Advancing in the understanding of coagulopathy during hemorrhagic shock: From the triad to the deadly pentad / Avanzando en el entendimiento de la coagulopatía durante el choque hemorrágico: de la tríada a la pentada mortal

Abstract The deadly triad concept represented a dogma in the definition of poor outcomes and death associated with major bleeding in trauma. This model of end-stage disease was then rapidly transferred to other major bleeding scenarios. However, and notwithstanding the fact that it represented a severe scenario, the original triad fails to establish a sequence, which would be relevant when defining the objectives during the initial treatment of severe bleeding. Likewise, this model admits only one scenario where all the conditions shall co-exist, knowing that each one of them contributes with a different risk burden. Based on a structured review, we propose a pentad model that includes a natural pattern of events occurring with hypoxemia as the main trigger for the development of hypocalcemia, hyperglycemia, acidosis and hypothermia, as surrogates of multi-organ impairment. This severity model of major bleeding considers coagulopathy as a result of the failure to restore the initial components of damage.

Resumen El concepto de la tríada mortal significó un dogma en la definición de malos desenlaces y muerte asociados al sangrado mayor en trauma. Este modelo de afectación terminal fue luego rápidamente trasladado a otros escenarios de sangrado mayor. Sin embargo y a pesar de significar un escenario de gravedad, la tríada original falla en adjudicar una secuencialidad, lo cual sería importante a la hora de definir los objetivos durante el tratamiento inicial de la hemorragia grave. De igual forma, solo admite un único escenario en donde deben coexistir todas las condiciones, cuando se sabe que cada una atribuye una carga diferencial de riesgo. A partir de una revisión estructurada proponemos un modelo de pentada que incluye un patrón natural de eventos que se implantan sobre la hipoxemia como principal detonante para el desarrollo de hipocalcemia, hiperglucemia, acidosis e hipotermia como representantes del deterioro en múltiples sistemas. Este modelo de gravedad del sangrado mayor culmina con la coagulopatía como resultante de la falla en la resolución de los demás componentes previos.

Safety and effectiveness of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal following a fixed-dose strategy.

OBJECTIVES: Early reversal of anticoagulation improves outcomes in major bleeding and emergency surgery. To reverse vitamin K antagonists (VKA), vitamin K in addition to prothrombin complex concentrate (PCC) is recommended. Dosing recommendations for VKA reversal provided by the manufacturer are 25-50 IU/kg depending on the baseline international normalised ratio (INR). Nevertheless, we recommend an initial fixed dose of 1000 IU, and additional 500 IU doses evaluated on a case-by-case basis. As there is a paucity of clinical data demonstrating the efficacy and safety of this strategy, we designed this study to assess the effectiveness and safety of a four-factor (4F)-PCC for VKA reversal following a fixed-dose strategy. METHODS: This was a retrospective study of adult patients who received 4F-PCC for VKA reversal. The primary outcome was INR correction. INR correction was achieved if the first INR draw after 4F-PCC was ≤1.5. Safety outcome was any confirmed thromboembolic event within 3 months after 4F-PCC. Secondary outcomes included activated partial thromboplastin time (aPTT) correction, as well as haemostatic effectiveness for bleeding patients. RESULTS: A total of 145 patients were included: 106 (73.1%) in the bleeding group and 39 (26.9%) in the emergency surgery group. The INR target was reached in 102 (70.3%) patients (p<0.0001). In one case, a thromboembolic complication was possibly related to 4F-PCC. The aPTT ratio target was reached in 113 (77.9%) patients (p<0.0001), and 79 of the 106 (74.5%) patients reversed for bleeding achieved haemostatic effectiveness. CONCLUSIONS: After 4F-PCC, the majority of patients achieved the target INR, meaning 4F-PCC is a useful modality for rapid INR reduction. The safety profile may be considered acceptable. Fixed-dose 4F-PCC was able to restore haemostasis rapidly while minimising the risk of adverse events and optimising available resources.

