RESUMO
BACKGROUND: Data on the factors that influence mortality after surgery in South Africa are scarce, and neither these data nor data on risk-adjusted in-hospital mortality after surgery are routinely collected. Predictors related to the context or setting of surgical care delivery may also provide insight into variation in practice. Variation must be addressed when planning for improvement of risk-adjusted outcomes. Our objective was to identify the factors predicting in-hospital mortality after surgery in South Africa from available data. METHODS: A multivariable logistic regression model was developed to identify predictors of 30-day in-hospital mortality in surgical patients in South Africa. Data from the South African contribution to the African Surgical Outcomes Study were used and included 3800 cases from 51 hospitals. A forward stepwise regression technique was then employed to select for possible predictors prior to model specification. Model performance was evaluated by assessing calibration and discrimination. The South African Surgical Outcomes Study cohort was used to validate the model. RESULTS: Variables found to predict 30-day in-hospital mortality were age, American Society of Anesthesiologists Physical Status category, urgent or emergent surgery, major surgery, and gastrointestinal-, head and neck-, thoracic- and neurosurgery. The area under the receiver operating curve or c-statistic was 0.859 (95% confidence interval: 0.827-0.892) for the full model. Calibration, as assessed using a calibration plot, was acceptable. Performance was similar in the validation cohort as compared to the derivation cohort. CONCLUSION: The prediction model did not include factors that can explain how the context of care influences post-operative mortality in South Africa. It does, however, provide a basis for reporting risk-adjusted perioperative mortality rate in the future, and identifies the types of surgery to be prioritised in quality improvement projects at a local or national level.
Assuntos
Atenção à Saúde/normas , Mortalidade Hospitalar , Modelos Estatísticos , Procedimentos Cirúrgicos Operatórios/mortalidade , Adulto , Regras de Decisão Clínica , Atenção à Saúde/estatística & dados numéricos , Feminino , Disparidades em Assistência à Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , África do Sul/epidemiologia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Resultado do TratamentoRESUMO
Agonism of the endothelial receptor APJ (putative receptor protein related to AT1; AT1: angiotensin II receptor type 1) has the potential to ameliorate congestive heart failure by increasing cardiac output without inducing hypertrophy. Although the endogenous agonist, pyr-apelin-13 (1), has shown beneficial APJ-mediated inotropic effects in rats and humans, such effects are short-lived given its extremely short half-life. Here, we report the conjugation of 1 to a fatty acid, providing a lipidated peptide (2) with increased stability that retains inotropic activity in an anesthetized rat myocardial infarction (MI) model. We also report the preparation of a library of 15-mer APJ agonist peptide-lipid conjugates, including adipoyl-γGlu-OEG-OEG-hArg-r-Q-hArg-P-r-NMeLeuSHK-G-Oic-pIPhe-P-DBip-OH (17), a potent APJ agonist with high plasma protein binding and a half-life suitable for once-daily subcutaneous dosing in rats. A correlation between subcutaneous absorption rate and lipid length/type of these conjugates is also reported.
Assuntos
Receptores de Apelina/agonistas , Lipídeos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Peptídeos/farmacologia , Animais , Receptores de Apelina/metabolismo , Relação Dose-Resposta a Droga , Injeções Intravenosas , Lipídeos/administração & dosagem , Lipídeos/química , Estrutura Molecular , Infarto do Miocárdio/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Ratos , Relação Estrutura-AtividadeRESUMO
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinonas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Ensaios Clínicos como Assunto , Cães , Descoberta de Drogas , Humanos , Isomerismo , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação , Piperazinas/química , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirróis/uso terapêutico , Quinazolinonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Feminino , Humanos , Camundongos SCID , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Relação Estrutura-Atividade , Suínos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirróis/farmacologia , Quinazolinonas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirróis/administração & dosagem , Pirróis/química , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Perioperative research is currently unco-ordinated in South Africa (SA), with no clear research agenda. OBJECTIVE: To determine the top ten national research priorities for perioperative research in SA. METHODS: A Delphi technique was used to establish consensus on the top ten research priorities. RESULTS: The top ten research priorities were as follows: (i) establishment of a national database of (a) critical care outcomes, and (b) critical care resources; (ii) a randomised controlled trial of preoperative B-type natriuretic peptide-guided medical therapy to decrease major adverse cardiac events following non-cardiac surgery; (iii) a national prospective observational study of the outcomes associated with paediatric surgical cases; (iv) a national observational study of maternal and fetal outcomes following operative delivery in SA; (v) a stepped-wedge trial of an enhanced recovery after surgery programme for (a) surgery, (b) obstetrics, (c) emergency surgery, and (d) trauma surgery; (vi) a stepped-wedge trial of a surgical safety checklist on patient outcomes in SA; (vii) a prospective observational study of perioperative outcomes after surgery in district general hospitals in SA; (viii) short-course interventions to improve anaesthetic skills in rural doctors; (ix) studies of the efficacy of simulation training to improve (a) patient outcomes, (b) team dynamics, and (c) leadership; and (x) development and validation of a risk stratification tool for SA surgery based on the South African Surgical Outcomes Study (SASOS) data. CONCLUSIONS: These research priorities provide the structure for an intermediate-term research agenda.
RESUMO
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.
RESUMO
Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure-activity relationships are discussed.
Assuntos
Aminoácidos/síntese química , Oxazóis/síntese química , Receptores de Complemento/agonistas , Aminoácidos/química , Aminoácidos/farmacologia , Arginina/análogos & derivados , Arginina/química , Arginina/farmacologia , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Macrófagos/efeitos dos fármacos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74µM (18µg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.
