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Sepsis severa y shock septico
- 2. TEMAS A TRATAR • Introducción ▫ Historia de la sepsis ▫ Definiciones ▫ Factores de riesgo ▫ Epidemiología ▫ Fisiopatología Surviving Sepsis Campaign ▫ Generalidades ▫ Resucitación inicial ▫ Diagnóstico ▫ Antibioticoterapia ▫ Control de la fuente ▫ Terapia con líquidos ▫ Vasopresores ▫ Inotrópicos ▫ Corticoesteroides ▫ Proteína C Activada recombinante humana ▫ Componentes sanguíneos • Terapia de Soporte para Sepsis Severa ▫ Ventilación mecánica ▫ Sedación, analgesia y bloqueo neuromuscular ▫ Control glucémico ▫ Reemplazo Renal ▫ Bicarbonato ▫ Profilaxis para Trombosis venosa ▫ Profilaxis para úlcera de estrés ▫ Descontaminación Digestiva selectiva
- 3. INTRODUCCIÓN
- 4. HISTORIA DE LA SEPSIS • Etimología ▫ Griega → sipsis ▫ Putrefacción o Descomposición
- 5. Reseña Histórica • 2735 a.C. ▫ Emperador Chino Sheng Nung. • 1862 d.C. ▫ Egipto → Papiro de Smith • Siglo 18 ▫ John Pringle → Anti-sepsis • Siglo 19 ▫ Ignaz Semmelweis → Técnicas anti-sépticas en puérperas ▫ Louis Pasteur → estreptococos como causa de sepsis puerperal. Hernández Botero, J.. Recuento histórico y análisis epistemológico de la sepsis secundaria a lesiones y su control quirúrgico. Desde el papiro de Edwin Smith hasta el pus bonum et laudabile. Iatreia, Norteamérica, 22 2 09
- 7. Definiendo Sepsis Síndrome de Respuesta Inflamatoria Sistémica (SIRS) Desórdenes autoinmunes, pancreatitis, vasculitis, tromboembolismo, quemaduras o cirugía. Dos o más de los siguientes criterios: 1. Temperatura >38.3ºC o <36ºC 2. Fc >90 lat/min 3. Fr >20 resp/min o PaCO2 <32 mmHg 4. GB >12,000 cells/mm3, <4000 cells/mm3, o >10 % bandas o formas celulares inmaduras.
- 8. Definiendo Sepsis SEPSIS Síndrome clínico que asocia una respuesta inflamatoria sistémica exacerbada a un foco infeccioso Dos o más de los criterios de SIRS con un foco infeccioso confirmado o sospechado 1. Temperatura >38.3ºC o <36ºC 2. Fc >90 lat/min 3. Fr >20 resp/min o PaCO2 <32 mmHg 4. GB >12,000 cells/mm3, <4000 cells/mm3, o >10 % bandas o formas celulares inmaduras.
- 9. Definiendo Sepsis SEPSIS SEVERA Sepsis + al menos 1 signo de hipoperfusión o disfunción orgánica 1. Áreas de piel moteada 2. Llenado capilar ≥3 seg 3. Gasto urinario <0,5 mL/Kg al menos una hora o terapia de reemplazo renal.* 4. Lactato >2 mmol/L 5. Cambios abruptos en el estado mental 6. Electroencefalograma (EEG) anormal 7. Trombocitopenia <100,000 plq/mL 8. Coagulación Intravascular diseminada 9. Lesión pulmonar aguda (ALI) o síndrome de distrés respiratorio(ARDS) 10. Disfunción cardíaca por ecocardiografía o medición directa del índice cardíaco *Surviving Sepsis Campaign 2008 : al menos 2 hrs.
- 10. Definiendo Sepsis SHOCK SÉPTICO Sepsis Severa + uno o ambos criterios a continuación: 1. Presión Arterial Media (PAM) <60 mmHg (o <80 mmHg si el paciente es hipertenso) a pesar de la resucitación con líquidos.* 2. Manetener PAM >60 mmHg (o >80 mmHg si es hipertenso) requiere dopamina >5 mcg/kg por min, noradrenalina <0.25 mcg/kg por min, or adrenalina <0.25 mcg/kg por min a pesar de la adecuada resucitación con líquidos. *Infusión de 20 a 30 mL/Kg de coloide, 40 a 60 mL/Kg de SSN. PCWP 12 a 20 mmHg. PVC : 8 a 12 mmHg.