Surgical site infection in adults undergoing major non-cardiac surgery and its association with anemia, El severe bleeding and intraoperative transfusion: A preliminary report from a prospective registry / Infección de sitio operatorio en adultos llevados a cirugía mayor no cardiaca y su relación con anemia, sangrado mayor y transfusión intraoperatoria: Informe preliminar de un registro prospectivo

Abstract Introduction: Surgical site infection (SSI) is among the most common healthcare-related infections. Given their greater morbidity and surgical complexity, patients undergoing major surgery are exposed to a high risk of SSI. Objective: To determine the incidence of SSI in adult patients undergoing major elective non-cardiac surgery, and to identify risk factors associated with its occurrence within the first 30 days after surgery. Methods: An analytical study was designed on the basis of a prospective institutional registry. Clinical and laboratory variables associated with perioperative management were recorded. An active search was conducted in order to find SSI episodes, renal failure and multiple organ dysfunction during the first 30 days after surgery. Adjusted logistic regression was done to identify potential associations between risk factors and the development of SSI. Results: Overall, 1501 patients were included. The incidence of SSI during the first 30 days after surgery was 6.72% (95% CI 5.57-8.11). ASA III, abdominal surgery and longer procedures were more frequent in the SSI group. Association with the occurrence of SSI was documented for preoperative hemoglobin levels (adjusted OR 0.79 [95% CI 0.72-0.88], p = 0.04), intraoperative transfusion (adjusted OR 2,47 [95% CI 1.16-5.27], p = 0.02) and major blood loss (adjusted OR 3.80 [95% CI 1.63-8.88], p = 0.04). Conclusion: Preoperative hemoglobin level, intraoperative transfusion and major bleeding are independent risk factors associated with the occurrence of SSI in adult patients undergoing major elective non-cardiac surgery.

Resumen Introducción: La infección del sitio operatorio (ISO) ocupa los primeros lugares entre las infecciones asociadas a la atención en salud. Con una mayor morbilidad y complejidad quirúrgica, los pacientes de cirugía mayor están expuestos a un alto riesgo de ISO. Objetivo: Determinar la incidencia de ISO en pacientes adultos sometidos a cirugía mayor electiva no cardiaca e identificar factores de riesgo relacionados con su aparición durante los primeros 30 días postoperatorios. Métodos: Se diseñó un estudio analítico a partir de un registro institucional prospectivo. Se registraron variables clínicas y de laboratorio relacionadas con el manejo perioperatorio. Se realizó una búsqueda activa de episodios de ISO, sepsis, falla renal y disfunción multiorgánica durante los primeros 30 días postoperatorios. Las potenciales asociaciones entre factores de riesgo y el desarrollo de ISO fueron identificadas mediante regresión logística ajustada. Resultados: Se incluyeron 1.501 pacientes. La incidencia de ISO durante los 30 días postoperatorios fue de 6,72 % [IC 95 % 5,57-8,11). El estado ASA III, la cirugía abdominal y los procedimientos de duración prolongada fueron más frecuentes en el grupo ISO. Se documentó asociación con la ocurrencia de ISO para los niveles de hemoglobina preoperatoria (OR ajustado 0,79 [IC 95 % 0,72-0,88], p = 0,04), transfusión intraoperatoria (OR ajustado 2,47 [IC 95 % 1,16-5,27], p = 0,02) y sangrado mayor intraoperatorio (OR ajustado 3,80 [IC 95 % 1,63-8,88], p = 0,04). Conclusiones: El nivel de hemoglobina preoperatoria, la transfusión intraoperatoria y el sangrado mayor son factores de riesgo asociados de forma independiente a la ocurrencia de ISO en pacientes adultos llevados a cirugía mayor electiva no cardiaca.

Efficacy and safety of high-dose intravenous iron as the first-choice therapy in outpatients with severe iron deficiency anemia.