Assuntos
Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Cristalografia por Raios X , Descoberta de Drogas , Estrutura Molecular , Oxidiazóis/químicaRESUMO
PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.
Assuntos
Aminas/química , Aminas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Aminas/síntese química , Carbolinas/síntese química , Carbolinas/química , Carbolinas/farmacologia , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-pim-1/química , Relação Estrutura-AtividadeRESUMO
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.
Assuntos
Indazóis/química , Indazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Descoberta de Drogas , Humanos , Relação Estrutura-AtividadeRESUMO
Replacement of the piperazine sulfonamide portion of the PI3Kα inhibitor AMG 511 (1) with a range of aliphatic alcohols led to the identification of a truncated gem-dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol (7). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing.
Assuntos
Álcoois/química , Inibidores de Fosfoinositídeo-3 Quinase , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Sulfonamidas/química , Triazinas/síntese química , Animais , Feminino , Meia-Vida , Fígado/metabolismo , Masculino , Camundongos , Camundongos Nus , Conformação Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/metabolismo , Piperazinas/farmacocinética , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Triazinas/metabolismo , Triazinas/farmacocinéticaRESUMO
The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Triazinas/farmacologia , Cristalografia por Raios X , Modelos Moleculares , Inibidores de Proteínas Quinases/químicaRESUMO
From humble beginnings, the University of Cape Town's Department of Anaesthesia has played a major role in the development of anaesthesia as a speciality, in South Africa and internationally. We highlight these contributions in clinical service, teaching and research, with particular emphasis on the department's leading role in the evolution of anaesthetic safety in adults and children: from the development of the treatment of malignant hyperthermia, to unique studies in mortality associated with anaesthesia, and modern contributions to improved drug safety. Innovations in anaesthetic techniques have contributed to significant surgical developments, including the first heart transplant. Furthermore, our research has contributed to major advances in obstetric and endocrine anaesthesia, and training in the department is recognised as being among the best in the world.
Assuntos
Anestesia/história , Faculdades de Medicina/história , Universidades/história , Anestesiologia/educação , História do Século XX , História do Século XXI , Humanos , África do SulRESUMO
A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Piperazinas/síntese química , Piridinas/síntese química , Sulfonamidas/síntese química , Triazinas/síntese química , Animais , Disponibilidade Biológica , Classe I de Fosfatidilinositol 3-Quinases/fisiologia , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Indazóis/farmacologia , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Purinas/síntese química , Purinas/farmacocinética , Purinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Transdução de Sinais , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonas/síntese química , Sulfonas/farmacocinética , Sulfonas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazinas/farmacocinética , Triazinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Hemodynamic responses to spinal anesthesia (SA) for cesarean delivery in patients with severe preeclampsia are poorly understood. This study used a beat-by-beat monitor of cardiac output (CO) to characterize the response to SA. The hypothesis was that CO would decrease from baseline values by less than 20%. METHODS: Fifteen patients with severe preeclampsia consented to an observational study. The monitor employed used pulse wave form analysis to estimate nominal stroke volume. Calibration was by lithium dilution. CO and systemic vascular resistance were derived from the measured stroke volume, heart rate, and mean arterial pressure. In addition, the hemodynamic effects of phenylephrine, the response to delivery and oxytocin, and hemodynamics during recovery from SA were recorded. Hemodynamic values were averaged for defined time intervals before, during, and after SA. RESULTS: Cardiac output remained stable from induction of SA until the time of request for analgesia. Mean arterial pressure and systemic vascular resistance decreased significantly from the time of adoption of the supine position until the end of surgery. After oxytocin administration, systemic vascular resistance decreased and heart rate and CO increased. Phenylephrine, 50 mug, increased mean arterial pressure to above target values and did not significantly change CO. At the time of recovery from SA, there were no clinically relevant changes from baseline hemodynamic values. CONCLUSIONS: Spinal anesthesia in severe preeclampsia was associated with clinically insignificant changes in CO. Phenylephrine restored mean arterial pressure but did not increase maternal CO. Oxytocin caused transient marked hypotension, tachycardia, and increases in CO.
Assuntos
Raquianestesia/métodos , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Hemodinâmica/fisiologia , Pré-Eclâmpsia/cirurgia , Adulto , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Cesárea , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Monitorização Intraoperatória/métodos , Ocitocina/farmacologia , Seleção de Pacientes , Fenilefrina/farmacologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Estudos Prospectivos , Valores de ReferênciaRESUMO
OBJECTIVE: Secondary insults of hypotension and hypoxia significantly impact on outcome in patients with traumatic brain injury (TBI). More than 4 hours' delay in evacuation of intracranial haematomas has been demonstrated to have an additional impact on outcome. The objective of this study was to document the incidence of these preventable secondary insults in patients admitted with moderate or severe brain injury. METHODOLOGY: All moderate and severe head injury patients admitted to Groote Schuur Hospital over a 3-month period were studied prospectively. Data were obtained from ambulance dockets, referral letters, patient charts and attending medical staff. Preventable secondary insults (hypotension, hypoxia) and time delay to assessment and surgery were documented. Outcome was assessed using the Glasgow outcome scale (GOS) at discharge or outpatient follow-up. RESULTS: Ninety-six patients were studied. Forty-nine patients experienced at least one recorded preventable event of hypoxia or hypotension. Seventeen had an intracranial haematoma requiring evacuation. The mean time interval between injury and surgery was 455 minutes. No haematoma was evacuated within 4 hours of injury. Patients referred via a primary or secondary care facility experienced a mean additional delay of 70 minutes. These results demonstrated a significant incidence of secondary injury and delay to assessment and surgery. We believe that education and a raised awareness of the impact of secondary insults may have a positive impact on TBI outcome in our referral area.