of ARDS displaying the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. The anti-coagulant actions of nebulised heparin limit fibrin deposition and progression of lung injury. Serendipitously, unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents its entry into mammalian cells. Nebulisation of heparin may therefore limit both fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. For these reasons we have initiated a multi-centre international trial of nebulised heparin in patients with COVID-19.Methods and interventionMechanically ventilated patients with confirmed or strongly suspected SARS-CoV-2 infection, hypoxaemia and an acute pulmonary opacity in at least one lung quadrant on chest X-ray, will be randomised to nebulised heparin 25,000 Units every 6 hours or standard care for up to 10 days while mechanically ventilated. The primary outcome is the time to separation from invasive ventilation to day 28, where non-survivors to day 28 are treated as though not separated from invasive ventilation.Ethics and disseminationThe study protocol has been submitted to the human research and ethics committee of St Vincent’s Hospital, Melbourne, Australia. Submission is pending in other jurisdictions. Results of this study will be published in scientific journals and presented at scientific meetings.Trial RegistrationACTRN: 12620000517976

Objectives To evaluate the introduction of a document for recording the resuscitation plans of patients at a tertiary hospital. The ‘Acute Resuscitation Plan’ (ARP) was introduced in September 2014, superseding the ‘Not for Cardiopulmonary Resuscitation (CPR)’ form. Unlike the Not for CPR form, the ARP was relevant to patients with and without resuscitation limits. Design Retrospective audit of the records of all admissions to the hospital from January-June 2014 (Not for CPR period) and January-June 2015 (ARP period). Main outcomes Incidence of resuscitation plans; proportion of ARPs specifying consultation with the patient (or representative) and with senior medical staff and; proportion of ARPs among older patients and those with significant comorbidity. Results Resuscitation plans were present for 453/23,325 (1.9%) admissions in the Not for CPR period vs. 1,801/24,037 (7.5%) in the ARP period (OR 4.1, 95%CI 3.7-4.5, P

The purpose of this study is to compare cases of rapid response team (RRT) review for early deterioration (48 hours after admission), intermediate deterioration (48 to168 hours after admission), late deterioration (≥168 hours after admission), and cardiac arrest and to determine the association between duration of hospitalization before RRT review and mortality.This is a retrospective cohort study of RRT cases from a single hospital over 5 years (2009-2013) using administrative data and data for the first RRT attendance of each hospital episode.Of 2843 RRT cases, 971 (34.2%) were early deterioration, 917 (32.3%) intermediate, 775 (27.3%) late, and 180 (6.3%) cardiac arrest. Compared with early deterioration patients, late deterioration patients were older (median, 71 vs 69 years; P = .005), had a higher Charlson comorbidity index (median, 2 vs 1; P.001), more often had RRT review for respiratory distress (32.5% vs 23.5%; P.001), more often received RRT-initiated not for resuscitation orders (8.4% vs 3.9%; P.001), less often were discharged directly home (27.9% vs 58.4%; P.001), and more often died in hospital (30.6% vs 12.8%; P.001). Compared with early deterioration and adjusted for confounders, the odds ratio of death in hospital for late deterioration was 2.36 (1.81-3.08; P.001).Late deterioration is frequently encountered by the RRT and, compared with early deterioration, is associated with greater clinical complexity and a worse hospital outcome.

To describe the frequency and hospital mortality of problems (diagnoses) encountered by a rapid response team (RRT), and to identify the most common diagnoses for RRT triggers and for treating units.For each RRT event in 2015 at a tertiary hospital for adults, we chose the diagnosis that best explained the RRT event from a pre-defined list after reviewing relevant test results and clinical notes.There were 937 RRT events during 700 admissions and there were 58 different RRT diagnoses in 11 diagnosis groups. The largest groups were neurological and consciousness problems (22.9%), circulatory problems (19.0%) and breathing problems (16.0%). The most common diagnoses were rapid atrial fibrillation (7.6%) and oversedation or narcosis (4.8%). When SpOThe RRT activation trigger provides only a general indication of the diagnosis. Some problems appear preventable and could provide a focus for unit-based quality initiatives. The mortality of some diagnoses is substantial, and this may help in setting treatment goals, but more work is needed to understand the association of RRT diagnosis and outcome.