BACKGROUND: Asymptomatic severe iron deficiency anemia is a common finding in subjects admitted to the outpatient anemia clinic. Although the condition can be easily be reversed with intravenous iron (IVI) therapy and several guidelines have suggested a restrictive threshold for using transfusion in hemodynamically stable patients, transfusion is often the rule in clinical practice. This study describes clinical practice results of IVI therapy without transfusion. STUDY DESIGN AND METHODS: In this multicenter retrospective observational study, data of severely anemic outpatients treated only with high-dose IVI with ferric carboxymaltose were collected. Inclusion criteria were hemoglobin (Hb) level of less than 7.0 g/dL and ferritin level of less than 30 ng/mL or mean corpuscular volume of less than 75 fL. RESULTS: Overall, 303 patients referred to the anemia clinic mainly from primary health care centers (46.2%) or the emergency department (28.7%) met the inclusion criteria. Median (interquartile range [IQR]) age was 47 (37-62) years and 84.5% were female. The median (IQR) Hb concentration at first visit was 6.5 (6.1-6.8) g/dL, 64 patients (21.1%) presented with a Hb level of less than 6.0 g/dL at diagnosis, and 11 of them (3.6%) had extreme anemia (Hb ≤ 5 g/dL). Gynecologic and gastroenteric bleeding were the main cause. After a mean IV administration of 1500 mg of iron, the Hb increased by a median of 5.7 g/dL. Thirteen patients experienced only mild side effects. CONCLUSIONS: In chronic very severe sideropenic anemias, third-generation IVI is effective and safe for quick correction and avoidance of red blood cell transfusion. These results suggest that more specific guidelines for this clinical setting are warranted.

Influence of Chronic Obstructive Pulmonary Disease on Volatile Organic Compounds in Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: The etiology of lung cancer is multifactorial. Exposure to tobacco smoke and the role played by the carcinogenic compounds that it contains would explain the common association between lung cancer and chronic obstructive pulmonary disease (COPD), which is closely linked to tobacco use. In both diseases, sustained inflammation is caused by increased oxidative stress (for example, lipid peroxidation). This generates low molecular weight substances called volatile organic compounds (VOC) that are excreted during breathing. VOC metabolomics provides an indirect measure of oxidative stress. OBJECTIVE: The aim of this study was to establish the relative influence of COPD on the VOC profile in patients with non-small cell lung cancer (NSCLC), by first studying the possible variation of VOC associated with lung cancer histology. PATIENTS AND METHODS: Exhaled air was tested in 107 NSCLC patients, who were divided into 2 groups: NSCLC with COPD and non-COPD with NSCLC. The exhaled air sample was obtained with the BIOVOC® sampler, and transferred to desorption tubes for later analysis by thermal desorption-gas chromatography-mass spectrometry. The VOC analysis showed lineal aldehydes and carboxylic acids. RESULTS AND CONCLUSIONS: No statistically significant differences were found in VOC associated with histology. NSCLC and COPD patients present a 1.7-fold (1.1-2.7) greater probability of detection of propionic acid (95% CI: 1.22-6.2) than patients without COPD or NSCLC (p = 0.013).

A System Dynamics Model to Predict the Human Monocyte Response to Endotoxins.

System dynamics is a powerful tool that allows modeling of complex and highly networked systems such as those found in the human immune system. We have developed a model that reproduces how the exposure of human monocytes to lipopolysaccharides (LPSs) induces an inflammatory state characterized by high production of tumor necrosis factor alpha (TNFα), which is rapidly modulated to enter into a tolerant state, known as endotoxin tolerance (ET). The model contains two subsystems with a total of six states, seven flows, two auxiliary variables, and 14 parameters that interact through six differential and nine algebraic equations. The parameters were estimated and optimized to obtain a model that fits the experimental data obtained from human monocytes treated with various LPS doses. In contrast to publications on other animal models, stimulation of human monocytes with super-low-dose LPSs did not alter the response to a second LPSs challenge, neither inducing ET, nor enhancing the inflammatory response. Moreover, the model confirms the low production of TNFα and increased levels of C-C motif ligand 2 when monocytes exhibit a tolerant state similar to that of patients with sepsis. At present, the model can help us better understand the ET response and might offer new insights on sepsis diagnostics and prognosis by examining the monocyte response to endotoxins in patients with sepsis.

A fast-track anaemia clinic in the Emergency Department: cost-analysis of intravenous iron administration for treating iron-deficiency anaemia.

