Identification and assessment of potentially high-mortality intensive care units using the ANZICS Centre for Outcome and Resource Evaluation clinical registry.

PURPOSE: A hospital's highest-risk patients are managed in the intensive care unit. Outcomes are determined by patients' severity of illness, existing comorbidities and by processes of care delivered. The Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE) manages a binational clinical registry to benchmark performance, and report and assess ICUs which appear to have worse outcomes than others. METHODS: A descriptive retrospective cohort study was undertaken to detail processes, outcomes, limitations and practical lessons learnt from monitoring ICU performance throughout Australia and New Zealand. All ICUs contributing to the ANZICS Adult Patient Database between 2009 and 2014 were included. A potential outlier ICU was defined as one with a statistically significantly higher standardised mortality ratio (SMR) than its peer group. RESULTS: There were 757 188 admissions to 168 ICUs. Of these, 27 ICUs (16%) were identified as potential outlier ICUs at least once. Data quality problems led to inaccurate or artificially elevated SMRs at 16/27 ICUs. Variation in diagnostic casemix partly or completely explained the elevated SMR at 15/27 ICUs. At nine ICUs where data quality and casemix differences did not explain the elevated SMR, process-of-care problems were identified. CONCLUSIONS: A combination of routine monitoring techniques, statistical analysis and contextual interpretation of findings is required to ensure potential outlier ICUs are appropriately identified. This ensures engagement and understanding from clinicians and jurisdictional health departments, while contributing to the improvement of ICU practices throughout Australia and New Zealand.

Timing of onset and burden of persistent critical illness in Australia and New Zealand: a retrospective, population-based, observational study.

BACKGROUND: Critical care physicians recognise persistent critical illness as a specific syndrome, yet few data exist for the timing of the transition from acute to persistent critical illness. Defining the onset of persistent critical illness as the time at which diagnosis and illness severity at intensive care unit (ICU) arrival no longer predict outcome better than do simple pre-ICU patient characteristics, we measured the timing of this onset at a population level in Australia and New Zealand, and the variation therein, and assessed the characteristics, burden of care, and hospital outcomes of patients with persistent critical illness. METHODS: In this retrospective, population-based, observational study, we used data for ICU admission in Australia and New Zealand from the Australian and New Zealand Intensive Care Society Adult Patient Database. We included all patients older than 16 years of age admitted to a participating ICU. We excluded patients transferred from another hospital and those admitted to an ICU for palliative care or awaiting organ donation. The primary outcome was in-hospital mortality. Using statistical methods in evenly split development and validation samples for risk score development, we examined the ability of characteristics to predict in-hospital mortality. FINDINGS: Between Jan, 2000, and Dec, 2014, we studied 1 028 235 critically ill patients from 182 ICUs across Australia and New Zealand. Among patients still in an ICU, admission diagnosis and physiological derangements, which accurately predicted outcome on admission (area under the receiver operating characteristics curve 0·898 [95% CI 0·897-0·899] in the validation cohort), progressively lost their predictive ability and no longer predicted outcome more accurately than did simple antecedent patient characteristics (eg, age, sex, or chronic health status) after 10 days in the ICU, thus empirically defining the onset of persistent critical illness. This transition occurred between day 7 and day 22 across diagnosis-based subgroups and between day 6 and day 15 across risk-of-death-based subgroups. Cases of persistent critical illness accounted for only 51 509 (5·0%) of the 1 028 235 patients admitted to an ICU, but for 1 029 345 (32·8%) of 3 138 432 ICU bed-days and 2 197 108 (14·7%) of 14 961 693 hospital bed-days. Overall, 12 625 (24·5%) of 51 509 patients with persistent critical illness died and only 23 968 (46·5%) of 51 509 were discharged home. INTERPRETATION: Onset of persistent critical illness can be empirically measured at a population level. Patients with this condition consume vast resources, have high mortality, have much less chance of returning home than do typical ICU patients, and require dedicated future research. ICU clinicians should be aware that the risk of in-hospital mortality can change quickly over the first 2 weeks of an ICU course and be sure to incorporate such changes in their decision making and prognostication. FUNDING: None.

Admission time to hospital: a varying standard for a critical definition for admissions to an intensive care unit from the emergency department.

OBJECTIVE: Time spent in the emergency department (ED) before admission to hospital is often considered an important key performance indicator (KPI). Throughout Australia and New Zealand, there is no standard definition of 'time of admission' for patients admitted through the ED. By using data submitted to the Australian and New Zealand Intensive Care Society Adult Patient Database, the aim was to determine the differing methods used to define hospital admission time and assess how these impact on the calculation of time spent in the ED before admission to an intensive care unit (ICU). METHODS: Between March and December of 2010, 61 hospitals were contacted directly. Decision methods for determining time of admission to the ED were matched to 67,787 patient records. Univariate and multivariate analyses were conducted to assess the relationship between decision method and the reported time spent in the ED. RESULTS: Four mechanisms of recording time of admission were identified, with time of triage being the most common (28/61 hospitals). Reported median time spent in the ED varied from 2.5 (IQR 0.83-5.35) to 5.1 h (2.82-8.68), depending on the decision method. After adjusting for illness severity, hospital type and location, decision method remained a significant factor in determining measurement of ED length of stay. CONCLUSIONS: Different methods are used in Australia and New Zealand to define admission time to hospital. Professional bodies, hospitals and jurisdictions should ensure standardisation of definitions for appropriate interpretation of KPIs as well as for the interpretation of studies assessing the impact of admission time to ICU from the ED. WHAT IS KNOWN ABOUT THE TOPIC?: There are standards for the maximum time spent in the ED internationally, but these standards vary greatly across Australia. The definition of such a standard is critically important not only to patient care, but also in the assessment of hospital outcomes. Key performance indicators rely on quality data to improve decision-making. WHAT DOES THIS PAPER ADD?: This paper quantifies the variability of times measured and analyses why the variability exists. It also discusses the impact of this variability on assessment of outcomes and provides suggestions to improve standardisation. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS?: This paper provides a clearer view on standards regarding length of stay in the ICU, highlighting the importance of key performance indicators, as well as the quality of data that underlies them. This will lead to significant changes in the way we standardise and interpret data regarding length of stay.