The 'Acute Resuscitation Plan' (ARP) is a document for recording the resuscitation plans of patients at a tertiary hospital for adult patients. The ARP was introduced at the hospital in September 2014, superseding the 'Not for Cardiopulmonary Resuscitation (CPR)' form. Unlike the Not for CPR form, the ARP was relevant to patients with and without resuscitation limits.To evaluate the introduction of the ARP.This study is a retrospective audit of the records of all admissions to the hospital from January to June 2014 (Not for CPR period) and January to June 2015 (ARP period). The main outcomes are the incidence of resuscitation plans, the proportion of ARP specifying consultation with the patient (or representative) and with senior medical staff, and the proportion of ARP among older patients and those with significant comorbidity.Resuscitation plans were present for 453 of 23 325 (1.9%) admissions in the Not for CPR period versus 1801 of 24 037 (7.5%) in the ARP period (odds ratio (OR) 4.1, 95% confidence interval (CI) 3.7-4.5, P0.001). A total of 42% of ARP specified 'care of the dying' in the event of arrest. Acknowledgement of the views of the patient (or representative) was indicated on 37% of ARP and of a senior physician on 28%. An ARP was not present for 67% of patients aged ≥90 years, 59% from aged care, 90% with metastatic cancer and 64% aged ≥80 years and with a Charlson comorbidity index ≥3.More patients had resuscitation plans after introducing the ARP. However, patients and senior physicians were often remote from the consultation process, and an ARP was not present for many patients likely to have a poor outcome from cardiopulmonary arrest.

a b s t r a c t We aimed to describe the characteristics of medical emergencies that occurred in the medical imaging department (MID) of a university hospital in Melbourne, Australia. A database of 'Respond Medical Emergency Team (MET)' and 'Respond Blue' calls was retrospectively examined for the period June 2003 to November 2010 in relation to events that occurred in the MID. The hospital medical imaging database was also examined in relation to these events and, where necessary, patients' notes were reviewed. Ethics approval was granted by the hospital ethics review board. There were 124 medical emergency calls in the MID during the study period, 28% Respond Blue and 72% Respond MET. Of these 124 calls, 26% occurred outside of usual work hours and 12% involved cardiac arrest. The most common reasons for the emergency calls were seizures (14%) and altered conscious state (13%). Contrast anaphylaxis precipitated the emergency in 4% of cases. In 83% of cases the emergency calls were for patients attending the MID for diagnostic imaging, the remainder being for a procedure. Of the scheduled imaging techniques, 45% were for computed tomog- raphy. The scheduled imaging was abandoned due to the emergency in 12% of cases. When performed, imaging informed patient management in 34% of cases in diagnostic imaging and in all cases in the context of image-guided procedures. Medical emergency calls in the MID often occurred outside usual work hours and were attributed to a range of medical problems. The emergencies occurred in relation to all imaging techniques and imaging informed patient management in many cases.

The goals were to collaborate with the MSX project and make the MSX platform reliable with a performance where pulsed polarimetry would be capable of adding a useful measurement and then to achieve a first measurement using pulsed polarimetry. The MSX platform (outside of laser blow off plasmas adjacent to magnetic fields which are low beta) is the only device that can generate high-beta magnetized collisionless supercritical shocks, and with a large spatial size of ~10 cm. Creating shocks at high Mach numbers and investigating the dynamics of the shocks was the main goal of the project. The MSX shocks scale to astrophysical magnetized shocks and potentially throw light on the generation of highly energetic particles via a mechanism like the Fermi process.

Treatment with drugs from multiple classes induces vascular injury with medial necrosis, hemorrhage, endothelial damage, and inflammation. Previous research has suggested early events might be occurring well in advance of the full lesions that appear forty-eight to seventy-two hours after dosing with SCH 351591, a PDE IV inhibitor. This study was performed to study early events in detail. Rats were dosed with 20 mg/kg of drug by gavage and sacrificed at times between fifteen and 240 minutes after dosing. Tissues were collected for histopathological analysis and gene expression studies. Serum was collected for biomarker analysis. The data from biomarker analysis showed a three-part response with an early phase that was maximal at fifteen to thirty minutes, a second phase from forty-five to 180 minutes, and the third phase that was starting to rise at four hours. The first phase included increases in lymphocytes, serum histamine, and serum nitrite. The second phase shows continued elevation of serum nitrite. The third phase was marked by an increase in serum GRO/CINC-1. At fifteen minutes, histopathology showed activation of mast cells, but not degranulation. Increases in endothelial activation and perivascular inflammatory cells were first apparent at thirty minutes and increased through 240 minutes.