BACKGROUND: A fast-track anaemia clinic (FTAC) for the management of moderate-to-severe iron-deficiency anaemia (IDA) was established in our Emergency Department in 2010. In this FTAC, the replacement of packed red cell transfusion by ferric carboxymaltose administration was proven to be safe and effective. The aim of this study was a cost-analysis of IDA management in the FTAC, comparing this management with the previous standard care pathway consisting of packed red cell transfusion, if needed, and referral to outpatient specialised care. MATERIALS AND METHODS: A cost study was performed for patients with IDA who were at risk of requiring transfusion (haemoglobin <9 g/dL) but did not require hospitalisation. Total IDA treatment costs in the FTAC were compared to those theoretically incurred if these patients had been managed using the standard care pathway. In addition, a sensitivity analysis considering variations of up to ±30% in ferric carboxymaltose and packed red cell acquisition costs was performed (49 possible scenarios). RESULTS: Between 2012 and 2015, 238 IDA patients were treated in the FTAC. The average treatment cost was € 594±337/patient in the FTAC group and € 672±301/patient in the standard care pathway group, with a saving of € 78±28/patient (95% CI, 22-133; p<0.001). The sensitivity analysis showed that IDA treatment costs in the FTAC (€ 480-722/patient), compared with those of the standard care pathway (€ 550-794/patient), resulted in significant cost-savings for all studied scenarios (€ 51-104/patient; p<0.005). DISCUSSION: The administration of ferric carboxymaltose for IDA management in a FTAC may be cost-saving compared with the standard care pathway.

¿Estamos logrando las recomendaciones actuales en trauma penetrante? Análisis preliminar de un registro institucional colombiano / Are we meeting current recommendations for the initial management of penetrating trauma? A preliminary analysis from a Colombian institutional registry

Abstract Introduction: To achieve minimal physiological goals in patients with penetrating thoracoabdominal trauma (TAPT) is essential to ensure adequate outcomes. Objectives: To determine the success in meting basic standards at the end of damage control surgery in subjects with TAPT: (1) Monitoring and prevention of hyperfibrinolysis; (2) central temperature >35 °C; (3) platelet count >50,000/mm³ and serum fibrinogen >150mg/dl; (4) hemoglobin levels >7.5 mg/dl and base deficit <6. Methods: Subjects >18 years old undergoing damage control surgery as a result of TAPT were prospectively collected at a referral center between October Oct-2012 and Dec-2014. Comparisons were done according to the Injury Severity Score (ISS) with a severity value indicator of >25. A p < 0.05 value was considered significant. Results:106 subjects with TAPT were enrolled. Administration of tranexamic acid was only reported in 52.7% of the patients, particularly in the group with low severity scores [Group ISS < 25 36.3% vs. group ISS > 25 65.8%. OR 3.37 (95% CI 1.2-9.85); p = 0.01]. Although the temperature was reported in 91% of the cases, only 66.2-71.4% reached the recommended goal. Serum fibrinogen was measured in 59.5% of the cases and only 52% met the recommended level. The base deficit values of <6 at the end of surgery were only accomplished in 40-43.8% of the subjects, with a significantly lower probability in the more severe patients [53% vs. 35.9%. OR 2.04 (95% CI 1.2-6.02); p = 0.042]. Conclusions: A considerable proportion of patients with TAPT does not meet the current recommendations at the end of damage control surgery.