- 11. Definiendo Sepsis SHOCK SÉPTICO REFRACTARIO Presenta los siguientes criterios: 1. Presión Arterial Media (PAM) <60 mmHg (o <80 mmHg si el paciente es hipertenso) a pesar de la resucitación con líquidos.* 2. Manetener PAM >60 mmHg (o >80 mmHg si es hipertenso) requiere dopamina > 15 mcg/kg por min, noradrenalina <0.25 mcg/kg por min, or adrenalina <0.25 mcg/kg por min a pesar de la adecuada resucitación con líquidos.
- 14. SEPSIS Pared celular bacteriana (endotoxina, peptidoglicano, muramil dipéptido y ác lipoteicoico) Productos bactericanos (enterotoxina B, Toxina-1, exotoxina A , proteína M) TNFᾳ IL-1 Fiebre, hipotensión, leucocitosis Citoquinas Proinflamatorias CD-14 Complemento Polimorfismo nucleótido simple (SNP) Linfotoxina a, IL-10, IL-18, IL-6, INFу, Ligandos lipopolisacáridos, HSP- 10, ECA-1, caspasas. apoptosis Isquemia tisular Lesión citopática NO ↓ O2 Coagulación y Fibrinólisis
- 15. SEPSIS Hipotensión Shock Distributivo ↓ADH ↑ NO ↑ P End ↓ RVP Lesión endotelial Edema alveolar e intersticial ARDS ALI Translocación bacteriana y endotoxina SER hepático Lesión Renal Aguda Necrosis tubular aguda Hipotensión Vasoconstricción Citocina s inflamatorias Encefalopatía Diseminación hematógena Cambios metabólicos Barrera hematoencefálica
- 16. DIAGNÓSTICO INICIAL • Encontrar foco infeccioso en primeras 6 h. • Historia clínica y examen físico dirigidos • Prioridad es la resucitación inicial.
- 17. “CAMPAÑA PARA LA SUPERVIVENCIA A LA SEPSIS Y EL SHOCK SÉPTICO”
- 18. CRITERIOS DE SEPSIS VARIABLES GENERALES Fiebre (>38.3°C) Hipotermia (36°C) Fc = 90/min Taquipnea Alteración del estado mental Edema significativo o balance líquido positivo (20 mL/kg en 24 hrs) Hiperglicemia (140 mg/dL o 7.7 mmol/L)en ausencia de diabetes VARIABLES INFLAMATORIAS Leucocitosis > 12,000 Leucopenia < 4,000 GB en cifras normales pero 10 % de formas inmaduras Proteína C reactiva plasmática (PCR) > 2 DE por arriba de VN (5ª6mg. L) Procalcitonina plasmática > 2 DE por arriba de VN. (1ng- ml)
- 19. CRITERIOS DE SEPSIS VARIABLE HEMODINÁMICA Hipotensión arterial (PS < 90 mm Hg; PAM < 70 mm Hg; o ↓PS > 40 mm Hg en adultos o < 2 DE por debajo de VN para la edad.) VARIABLES DE DISFUNCIÓN ORGÁNICA Hipoxemia arterial ( Kirby <300) Oliguria aguda (<0,5 mL/kg hr.) ↑ creatinina (>0,5 mg/dL) Alteración de coagulación (INR >1,5 o PTT >60 seg) Íleo Trombocitopenia (<100,000/uL) Hiperbilirrubinemia (>4 mg/dL) VARIABLE DE PERFUSIÓN TISULAR Hiperlactacidemia Disminución de llenado capilar o moteado
- 20. CRITERIOS DE SEPSIS SEPSIS SEVERA 1. Hipotensión inducida por sepsis 2. Lactato mucho mayor que el límite superior del VN. 3. Gasto urinario <0.5 mL/kg hr por 2 hrs, a pesar de la adecuada resucitación con líquidos 4. ALI con PaO2/FIO2 <250 en ausencia de neumonía 5. ALI with PaO2/FIO2 <200 en presencia de neumonía 6. Creatinina >2.0 mg/dL (176.8 mol/L) 7. Bilirrubina >2 mg/dL (34.2 mol/L) 8. Conteo plaquetario <100,000 9. Coagulopatía (INR >1.5)
- 21. RESUCITACIÓN INICIAL • Recomendación fuerte “Se Recomienda” oRecomendación débil “Se Sugiere” • Iniciar resucitación inmediatamente en pacientes con hipotensión o lactato >4 mmol/L, no postergarlo si aún no puede ser admitido a UCI • Evidencia 1C
