The Critical Care Society of Southern Africa Consensus Statement on ICU Triage and Rationing (ConICTri).

Background. In South Africa (SA), intensive care is faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience daily the consequences of limited resources. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are frequently necessary in SA, particularly in the publicly funded health sector. Purpose. The purpose of this consensus statement is to examine key questions that arise when considering the status of ICU resources in SA, and more specifically ICU admission, rationing and triage decisions. The accompanying guideline in this issue is intended to guide frontline triage policy and ensure the best utilisation of intensive care in SA, while maintaining a fair distribution of available resources. Fair and efficient triage is important to ensure the ongoing provision of high-quality care to adult patients referred for intensive care. Recommendations. In response to 14 key questions developed using a modified Delphi technique, 29 recommendations were formulated and graded using an adapted GRADE score. The 14 key questions addressed the status of the provision of ICU services in SA, the degree of resource restriction, the efficiency of resource management, the need for triage, and how triage could be most justly implemented. Important recommendations included the need to formally recognise and accurately quantify the provision of ICU services in SA by national audit; actively seek additional resources from governmental bodies; consider methods to maximise the efficiency of ICU care; evaluate lower level of care alternatives; develop a triage guideline to assist policy-makers and frontline practitioners to implement triage decisions in an efficient and fair way; measure and audit the consequence of triage; and promote research to improve the accuracy and consistency of triage decisions. The consensus document and guideline should be reviewed and revised appropriately within 5 years. Conclusion. In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, recommendations and a guideline have been developed to guide policy-making and assist frontline triage decision-making in SA. These documents are not a complete plan for quality practice but rather the beginning of a long-term initiative to engage clinicians, the public and administrators in appropriate triage decision-making, and promote systems that will ultimately maximise the efficient and fair use of available ICU resources.

The Critical Care Society of Southern Africa Consensus Guideline on ICU Triage and Rationing (ConICTri).

Background. In South Africa (SA), administrators and intensive care practitioners are faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience the consequences of limited resources daily. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are routinely necessary in SA, particularly in the publicly funded health sector. Purpose. The purpose of this guideline is to utilise the relevant recommendations of the associated consensus meeting document and other internationally accepted principles to develop a guideline to inform frontline triage policy and ensure the best utilisation of adult intensive care in SA, while maintaining the fair distribution of available resources. Recommendations. An overall conceptual framework for the triage process was developed. The components of the framework were developed on the basis that patients should be admitted preferentially when the likely incremental medical benefit derived from ICU admission justifies admission. An estimate of likely resource use should also form part of the triage decision, with those patients requiring relatively less resources to achieve substantial benefit receiving priority for admission. Thus, the triage system should maximise the benefits obtained from ICU resources available for the community. Where possible, practical examples of what the consensus group agreed would be considered appropriate practice under specified South African circumstances were provided, to assist clinicians with practical decision-making. It must be stressed that this guideline is not intended to be prescriptive for individual hospital or regional practice, and hospitals and regions are encouraged to develop specified local guidelines with locally relevant examples. The guideline should be reviewed and revised if appropriate within 5 years. Conclusion. In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, this guideline has been developed to guide policy-making and assist frontline triage decision-making in SA. This document is not a complete plan for quality practice, but rather a template to support frontline clinicians, guide administrators and inform the public regarding appropriate triage decision-making.

The Critical Care Society of Southern Africa Consensus Statement on ICU Triage and Rationing (ConICTri).

Background: In South Africa (SA), intensive care is faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience daily the consequences of limited resources. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are frequently necessary in SA, particularly in the publicly funded health sector. Purpose: The purpose of this consensus statement is to examine key questions that arise when considering the status of ICU resources in SA, and more specifically ICU admission, rationing and triage decisions. The accompanying guideline in this issue is intended to guide frontline triage policy and ensure the best utilisation of intensive care in SA, while maintaining a fair distribution of available resources. Fair and efficient triage is important to ensure the ongoing provision of high-quality care to adult patients referred for intensive care. Recommendations: In response to 14 key questions developed using a modified Delphi technique, 29 recommendations were formulated and graded using an adapted GRADE score. The 14 key questions addressed the status of the provision of ICU services in SA, the degree of resource restriction, the efficiency of resource management, the need for triage, and how triage could be most justly implemented. Important recommendations included the need to formally recognise and accurately quantify the provision of ICU services in SA by national audit; actively seek additional resources from governmental bodies; consider methods to maximise the efficiency of ICU care; evaluate lower level of care alternatives; develop a triage guideline to assist policy-makers and frontline practitioners to implement triage decisions in an efficient and fair way; measure and audit the consequence of triage; and promote research to improve the accuracy and consistency of triage decisions. The consensus document and guideline should be reviewed and revised appropriately within 5 years. Conclusion: In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, recommendations and a guideline have been developed to guide policy-making and assist frontline triage decision-making in SA. These documents are not a complete plan for quality practice but rather the beginning of a long-term initiative to engage clinicians, the public and administrators in appropriate triage decision-making, and promote systems that will ultimately maximise the efficient and fair use of available ICU resources.