Introducción: El logro de metas fisiológicas mínimas en pacientes con trauma toracoabdominal penetrante (TTAP) es fundamental para garantizar adecuados desenlaces. Objetivos: Determinar el éxito en el logro de estándares básicos al final de la cirugía de control de daños en sujetos con TTAP: 1.Monitorización y prevención de hiperfibrinolisis; 2.Temperatura central > 35 °C; 3.Niveles plaquetarios>50.000/mm3 y de fibrinógeno sérico > 150 mg/dl; 4.Niveles de hemoglobina > 7.5 mg/dl y déficit de base < 6. Métodos: Se recolectaron prospectivamente sujetos > 18 años llevados a cirugía de control de daños por TTAP en un centro de remisión entre Oct-2012 y Dic-2014. Las comparaciones se realizaron según el Injury severity score (ISS) teniendo como indicador de severidad un valor >25. Se consideró significativo un valor de p < 0.05. Resultados: Se registraron 106 sujetos con TTAP. La aplicación de ácido tranexámico solo se reportó en 52.7% de los pacientes, especialmente en el grupo con puntajes de severidad bajos [Grupo ISS<25 36.3% vs. grupo ISS > 25 65.8%. OR 3.37 (IC95% 1.2-9.85); p = 0.01]. A pesar de que la temperatura fue reportada en 91% de los casos, solo 66.2-71.4% alcanzaron la meta recomendada. El fibrinógeno sérico fue valorado en 59.5% de los sujetos y solo 52% alcanzaron la recomendación. Valores de déficit de base < 6 Al final de cirugía solo se lograron en 40-43.8% de los sujetos, con una probabilidad significativamente menor en los sujetos más graves [53% vs. 35.9%. OR 2.04 (IC95% 1.2-6.02); p = 0.042]. Conclusiones: Una proporción considerable de pacientes con TTAP no logran las recomendaciones actuales al final de la cirugía de control de daños.

The effectiveness and safety of pharmacological prophylaxis against venous thromboembolism in patients with moderate to severe traumatic brain injury: A systematic review and meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is a common, potentially fatal complication after traumatic brain injury (TBI). The objective was to evaluate the effectiveness and safety of pharmacologic VTE prophylaxis in moderate to severe TBI patients, and its use in hospitals. DATA SOURCES: A systematic review of the literature was conducted using Medline, Embase, Central database, Google scholar, and the SciELO from 1966 to 2014. STUDY SELECTION & DATA EXTRACTION: All studies providing information on the following variables-use of VTE prophylaxis (both pharmacological and nonpharmacological), initiation of treatment, application of specific protocols, rates of VTE and hemorrhagic progression of the traumatic brain injury on computed tomographic scan-were included. The random effects model was used to calculate pooled effect estimates. Heterogeneity among studies was assessed using the Cochran Q homogeneity test. A forest plot was constructed, and aggregate odds ratio was computed. Potential publication bias was evaluated using funnel plots. METHODS & MAIN RESULTS: A total of 12 retrospective observational studies were identified, totaling 8,747 patients. Six studies (3,325 patients) were used to analyze the safety and five (2,105 patients) to analyze the effectiveness of pharmacological versus nonpharmacological prophylaxis, without considering the timing of treatment. Four studies (1,371 patients) were used to evaluate early versus late pharmacologic prophylaxis, with results favoring early administration (odds ratio, 0.46; 95% confidence interval, 0.24-0.88; p < 0.05; I, 46%) and showing no significant differences regarding safety. Three studies (4,133 patients), used to analyze VTE prophylaxis protocols, showed significant heterogeneity (p < 0.01). CONCLUSION: When we compared mechanical and pharmacological prophylaxis, the results were heterogeneous; and thus, their potential differences could not be assessed. In some studies, the introduction of prophylaxis protocols in neurocritical patient care improved their effectiveness. Early pharmacologic prophylaxis, in the first 72 hours after TBI, was more effective than late, when there was no hemorrhagic progression within 24 hours after injury; no significant differences were found regarding safety. LEVEL OF EVEDINCE: Systematic review/meta-analysis, level III.

A fast-track anaemia clinic in the Emergency Department: feasibility and efficacy of intravenous iron administration for treating sub-acute iron deficiency anaemia.