- 22. RESUCITACIÓN INICIAL Metas de Resucitación PVC 8-12 mm Hg Gasto Urinario ≥0,5 mL/Kg/hr SVO2 ≥70 % o Venosa mixta ≥65% PAM ≥65 mm Hg Evidencia 1C o Si no se consigue el objetivo de saturación venosa de O2: a) Considerar más fluidos b) Transfundir GRE para mantener hematocrito ≥30% y/o c) Iniciar infusión de dobutamina, máximo 20 ug/kg/min o Evidencia 2C
- 23. DIAGNÓSTICO • Obtener cultivos apropiados antes de iniciar antibióticos si esto no retrasa significativamente la administración de los antimicrobianos ▫ Evidencia 1C
- 24. DIAGNÓSTICO Realizar estudios de imagen lo más pronto posible para confirmar o descartar cualquier fuente de infección, si es seguro hacerlo. ▫ Evidencia 1C
- 25. ANTIBIOTICOTERAPIA • Comenzar antibióticos IV tan pronto como sea posible y siempre en la primera hora de reconocer una sepsis severa y shock séptico. ▫ Evidencia 1D y 1B • Amplio espectro: uno o más agentes activos contra bacterias/hongos y con buena penetración al foco infeccioso ▫ Evidencia 1B
- 26. ANTIBIOTICOTERAPIA • Revaluar el régimen antimicrobiano diariamente para optimizar la eficacia, prevenir la resistencia, evitar toxicidad y minimizar costos. ▫ Evidencia 1C oConsiderar terapia combinada en infección por pseudomona oEvidencia 2D
- 27. ANTIBIOTICOTERAPIA oConsiderar terapia empírica combinada en pacientes neutropénicos oEvidencia 2D oTerapia combinada ≤3-5 días y disminución gradual de la dosis siguiendo susceptibilidades oEvidencia 2D
- 28. ANTIBIOTICOTERAPIA • Duración de la terapia típicamente limitado a 7- 10 días, más tiempo si la respuesta es lenta, foco infeccioso no drenable o déficit inmunológico • Evidencia 1D • Detener terapia antimicrobiana si no se encuentra causa infecciosa. ▫ Evidencia 1D
- 29. CONTROL DE LA FUENTE INFECCIOSA • Un sitio anatómico específico de infección debe ser establecido lo más pronto posible y en las primeras 6 horas de inicio. ▫ Evidencia 1C y 1D • Implementar medidas de control de la fuente tan pronto como sea posible luego de una reanimación inicial exitosa. ▫ Evidencia 1C
- 30. CONTROL DE LA FUENTE INFECCIOSA • Evaluación formal del paciente para un foco de infección para establecer medidas de control. ▫ Evidencia 1C
- 31. CONTROL DE LA FUENTE INFECCIOSA • Elegir la medida de control con la máxima eficacia y la mínima alteración fisiológica. ▫ Evidencia 1 D • Remover un dispositivo de acceso IV si está potencialmente infectado. ▫ Evidencia 1C
- 32. Restitución de Líquidos • Usar cristaloides o coloides ▫ Evidencia 1B • PVC ≥ 8 mm Hg (≥12 mm Hg si tiene ventilación mecánica) ▫ Evidencia 1C • Usar técnicas para administrar fluidos mientas esté asociada a mejoría hemodinámica. ▫ Evidencia 1D
- 33. Restitución de Líquidos • Administrar 1 L de cristaloides o 300-500 mL de coloides por 30 mins. Aumentar la velocidad de infusión si se sospecha de hipoperfusión por sepsis. ▫ Evidencia 1D • La velocidad de infusión debe reducirse si la presión de llenado cardíaco aumenta sin mejoría hemodinámica ▫ Evidencia 1D
- 34. • Mantener PAM ≥65 mm Hg ▫ Evidencia 1C • Noradrenalina y dopamina por vía central son los vasopresores iniciales de elección ▫ Evidencia 1C oAdrenalina, fenilefrina o vasopresina no deberían ser administrados en el shock séptico oEvidencia 2C