The genotoxicity testing battery is highly sensitive for detection of chemical carcinogens. However, it features a low specificity and provides only limited mechanistic information required for risk assessment of positive findings. This is especially important in case of positive findings in the in vitro chromosome damage assays, because chromosome damage may be also induced secondarily to cell death. An increasing body of evidence indicates that toxicogenomic analysis of cellular stress responses provides an insight into mechanisms of action of genotoxicants. To evaluate the utility of such a toxicogenomic analysis we evaluated gene expression profiles of TK6 cells treated with four model genotoxic agents using a targeted high density real-time PCR approach in a multilaboratory project coordinated by the Health and Environmental Sciences Institute Committee on the Application of Genomics in Mechanism-based Risk Assessment. We show that this gene profiling technology produced reproducible data across laboratories allowing us to conclude that expression analysis of a relevant gene set is capable of distinguishing compounds that cause DNA adducts or double strand breaks from those that interfere with mitotic spindle function or that cause chromosome damage as a consequence of cytotoxicity. Furthermore, our data suggest that the gene expression profiles at early time points are most likely to provide information relevant to mechanisms of genotoxic damage and that larger gene expression arrays will likely provide richer information for differentiating molecular mechanisms of action of genotoxicants. Although more compounds need to be tested to identify a robust molecular signature, this study confirms the potential of toxicogenomic analysis for investigation of genotoxic mechanisms.

Differences in hybridization platforms used in gene array analysis experiments can lead to significant differences in hybridization results. In this study we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to investigate discrepant results between the National Institute of Environmental Health Sciences cDNA and Affymetrix oligo platforms used to evaluate hepatic gene expression changes in rats exposed to methapyrilene. Caldesmon cDNA platform hybridization results showed decreases in gene expression levels for the high-dose methapyrilene 7-day pooled samples compared with their controls. By contrast, the Affymetrix oligonucleotide platform showed increases in expression levels for these samples. Quantitative gene expression measurements provide an explanation for the discrepancies observed for these samples. In the case of caldesmon, there is a 74-base sequence in the cDNA clone that is absent in the Affymetrix sequence. The amplicon based on the cDNA clone shows > 100-fold suppression relative to the day 7 high-dose methapyrilene-pooled control. These data demonstrate the importance of using a "gold standard," such as qRT-PCR to confirm key hybridization results as well as to understand the sources of discrepancies resulting from different hybridization platforms.

Purpose. A conventional approach to assess cytochrome P450 (CYP) induction in preclinical animal models involves daily dosing for a least a week followed by Western blot and/or enzyme activity analysis. To evaluate the potential benefit of a third more specific and sensitive assay, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), with the objective of reducing the duration of the conventional 1-week study, we simultaneously assessed gene expression by qRT-PCR along with Western blots and enzyme activity assays as a time course in an in vivo model.

The 14-bed intensive care unit of a tertiary referral hospital adopted a guideline to start docusate sodium with sennosides when enteral nutrition was started. This replaced a guideline to start aperients after 24h of enteral nutrition if no bowel action had occurred. We sought to determine the effect of this change on the incidence of diarrhoea and constipation in intensive care.Retrospective audit of the medical records of consecutive adult patients admitted to intensive care and given enteral nutrition, excluding those with a primary gastrointestinal system diagnosis, between Jan-Aug 2011 (the delayed group, n=175) and Jan-Aug 2012 (the early group, n=175). The early aperient guideline was implemented during Sep-Dec 2011.The early and delayed groups were similar in age (median 62 years vs. 64 years; P=0.17), sex (males 65% vs. 63%; P=0.91), and postoperative cases (31% vs. 33%; P=0.82) and had similar proportions who received mechanical ventilation (95% vs. 95%; P=1.00), an inotrope or vasopressor (63% vs. 70%; P=0.17), renal replacement therapy (8% vs. 10%; P=0.71), opiates (77% vs. 80%; P=0.60), antibiotics (89% vs. 91%; P=0.72) and metoclopramide (46% vs. 55%; P=0.11). A significantly larger proportion of the early group received an aperient (54% vs. 29%, P0.001) and experienced diarrhoea (38% vs. 27%, P=0.04), but the groups had similar proportions affected by constipation (42% vs. 43%, P=0.91).Changing guidelines from delayed to early aperient administration was associated with an increase in the incidence of diarrhoea but was not associated with the incidence of constipation. These findings do not support changing guidelines from delayed to early aperient administration.