Herpes simplex virus immediate-early ICP0 protein inhibits Toll-like receptor 2-dependent inflammatory responses and NF-kappaB signaling.

The discovery of the Toll-like receptors (TLRs) and their importance in the regulation of host responses to infection raised attention to the complex interplay between viral gene products and the host innate immune responses in determining the outcome of virus infection. Robust inflammatory cytokine responses are observed in herpes simplex virus (HSV)-infected animals and cells. Our studies have demonstrated that Toll-like receptor 2 (TLR2) activation by HSV results in NF-κB activation with concomitant inflammatory cytokine production and that TLR2 activation plays a critical role in HSV-induced pathology and mortality. Here we demonstrate that the HSV-1 immediate-early ICP0 protein reduces the TLR2-mediated inflammatory response to HSV 1 (HSV-1) infection. Expression of ICP0 alone is sufficient to block TLR2-driven responses to both viral and nonviral ligands at or downstream of the MyD88 adaptor and upstream of p65. ICP0 alone can also reduce the levels of MyD88 and Mal (TIRAP). In HSV-infected cells, the E3 ligase function of ICP0 and cellular proteasomal activity are required for the inhibitory activity. Our results argue for a model in which ICP0 promotes the degradation of TLR adaptor molecules and inhibition of the inflammatory response, much as it inhibits the interferon response by sequestration and degradation of interferon regulatory factor 3 (IRF-3).

Immunization with a replication-defective herpes simplex virus 2 mutant reduces herpes simplex virus 1 infection and prevents ocular disease.

Ocular infections with herpes simplex virus 1 can lead to corneal scarring and blindness, with herpes keratitis being the major infectious cause of blindness. There is currently no clinically approved vaccine and nearly all developmental vaccines are targeted against HSV-2 and genital herpes. We tested the ability of an HSV-2 replication-defective virus, a genital herpes vaccine candidate, to protect against HSV-1 corneal infection. Immunization with HSV-2 dl5-29 reduced viral replication in the cornea, prevented ocular disease and reduced latent infection by the HSV-1 strain. Therefore, this HSV-2 replication-defective mutant strain may have applications for prevention of herpes keratitis and genital herpes due to HSV-1 infection.

Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia.

CD8+ T-cell persistence can be seen in ganglia harboring latent herpes simplex virus (HSV) infection. While there is some evidence that these cells suppress virus reactivation, this view remains controversial. Given that maintenance of latency by CD8+ T cells would necessitate ongoing exposure to antigen within this site, we sought evidence for such chronic stimulation. Initial experiments showed infiltration by activated but not naïve CD8+ T cells into ganglia harboring latent HSV infection. While such infiltration was independent of T-cell specificity, once recruited, only virus-specific T cells expressed high levels of preformed granzyme B, a marker of ongoing activation. Moreover, bone marrow replacement chimeras showed that these elevated granzyme levels were totally dependent on presentation by parenchymal cells within the ganglia. Overall, this study argues that activated CD8+ T cells are nonspecifically recruited into latently infected ganglia, and in this site they are exposed to ongoing antigen stimulation, most likely by infected neuronal cells.

Cutting edge: prolonged antigen presentation after herpes simplex virus-1 skin infection.

It has been reported that MHC class I-restricted Ag presentation persists for only a short period following infection with certain pathogens, declining in parallel with the emergence of specific CTL activity. We have examined this issue in the case of murine infection with HSV-1. We found that the period of Ag presentation capable of priming naive CD8(+) T cells is comparatively prolonged, persisting for at least 7 days after infection, and continuing despite the appearance of localized CTL activity. Ag presentation was abbreviated to 3 or 4 days postinfection by surgical excision of the inoculation site early after infection. This intervention attenuated the size of the primary CTL response, implying that prolonged presentation is necessary to drive maximal CTL expansion. Combined, these data show that, in some types of infection, CTL priming can extend well beyond the first 24-48 h after primary inoculation.

Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation.

HSV infects skin or mucosal epithelium as well as entering the sensory nerves and ganglia. We have used TCR-transgenic T cells specific for the immunodominant class I-restricted determinant from HSV glycoprotein B (gB) combined with a flank zosteriform model of infection to examine the ability of CD8+ T cells to deal with infection. During the course of zosteriform disease, virus rapidly spreads from the primary inoculation site in the skin to sensory dorsal root ganglia and subsequently reappears in the distal flank. Virus begins to be cleared from all sites about 5 days after infection when gB-specific CD8+ T cells first appear within infected tissues. Although activated gB-specific effectors can partially limit virus egress from the skin, they do so only at the earliest times after infection and are ineffective at halting the progression of zosteriform disease once virus has left the inoculation site. In contrast, these same T cells can completely clear ongoing lytic replication if transferred into infected immunocompromised RAG-1-/- mice. Therefore, we propose that the role of CD8+ T cells during the normal course of disease is to clear replicating virus after infection is well established rather than limit the initial spread of HSV from the primary site of inoculation.

Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells.

The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8alpha+ dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.