- 35. o Usar adrenalina como agente de primera elección en shock séptico cuando la PA no ha respondido adecuadamente con DA o NA. o Evidencia 2B • No usar bajas dosis de DA para protección renal ▫ Evidencia 1 A • En pacientes que requieren vasopresores se deberá insertar una línea arterial tan pronto como sea posible ▫ Evidencia 1D
- 36. • Usar dobutamina en pacientes con disfunción miocárdica ▫ Evidencia 1C • No incrementar el índice cardíaco a niveles supranormales. ▫ Evidencia 1B
- 37. USO DE CORTICOIDES oConsiderar hidrocortisona IV para adultos con shock séptico cuando la hipotensión responde pobremente a la resucitación adecuada con líquidos y vasopresores oEvidencia 2C oPrueba de estimulación con ACTH no se recomienda para identificar pacientes que deban recibir hidrocortisona. oEvidencia 2B
- 38. USO DE CORTICOIDES oSe prefiere Hidrocortisona a dexametasona oEvidencia 2B oFludocortisona (50 ug VO x día) puede ser incluido como alternativa a hidrocortisona oEvidencia 2C oPueden retirarse los corticoides una vez que los vasopresores dejen de requerirse. oEvidencia 2D
- 39. USO DE CORTICOIDES • Hidrocortisona <300 mg/día ▫ Evidencia 1 A • No usar corticoides para tratar sepsis en ausencia de shock a menos que el paciente presente causa previa para hacerlo. ▫ Evidencia 1D
- 40. Proteína C activada recombinante humana • Los pacientes adulto con sepsis severa y bajo riesgo de muerte no deberían recibirlo ▫ Evidencia 1 A oConsiderar esta terapia en adultos con disfunción orgánica y alto riesgo de muerte por sepsis, si no hay contraindicaciones oEvidencia 2B y 2C
- 41. PRODUCTOS SANGUÍNEOS • Administrar GRE cuando la Hb <7,0 g/dL (<70 g/L) para lograr 7,0-9,0 g/dL en adultos. ▫ Evidencia 1B • No usar eritropoyetina para tratar anemia relacionada a sepsis. Sólo se usará por otras razones. ▫ Evidencia 1B • No usar terapia antitrombina ▫ Evidencia 1B
- 42. PRODUCTOS SANGUÍNEOS o No dar PFC para corregir anomalías de la coagulación a menos que esté sangrando o se le realizarán procedimientos. o Evidencia 2D o Administrar plaquetas cuando: 1. <5000/mm3 aunque no esté sangrando 2. 5000-30 000 y exista sangrado significativo 3. Conteo plaquetario ≥ 50 000 sólo para cirugía o procedimientos invasivos o Evidencia 2D
- 43. VENTILACIÓN MECÁNICA • Volumen corriente de 6 mL/Kg del peso ideal en pacientes con ALI/ARDS. ▫ Evidencia 1B • Alcanzar un límite superior de Presión meseta ≤30 cm H20 ▫ Evidencia 1C • Incrementar PaCO2 de ser necesario para minimizar la presión meseta y VT ▫ Evidencia 1C
- 44. VENTILACIÓN MECÁNICA • Colocar PEEP para evitar el colapso pulmonar al final de la expiración. ▫ Evidencia 1C • Mantener pacientes en ventilación mecánica con respaldo a 45° a menos que esté contraidicado y entre 30° a 45°. ▫ Evidencia 1B y 2C
- 45. VENTILACIÓN MECÁNICA oConsiderar usar la posición prona para ARDS si se requieren mejorar niveles de FiO2 o presión meseta, a menos que represente un riesgo. oEvidencia 2C oVentilación no invasiva puede considerarse en la minoría de pacientes con ALI/ARDS con falla respiratoria hipoxémica leve a moderada. oEvidencia 2B