The Critical Care Society of Southern Africa Consensus Guideline on ICU Triage and Rationing (ConICTri).

Background: In South Africa (SA), administrators and intensive care practitioners are faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience the consequences of limited resources daily. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are routinely necessary in SA, particularly in the publicly funded health sector. Purpose: The purpose of this guideline is to utilise the relevant recommendations of the associated consensus meeting document and other internationally accepted principles to develop a guideline to inform frontline triage policy and ensure the best utilisation of adult intensive care in SA, while maintaining the fair distribution of available resources. Recommendations: An overall conceptual framework for the triage process was developed. The components of the framework were developed on the basis that patients should be admitted preferentially when the likely incremental medical benefit derived from ICU admission justifies admission. An estimate of likely resource use should also form part of the triage decision, with those patients requiring relatively less resources to achieve substantial benefit receiving priority for admission. Thus, the triage system should maximise the benefits obtained from ICU resources available for the community. Where possible, practical examples of what the consensus group agreed would be considered appropriate practice under specified South African circumstances were provided, to assist clinicians with practical decision-making. It must be stressed that this guideline is not intended to be prescriptive for individual hospital or regional practice, and hospitals and regions are encouraged to develop specified local guidelines with locally relevant examples. The guideline should be reviewed and revised if appropriate within 5 years. Conclusion: In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, this guideline has been developed to guide policy-making and assist frontline triage decision-making in SA. This document is not a complete plan for quality practice, but rather a template to support frontline clinicians, guide administrators and inform the public regarding appropriate triage decision-making.

Risk prediction models for delirium in the intensive care unit after cardiac surgery: a systematic review and independent external validation.

Numerous risk prediction models are available for predicting delirium after cardiac surgery, but few have been directly compared with one another or been validated in an independent data set. We conducted a systematic review to identify validated risk prediction models of delirium (using the Confusion Assessment Method-Intensive Care Unit tool) after cardiac surgery and assessed the transportability of the risk prediction models on a prospective cohort of 600 consecutive patients undergoing cardiac surgery at a university hospital in Hong Kong from July 2013 to July 2015. The discrimination (c-statistic), calibration (GiViTI calibration belt), and clinical usefulness (decision curve analysis) of the risk prediction models were examined in a stepwise manner. Three published high-quality intensive care unit delirium risk prediction models (n=5939) were identified: Katznelson, the original PRE-DELIRIC, and the international recalibrated PRE-DELIRIC model. Delirium occurred in 83 patients (13.8%, 95% CI: 11.2-16.9%). After updating the intercept and regression coefficients in the Katznelson model, there was fair discrimination (0.62, 95% CI: 0.58-0.66) and good calibration. As the original PRE-DELIRIC model was already validated externally and recalibrated in six countries, we performed a logistic calibration on the recalibrated model and found acceptable discrimination (0.75, 95% CI: 0.72-0.79) and good calibration. Decision curve analysis demonstrated that the recalibrated PRE-DELIRIC risk model was marginally more clinically useful than the Katznelson model. Current models predict delirium risk in the intensive care unit after cardiac surgery with only fair to moderate accuracy and are insufficient for routine clinical use.

Identification of ubiquitin ligases required for skeletal muscle atrophy.

Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein.

The Grb2 and Shc adapter proteins play critical roles in coupling activated growth factor receptors to several cellular signaling pathways. To assess the role of these molecules in mammary epithelial development and tumorigenesis, we have generated transgenic mice which individually express the Grb2 and Shc proteins in the mammary epithelium. Although mammary epithelial cell-specific expression of Grb2 or Shc accelerated ductal morphogenesis, mammary tumors were rarely observed in these strains. To explore the potential role of these adapter proteins in mammary tumorigenesis, mice coexpressing either Shc or Grb2 and a mutant form of polyomavirus middle T (PyV mT) antigen in the mammary epithelium were generated. Coexpression of either Shc or Grb2 with the mutant PyV mT antigen resulted in a dramatic acceleration of mammary tumorigenesis compared to parental mutant PyV mT strain. The increased rate of tumor formation observed in these mice was correlated with activation of the epidermal growth factor receptor family and mitogen-activated protein kinase pathway. These observations suggest that elevated levels of the Grb2 or Shc adapter protein can accelerate mammary tumor progression by sensitizing the mammary epithelial cell to growth factor receptor signaling.