BACKGROUND: Clinically significant anaemia, requiring red blood cell transfusions, is frequently observed in Emergency Departments (ED). To optimise blood product use, we developed a clinical protocol for the management of iron-deficiency anaemia in a fast-track anaemia clinic within the ED. MATERIALS AND METHODS: From November 2010 to January 2014, patients presenting with sub-acute, moderate-to-severe anaemia (haemoglobin [Hb] <11 g/dL) and confirmed or suspected iron deficiency were referred to the fast-track anaemia clinic. Those with absolute or functional iron deficiency were given intravenous (IV) ferric carboxymaltose 500-1,000 mg/week and were reassessed 4 weeks after receiving the total iron dose. The primary study outcome was the haematological response (Hb≥12 g/dL and/or Hb increment ≥2 g/dL). Changes in blood and iron parameters, transfusion rates and IV iron-related adverse drug effects were secondary outcomes. RESULTS: Two hundred and two anaemic patients with iron deficiency (150 women/52 men; mean age, 64 years) were managed in the fast-track anaemia clinic, and received a median IV iron dose of 1,500 mg (1,000-2,000 mg). Gastro-intestinal (44%) or gynaecological (26%) bleeding was the most frequent cause of the anaemia. At follow-up (183 patients), the mean Hb increment was 3.9±2.2 g/dL; 84% of patients were classified as responders and blood and iron parameters normalised in 90%. During follow-up, 35 (17%) patients needed transfusions (2 [range: 1-3] units per patient) because they had low Hb levels, symptoms of anaemia and/or were at risk. Eight mild and one moderate, self-limited adverse drug effects were witnessed. DISCUSSION: Our data support the feasibility of a clinical protocol for management of sub-acute anaemia with IV iron in the ED. IV iron was efficacious, safe and well tolerated. Early management of anaemia will improve the use of blood products in the ED.

Motivos de consulta de pacientes con enfermedades autoinmunes sistémicas en el servicio de urgencias de un hospital terciario / Causes for consultation in the emergency room among patients with systemic autoimmune diseases

Background: The causes of acute decompensations of patients with systemic autoimmune diseases are not well known. Aim: To describe the causes for consultation in an emergency room of patients with systemic autoimmune diseases. Material and Methods: Review of medical records of patients with systemic autoimmune diseases, aged over 14 years, consulting in an emergency room of a general hospital during three months. Results: In the study period, 166 patients with systemic autoimmune diseases consulted in the emergency room, of a total of 18,153 consultations (0.9%). Patients with rheumatoid arthritis were those that consulted with higher frequency (37%) followed by patients with systemic lupus erythematosus (21%). The most common causes for consultation were cardiovascular diseases in 25%, followed by digestive disorders in 15%. The most common diagnosis was chest pain with suspected ischemic heart disease in 36%. No differences in cardiovascular risk factors were observed between those patients consulting for cardiovascular diseases and those consulting for other causes. Conclusions: The most common cause of consultation in the emergency room of patients with systemic autoimmune diseases is cardiovascular.

Traumatismo cráneo-encefálico (TCE) y anticoagulación: Aspectos esenciales. / Traumatic brain injury (TBI) and anticoagulation: Key points

Resumen: Los traumatismos craneoencefálicos (TCE) constituyen un motivo de consulta frecuente en cualquier Servicio de Urgencias. Estados Unidos reporta hasta 1,7 millones de afectados en un año. En España la cifra, solo de TCE leve, se estima en 92000 por año. Los varones, sobre todo después de 65 años, constituyen el grupo más afectado y la caída desde su altura el mecanismo más frecuente. La asociación con tratamiento anticoagulante oral (TAO), agrega mayor complejidad a su manejo y constituye un tema en revisión constante. La necesidad de revertir la anticoagulación, los métodos para lograrlo, la indicación de un segundo control tomográfico en los pacientes con TCE leve-moderado, los algoritmos que orienten y organicen mejor las posibles conductas a seguir, continúan siendo aspectos en revisión. Una adecuada valoración inicial, control TC solo ante deterioro neurológico, y reversión de anticoagulación con complejo protrombínico permiten un manejo eficaz.

Abstract: Traumatic brain injury (TBI) is a frequent reason of consultation in any Emergency Room. The United States report up to 1.7 million affected individuals persons. In Spain, the figure corresponding only to mild TBI is estimated at 92,000 patients per year. Males, specially after age 65, are the most affected group and the most frequent injury mechanism is a a all from their height. The association with oral anticoagulant therapy (OAT) increases the complexity of its managament and is an issue under permanent review. The need to reverse anticoagulation, the methods to achieve it, the prescription of a second CT control in patients with mild to moderate TBI, the algorithms to better guide and organize the possible courses of action are still issues under review. An adequate initial assessment, a CT control only in case of neurological damage and reversion of anticoagulation with prothrombin complex allow an effective management.