- 46. VENTILACIÓN MECÁNICA • Usar un protocolo de destete de la ventilación y respiraciones espontáneas regularmente para evaluar la posibilidad de descontinuar la VM. 1. Baja presión soporte con presión positiva continua a 5 cm H2O o barra en T. 2. Estar despierto, hemodinámicamente estable sin vasopresores, no condiciones potencialmente serias, baja presión ventilatoria. Bajo FiO2. ▫ Evidencia 1 A
- 47. VENTILACIÓN MECÁNICA • No usar catéter de arteria pulmonar para monitorear rutinariamente pacientes con ALI/ARDS ▫ Evidencia 1 A • Usar estrategia conservadora de fluidos para pacientes con ALI establecido que no tienen hipoperfusión. ▫ Evidencia 1C
- 48. SEDACIÓN y ANALGESIA • Usar protocolos de sedación para una meta de sedación en pacientes críticos con ventilación mecánica. ▫ Evidencia 1B • Usar bolos intermitentes de sedación o infusión continua de manera escalonada con interrupción diariamente para producir despertar. Titular de ser necesario. ▫ Evidencia 1 B
- 49. Bloqueo Neuromuscular • Evitar bloqueadores neuromusculares de ser posible. Monitorear respuesta si se mantiene infusión continua. ▫ Evidencia 1B
- 50. CONTROL GLUCÉMICO • Usar insulina IV para controlar hiperglucemia en pacientes con sepsis severa seguido de estabilización en UCI. ▫ Evidencia 1 B
- 51. CONTROL GLUCÉMICO • Pacientes críticamente enfermos con hiperglucemia persistente deberían iniciar tratamiento para mantener valores por debajo de 180 mg/dL. • Una vez iniciada la insulina IV el rango de glucosa debe ser 140-180 mg/dL en la mayoría de los pacientes. ▫ Evidencia Grado A • Valores 110-140 mg/dL apropiado para pacientes seleccionados ▫ Evidencia Grado C
- 52. CONTROL GLUCÉMICO • Proveer una fuente de glucosa y monitoreo de sus niveles cada 1-2 hrs (4 hrs si está estable) en pacientes que reciben insulina IV. ▫ Evidencia 1 C • Interpretar con precaución niveles bajos de glucosa dependiendo de la técnica empleada ya que puede sobrestimar los valores arteriales o plasmáticos ▫ Evidencia 1 B
- 53. PROFILAXIS PARA TVP • Usar heparina no fraccionada (HNF) o de bajo peso molecular (HBPM) a menos que esté contraindicada ▫ Evidencia 1 A • Usar medidas mecánicas profilácticas cuando la heparina está contraindicada ▫ Evidencia 1 A
- 54. PROFILAXIS PARA TVP oUsar una combinación de terapia farmacológica y mecánica para pacientes quienes están con muy alto riesgo de TVP ▫ Evidencia 2C • En pacientes con muy alto riesgo, HBPM debería utilizarse en lugar de HNF. ▫ Evidencia 2C
- 55. PROFILAXIS ÚLCERAS DE ESTRÉS • Usar antagonistas H2 o inhibidor de bomba de protones. ▫ Evidencia 1 A y 1 B
- 56. BIBLIOGRAFÍA • Hernández Botero, J.. Recuento histórico y análisis epistemológico de la sepsis secundaria a lesiones y su control quirúrgico. Desde el papiro de Edwin Smith hasta el pus bonum et laudabile. Iatreia, Norteamérica, 22 2 09 2009. • Neviere R. Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis. Up-to-date. Apr 2012. Last update: May 2, 2012. • Neviere R. Pathophysiology of sepsis. Up-to-date. Apr 2012. Last update: mar 19, 2012.
- 57. • Standards of Medical Care in Diabetes 2012. Diabetes Care, Volume 35, Supplement 1, January 2012.