Identification of residues that control specific binding of the Shc phosphotyrosine-binding domain to phosphotyrosine sites.

The Shc adaptor protein contains two phosphotyrosine [Tyr(P)]binding modules--an N-terminal Tyr(P) binding (PTB) domain and a C-terminal Src homology 2 (SH2) domain. We have compared the ability of the Shc PTB domain to bind the receptors for nerve growth factor and insulin, both of which contain juxtamembrane Asn-Pro-Xaa-Tyr(P) motifs implicated in PTB binding. The Shc PTB domain binds with high affinity to a phosphopeptide corresponding to the nerve growth factor receptor Tyr-490 autophosphorylation site. Analysis of individual residues within this motif indicates that the Asn at position -3 [with respect to Tyr(P)], in addition to Tyr(P), is critical for PTB binding, while the Pro at position -2 plays a less significant role. A hydrophobic amino acid 5 residues N-terminal to the Tyr(P) is also essential for high-affinity binding. In contrast, the Shc PTB domain does not bind stably to the Asn-Pro-Xaa-Tyr(P) site at Tyr-960 in the activated insulin receptor, which has a polar residue (Ser) at position -5. Substitution of this Ser at position -5 with Ile markedly increased binding of the insulin receptor Tyr-960 phosphopeptide to the PTB domain. These results suggest that while the Shc PTB domain recognizes a core sequence of Asn-Pro-Xaa-Tyr(P), its binding affinity is modulated by more N-terminal residues in the ligand, which therefore contribute to the specificity of PTB-receptor interactions. An analysis of residues in the Shc PTB domain required for binding to Tyr(P) sites identified a specific and evolutionarily conserved Arg (Arg-175) that is uniquely important for ligand binding and is potentially involved in Tyr(P) recognition.

A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides.

BACKGROUND: Signal transduction by growth factor receptor protein-tyrosine kinases is generally initiated by autophosphorylation on tyrosine residues following ligand binding. Phosphotyrosines within activated receptors form binding sites for the Src homology 2 (SH2) domains of cytoplasmic signalling proteins. One such protein, Shc, is tyrosine phosphorylated in response to a large number of growth factors and cytokines. Phosphorylation of Shc on tyrosine residue Y317 allows binding to the SH2 domain of Grb2, and hence stimulation of the Ras pathway. Shc is therefore implicated as an adaptor protein able to couple normal and oncogenic protein-tyrosine kinases to Ras activation. Shc itself contains an SH2 domain at its carboxyl terminus, but the function of the amino-terminal half of the protein is unknown. RESULTS: We have found that the Shc amino-terminal region binds to a number of tyrosine-phosphorylated proteins in v-src-transformed cells. This domain also bound directly to the activated epidermal growth factor (EGF) receptor. A phosphotyrosine (pY)-containing peptide modeled after the Shc-binding site in polyoma middle T antigen (LLSNPTpYSVMRSK) was able to compete efficiently with the activated EGF receptor for binding to the Shc amino terminus. This competition was dependent on phosphorylation of the tyrosine residue within the peptide, and was abrogated by deletion of the leucine residue at position -5. The Shc amino-terminal domain also bound to the autophosphorylated nerve growth factor receptor (Trk), but bound significantly less well to a mutant receptor in which tyrosine Y490 in the receptor's Shc-binding site had been substituted by phenylalanine. CONCLUSION: These data implicate the amino-terminal region of Shc in binding to activated receptors and other tyrosine-phosphorylated proteins. Binding appears to be specific for phosphorylated tyrosine residues within the sequence NPXpY, which is conserved in many Shc-binding sites. The Shc amino-terminal region bears only very limited sequence identify to known SH2 domains, suggesting that it represents a new class of phosphotyrosine-binding modules. Consistent with this view, the amino-terminal Shc domain is highly conserved in a Drosophila Shc homologue. Binding of Shc to activated receptors through its amino terminus could leave the carboxy-terminal SH2 domain free for other interactions. In this way, Shc may function as an adaptor protein to bring two tyrosine-phosphorylated proteins together.