To compare the admission characteristics, discharge destination and mortality of patients reviewed by the rapid response team (RRT) for deterioration with those of other hospital patients; and to determine the association between RRT review for deterioration and mortality.Acute admissions of adult patients to a tertiary hospital between 1 January 2008 and 31 December 2011 were identified from administrative data. Data for each patient's first admission were merged with RRT data on the first RRT event of each admission, if any. RRT events involving cardiac arrest were classified as arrest events and all others as deterioration events.Of 43 385 patients in the cohort, 1117 (2.57%) had RRT review for deterioration and 91 (0.21%) for cardiac arrest. Deterioration events occurred a median of 3.23 days after admission. Advanced treatments were instituted in 38.59% of deterioration events, and a new not-for resuscitation order for 5.55%. Compared with those not reviewed by the RRT, patients in the deterioration group were older (median, 70 v 60 years, P0.001) and had a higher Charlson comorbidity index (median, 1 v 0, P0.001). They also more often died in hospital (18.80% v 1.42%, P0.001) or were discharged to another hospital (37.51% v 13.39%, P0.001) and more often died in the 90 days after admission (24.44% v 3.48%, P0.001). Their adjusted odds ratio of death in the 90 days after admission was 5.85 (95% CI, 4.97-6.89, P0.001).Patients reviewed for deterioration were older and had greater comorbidity than patients the RRT was not called to review. RRT review for deterioration was an independent risk factor for mortality.

To determine the effect of spending time as an outlier (ie, an inpatient who spends time away from his or her "home" ward) on the frequency of emergency calls for patients admitted to a tertiary referral hospital.Observational cohort study of all patients admitted to a university-affiliated tertiary referral hospital in Melbourne, Victoria, between 1 July 2009 and 30 November 2011.The number of emergency calls per hospital admission, with reference to location within the hospital.There were 58,158 admissions during the study period. The median age of admitted patients was 61 years, 55% were male, and the inhospital mortality was 1.40%. In 11,034 admissions (18.97%), patients spent time as outliers. Inhospital mortality was 2.57% in the outlier group versus 1.12% in the non-outlier group (P0.001). After adjusting for age, same-day admission, 10-year predicted mortality, interhospital transfer and high-risk clinical units, outlier status was associated with a 53% increase in emergency calls (P0.001).This study found a strong association between time spent away from a patient's home ward and the number of emergency calls. We postulate that outlier patients are at risk as they may have therapeutic and monitoring needs that are only available on their home ward. With increasing pressure to move patients out of the emergency department, the number of outlier patients may increase.

Aims To evaluate the effect of automated external defibrillators (AEDs) on patient survival and to describe the performance of AEDs after in-hospital cardiac arrest. Methods Prospectively collected data were analysed for cardiac arrests in the general patient care areas of a teaching hospital during the 3 years before and the 3 years after the deployment of AEDs. The association between availability of an AED and survival to hospital discharge was assessed using multivariate logistic regression. AED performance during automated management of the initial rhythms was assessed using information captured by the AEDs. Results There were 84 cardiac arrests in the AED period and 82 in the pre-AED period. Patient and event characteristics were similar in each period. The initial rhythm was shockable in 16% of cases. Return of spontaneous circulation was higher in the AED period (54% vs. 35%, P = 0.02) but the proportion of hospital survivors in each period was similar (22% vs. 19%, P = 0.56). The adjusted odds ratio for hospital survival when an AED was available was 1.22 (95% CI 0.53–2.84, P = 0.64). An AED was applied in 77/84 (92%) possible cases. Median interruption to chest compressions was 12 s (inter-quartile range 12–13). An automated shock was delivered in 8/13 (62%) possible cases. Conclusions Availability of AEDs was not independently associated with hospital survival. Shockable presenting rhythms were not common and, in keeping with the manufacturer's specifications, the AEDs did not shock all potentially shockable rhythms. The hands-off time associated with automated rhythm management was considerable.