Notas del editor
- As long ago as 2735 B.C., the Chinese Emperor, Sheng Nung, wrote about the use of herbal medicines to treat fever brought on by sepsis. La reseña más antigua que tenemos de sepsis asociada a heridas se remonta al papiro descubierto por Edwin Smith en 1862 en las afueras de Luxor, Egipto.3 Redactado cerca de 1600 a. C., este papiro parece ser la copia de otro manuscrito muy anterior que data del año 3000 a. C., por lo cual se lo considera el tratado de cirugía más antiguo que se conoce.4,5 En él se hace referencia a 48 casos de lesiones traumáticas entre heridas, fracturas y luxaciones en diversas partes del cuerpo explicando sus síntomas y signos así como su seguimiento, pronóstico y tratamiento The concept of anti-sepsis (an organized, rational effort to prevent and treat sepsis) was originated by John Pringle, Surgeon General of the British army in the 18th century. A century later, Ignaz Semmelweis introduced antiseptic techniques for the care of women during childbirth. Semmelweis's advances brought the death rate from puerperal fever down from 13.6% of all women who were giving birth to 1.5%. In 1879, the French physician Louis Pasteur identified the streptococcus bacteria as the cause of puerperal sepsis.
- Adequate fluid resuscitation is defined as infusion of 20 to 30 mL/kg of starch, infusion of 40 to 60 mL/kg of saline solution, or a measured pulmonary capillary wedge pressure (PCWP, also known as the pulmonary artery occlusion pressure) of 12 to 20 mmHg. For patients who have a central venous catheter rather than a pulmonary arterial catheter, a central venous pressure (CVP) of 8 to 12 mmHg is a reasonable substitute.
- Refractory septic shock exists if maintaining the systemic mean blood pressure >60 mmHg (or >80 mmHg if the patient has baseline hypertension) requires dopamine >15 mcg/kg per min, norepinephrine >0.25 mcg/kg per min, or epinephrine >0.25 mcg/kg per min despite adequate fluid resuscitation. Adequate fluid resuscitation is defined as infusion of 20 to 30 mL/kg of starch, infusion of 40 to 60 mL/kg of saline solution, or a measured pulmonary capillary wedge pressure (PCWP, also known as the pulmonary artery occlusion pressure) of 12 to 20 mmHg.
- Bacteremia – Patients with bacteremia often develop systemic consequences of infection. In a study of 270 blood cultures, 95 percent of positive blood cultures were associated with sepsis, severe sepsis, or septic shock [11]. Advanced age (≥65 years) – The incidence of sepsis is disproportionately increased in older adult patients and age is an independent predictor of mortality due to sepsis. Moreover, older adult non-survivors tend to die earlier during hospitalization and older adult survivors more frequently require skilled nursing or rehabilitation after hospitalization [12 Immunosuppression – Comorbidities that depress host-defense (eg, neoplasms, renal failure, hepatic failure, AIDS) and immunosuppressant medications are common among patients with sepsis, severe sepsis, or septic shock. Community acquired pneumonia – Severe sepsis and septic shock develop in approximately 48 and 5 percent, respectively, of patients with community-acquired pneumonia [13]. Genetic factors – Both experimental and clinical studies have confirmed that genetic factors can increase the risk of infection. In few cases, monogenic defects underlie vulnerability to specific infection, but genetic factors are typically genetic polymorphisms. Genetic studies of susceptibility to infection have initially focused on defects of antibody production, or a lack of T cells, phagocytes, natural killer cells, or complement. Recently, genetic defects have been identified that impair recognition of pathogens by the innate immune system, increasing susceptibility to specific classes of microorganisms [14].