To evaluate the effect of the introduction of automated external defibrillators (AEDs) on survival after inhospital cardiac arrest.Before-and-after study that compared patients during the 2 years before (8 November 2005 to 7 November 2007) and the year after (8 November 2007 to 7 November 2008) the deployment of AEDs to the non-critical care areas of a university teaching hospital.Return of spontaneous circulation (ROSC) and survival to hospital discharge.55 in-hospital cardiac arrests occurred in the 2-year pre-AED period and 31 in the 1-year AED period. Patients had similar baseline characteristics in the pre-AED and AED periods including witnessed arrest (53% v 48%), arrest in an acute inpatient ward (78% v 90%), and initial arrest rhythm of pulseless ventricular tachycardia or ventricular fibrillation (18% v 16%). The proportions of patients with ROSC were similar in the pre-AED and AED periods (42% v 55%), as were the proportions who survived to hospital discharge (22% v 29%). In the AED period, the relative risk of ROSC was 1.31 (95% CI, 0.84- 2.04) and the relative risk of survival to hospital discharge was 1.33 (95% CI, 0.63-2.80).ROSC and survival to hospital discharge did not change significantly after deployment of AEDs. The existence of a timely and robust resuscitation response with relatively good baseline outcomes, and the low proportion of initial shockable arrest rhythms may have limited the capacity of AEDs to improve survival.

Assessment of cytochrome P450 (CYP) induction at the mRNA level in preclinical rodent studies has gained interest in recent years, but there are still concerns regarding correlations between the mRNA and the enzyme activity levels, especially in mice. The purpose of the present study was to systematically evaluate patterns of temporal changes of CYPs 1a1, 1a2, 2b10, 3a11, and 4a10 at mRNA, protein, and activity levels in order to determine to what extent mRNA levels could be used either qualitatively or quantitatively for the assessment of CYP enzyme induction. In this study, livers from male CD-1 mice treated daily with beta-naphthoflavone, phenobarbital, dexamethasone, clofibrate, and control vehicles were collected for RNA and microsomal analysis after 0.5, 1, 2, 4, and 8 days of daily dose. The results revealed a good correlation among mRNA, protein, and enzyme activity levels, with the best correlation at the time points between Days 2 and 8, suggesting that the appropriate time to monitor CYP mRNA may be beyond Day 2 of chemical treatments. Based on these results, we concluded that the mRNA approach is a useful tool to monitor CYP induction in mice, particularly when treatment duration is beyond 2 days.

Drug-associated vascular injury can be caused by phosphodiesterase (PDE) IV inhibitors and drugs from several other classes. The pathogenesis is poorly understood, but it appears to include vascular and innate immunological components. This research was undertaken to identify changes in peripheral blood associated with vascular injury caused by PDE IV inhibitors. We evaluated twelve proteins, serum nitrite, and leukocyte populations in peripheral blood of rats treated with experimental PDE IV inhibitors. We found that these compounds produced histological microvascular injury in a dose- and time-dependent manner. Measurement of these serum proteins showed changes in eight of the twelve examined. Changes were seen in the levels of: tissue inhibitor of metalloproteinase-1, α1-acid glycoprotein, GRO/CINC-1, vascular endothelial growth factor, C-reactive protein, haptoglobin, thrombomodulin, and interleukin-6. No changes were seen in levels of tumor necrosis factor-α, hepatocyte growth factor, nerve growth factor, and granulocyte-monocyte colony stimulating factor. Serum levels of nitrite were also increased. Circulating granulocyte numbers were increased, and lymphocyte numbers were decreased. The changes in these parameters showed both a dose- and time-dependent association with histopathologic changes. These biomarkers could provide an additional tool for the nonclinical and clinical evaluation of investigational compounds.