- Effects of microorganisms — Bacterial cell wall components (endotoxin, peptidoglycan, muramyl dipeptide, and lipoteichoic acid) and bacterial products (staphylococcal enterotoxin B, toxic shock syndrome toxin-1, Pseudomonas exotoxin A, and M protein of hemolytic group A streptococci) may contribute to the progression of a local infection to sepsis [10]. This is supported by the following observations regarding endotoxin, a lipopolysaccharide found in the cell wall of gram negative bacteria: Endotoxin is detectable in the blood of septic patients. Elevated plasma levels of endotoxin are associated with shock and multiple organ dysfunction (table 2). Endotoxin reproduces many of the features of sepsis when it is infused into humans, including activation of the complement, coagulation, and fibrinolytic systems [11,12]. These effects may lead to microvascular thrombosis and the production of vasoactive products, such as bradykinin. Excess proinflammatory mediators — Large quantities of proinflammatory cytokines released in patients with sepsis may spill into the bloodstream, contributing to the progression of a local infection to sepsis. These include tumor necrosis factor-alpha (TNFa) and interleukin-1 (IL-1), whose plasma levels peak early and eventually decrease to undetectable levels. Both cytokines can cause fever, hypotension, leukocytosis, induction of other proinflammatory cytokines, and the simultaneous activation of coagulation and fibrinolysis (table 1). The evidence indicating that TNFa has an important role in sepsis is particularly strong. It includes the following: circulating levels of TNFa are higher in septic patients than non-septic patients with shock [13], infusion of TNFa produces symptoms similar to those observed in septic shock [14], and anti-TNFa antibodies protect animals from lethal challenge with endotoxin [15]. The high levels of TNFa in sepsis are due in part to the binding of endotoxin to lipopolysaccharide (LPS)-binding protein and its subsequent transfer to CD14 on macrophages, which stimulates TNFa release [16]. Complement activation — The complement system is a protein cascade that helps clear pathogens from an organism [17,18]. It is described in detail separately. (See "Complement pathways".) There is evidence that activation of the complement system plays an important role in sepsis; most notably, inhibition of the complement cascade decreases inflammation and improves mortality in animal models: In a rodent model of sepsis, a complement fragment 5a receptor (C5aR) antagonist decreased mortality, inflammation, and vascular permeability [19,20]. In contrast, increased production of complement fragment 5a (C5a) and increased expression of C5aR enhanced neutrophil trafficking [21,22]. In several animal models of sepsis (lipopolysaccharide injection in mice and rats, Escherichia coli infusion in dogs and baboons, and cecal ligation and puncture in mice), a complement fragment 1 (C1) inhibitor decreased mortality, inflammation, and vascular permeability [23-27]. Genetic susceptibility — The single nucleotide polymorphism (SNP) is the most common form of genetic variation. SNPs are stable substitutions of a single base that have a frequency of more than one percent in at least one population and are strewn throughout the genome, including promoters and intergenic regions. At most, only 2 to 3 percent alter the function or expression of a gene. The total number of common SNPs in the human genome is estimated to be more than 10 million. SNPs are used as genetic markers. Various SNPs are associated with increased susceptibility to infection and poor outcomes. They include SNPs of genes that encode cytokines (eg, TNF, lymphotoxin-alpha, IL-10, IL-18, IL-1 receptor antagonist, IL-6, and interferon gamma), cell surface receptors (eg, CD14, MD2, toll-like receptors 2 and 4, and Fc-gamma receptors II and III), lipopolysaccharide ligands (lipopolysaccharide binding protein, bactericidal permeability increasing protein), mannose-binding lectin, heat shock protein 70, angiotensin I-converting enzyme, plasminogen activator inhibitor, and caspase-12 [28]. SYSTEMIC EFFECTS OF SEPSIS — Widespread cellular injury may occur when the immune response becomes generalized; cellular injury is the precursor to organ dysfunction. The precise mechanism of cellular injury is not understood, but its occurrence is indisputable as autopsy studies have shown widespread endothelial and parenchymal cell injury. Mechanisms proposed to explain the cellular injury include: tissue ischemia (insufficient oxygen relative to oxygen need), cytopathic injury (direct cell injury by proinflammatory mediators and/or other products of inflammation), and an altered rate of apoptosis (programmed cell death). Tissue ischemia — Significant derangement in metabolic autoregulation, the process that matches oxygen availability to changing tissue oxygen needs, is typical of sepsis. In addition, microcirculatory and endothelial lesions frequently develop during sepsis. These lesions reduce the cross-sectional area available for tissue oxygen exchange, disrupting tissue oxygenation and causing tissue ischemia and cellular injury: Microcirculatory lesions – The microcirculatory lesions may be the result of imbalances in the