Drug-induced renal injury is a common finding in the early preclinical phase of drug development. But the specific genes responding to renal injury remain poorly defined. Identification of drug-induced gene changes is critical to provide insights into molecular mechanisms and detection of renal damage. To identify genes associated with the development of drug-induced nephrotoxicity, a literature survey was conducted and a panel of 48 genes was selected based on gene expression changes in multiple published studies. Male Sprague-Dawley rats were dosed daily for 1, 3 or 5 days to the known nephrotoxicants gentamicin, bacitracin, vancomycin and cisplatin, or the known hepatotoxicants ketoconazole, 1-naphthyl isothiocyanate and 4,4-diaminodiphenylmethane. Histopathological evaluation and clinical chemistry revealed renal proximal tubular necrosis in rats treated with the nephrotoxicants, but not from those treated with the hepatotoxicants. RNA was extracted from the kidney, and RT-PCR was performed to evaluate expression profiles of the selected genes. Among the genes examined, 24 genes are confirmed to be highly induced or repressed in rats treated with nephrotoxicants; further investigation identified that 5 of the 24 genes were also altered by hepatotoxicants. These data led to the identification of a set of genomic biomarker candidates whose expression in kidney is selectively regulated only by nephrotoxicants. Among those genes displaying the highest expression changes specifically in nephrotoxicant-treated rats were kidney injury molecule 1 (Kim1), lipocalin 2 (Lcn2), and osteopontin (Spp1). The establishment of such a genomic marker set offers a new tool in our ongoing quest to monitor nephrotoxicity.

Gene expression patterns using microarrays have been described for rodent models of nephrotoxicity. To determine if significant gene expression changes previously identified have application across multiple species, we studied quantitative gene expression changes in the kidneys of female cynomolgus monkeys after exposure to two nephrotoxicants. Animals were dosed with the aminoglycoside gentamicin (10 mg/kg), the experimental oligosaccharide antibiotic everninomicin (30 or 60 mg/kg), or a combination of gentamicin (10 mg/kg) and everninomicin (30 mg/kg) for 7 days. Monkeys receiving these drugs in combination developed renal lesions as early as Day 1. By Day 7, monkeys dosed with 60 mg/kg everninomicin alone also developed renal lesions, while the group exposed to both compounds had more extensive renal damage. The modulation of several genes previously reported to be associated with nephrotoxicity in rodent models was confirmed using quantitative real-time PCR. Among these, waf-1, matrix metalloproteinase-9, and vimentin exhibited changes consistent with the definition of a genomic indicator of toxicity. In addition, we identified three early gene biomarkers that may be predictive of drug-induced nephrotoxicity: clusterin, osteopontin, and hepatitis A virus cellular receptor-1. Logistic regression demonstrated a high degree of correlation between changes in gene expression and the probability of the development of histopathologic lesions. These results are the first confirming rodent gene expression changes associated with nephrotoxicity in a nonhuman primate model and provide preliminary evidence for identifying early gene expression changes predicting the onset of drug-induced renal tubular damage in cynomolgus monkeys.

Cardiac surgery with cardiopulmonary bypass triggers an acute inflammatory response in the lungs. This response gives rise to fibrin deposition in the microvasculature and alveoli of the lungs. Fibrin deposition in the microvasculature increases alveolar dead space, while fibrin deposition in alveoli causes shunting. We investigated whether prophylactic nebulised heparin could limit this form of lung injury. We undertook a single-centre double-blind randomised trial. Forty patients undergoing elective cardiac surgery with cardiopulmonary bypass were randomised to prophylactic nebulised heparin (50,000 U) or placebo. The primary endpoint was the change in arterial oxygen levels over the operative period. Secondary endpoints included end-tidal CO2, the alveolar dead space fraction and bleeding complications. We found nebulised heparin did not improve arterial oxygen levels. Nebulised heparin was, however, associated with a lower alveolar dead space fraction ( P 2 elimination at the end of surgery.

INTRODUCTION: Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulised heparin improved lung function in patients expected to require prolonged mechanical ventilation.METHODS: Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomised placebo-controlled trial of nebulised heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomisation.RESULTS: Nebulised heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point ventilator free days amongst survivors at day 28 (22.6 4.0 versus 18.0 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.CONCLUSIONS: Nebulised heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings. Trial registration: The Australian Clinical Trials Registry (ACTR-12608000121369)