coagulation and fibrinolytic systems, both of which are activated during sepsis. Endothelial lesions – The endothelial lesions may be a consequence of interactions between endothelial cells and activated polymorphonuclear leukocytes (PMNs). The increase in receptor-mediated neutrophil-endothelial cell adherence induces the secretion of reactive oxygen species, lytic enzymes, and vasoactive substances (nitric oxide, endothelin, platelet-derived growth factor, and platelet activating factor) into the extracellular milieu, which may injure the endothelial cells. Another factor contributing to tissue ischemia in sepsis is that erythrocytes lose their normal ability to deform within the systemic microcirculation [29-31]. Rigid erythrocytes have difficulty navigating the microcirculation during sepsis, causing excessive heterogeneity in the microcirculatory blood flow and depressed tissue oxygen flux. Cytopathic injury — Proinflammatory mediators and/or other products of inflammation may cause sepsis-induced mitochondrial dysfunction (eg, impaired mitochondrial electron transport) via a variety of mechanisms, including direct inhibition of respiratory enzyme complexes, oxidative stress damage, and mitochondrial DNA breakdown [32]. Such mitochondrial injury leads to cytotoxicity. There are several lines of evidence that support this belief: Cell culture experiments have shown that endotoxin, TNFa, and nitric oxide cause destruction and/or dysfunction of inner membrane and matrix mitochondrial proteins, followed by degeneration of the mitochondrial ultrastructure. These changes are followed by measurable changes in other cellular organelles by several hours [33]. The end result is functional impairment of mitochondrial electron transport, disordered energy metabolism, and cytotoxicity. Studies using various animal models have found normal or supranormal oxygen tension in organs during sepsis, suggesting impaired oxygen utilization at the mitochondrial level. As examples, a study in resuscitated endotoxemic pigs found a supranormal ileomucosal oxygen tension [34], while a study in endotoxemic rats found an elevated oxygen tension in the bladder epithelium [35]. The clinical relevance of mitochondrial dysfunction in septic shock was suggested by a study of 28 critically ill septic patients who underwent skeletal muscle biopsy within 24 hours of admission to the ICU [36]. Skeletal muscle ATP concentrations, a marker of mitochondrial oxidative phosphorylation, were significantly lower in the 12 patients who died of sepsis than in 16 survivors. In addition, there was an association between nitric oxide overproduction, antioxidant depletion, and severity of clinical outcome. Thus, cell injury and death in sepsis may be explained by cytopathic (or histotoxic) anoxia, which is an inability to utilize oxygen even when present. Mitochondria can be repaired or regenerated by a process called biogenesis. Mitochondrial biogenesis may prove to be an important therapeutic target, potentially accelerating organ dysfunction and recovery from sepsis [37]. Apoptosis — Apoptosis (also called programmed cell death) describes a set of regulated physiologic and morphologic cellular changes leading to cell death. This is the principal mechanism by which senescent or dysfunctional cells are normally eliminated and the dominant process by which inflammation is terminated once an infection has subsided. During sepsis, proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, thereby prolonging or augmenting the inflammatory response and contributing to the development of multiple organ failure. Sepsis also induces extensive lymphocyte and dendritic cell apoptosis, which alters the immune response efficacy and results in decreased clearance of invading microorganisms. Apoptosis of lymphocytes has been observed at autopsies in both animal and human sepsis. The extent of lymphocyte apoptosis correlates with and the severity of the septic syndrome and the level of immunosuppression. Apoptosis has been also observed in parenchymal cells, endothelial, and epithelial cells. Several experiments studies show that inhibiting apoptosis protect animal from organ dysfunction and lethality [38,39]. Immunosuppression — Clinical observations and animal studies suggest that the excess inflammation of sepsis may be followed by immunosuppression [40-42]. Among the evidence supporting this hypothesis, an observational study removed the spleens and lungs from 40 patients who died with active severe sepsis and then compared them with the spleens from 29 control patients and the lungs from 30 control patients [43]. The median duration of sepsis was four days. The secretion of proinflammatory cytokines (ie, tumor necrosis factor, interferon gamma, interleukin-6, and interleukin-10) from the splenocytes of patients with severe sepsis was generally less than 10 percent that of controls, following stimulation with either anti-CD3/anti-CD28 or lipopolysaccharide. Moreover, the cells from the lungs and spleens of patients with severe sepsis exhibited increased expression of inhibitory receptors and ligands, as well as expansion of suppressor cell populations, compared with cells from control patients. The inability to secrete proinflammatory cytokines combined with enhanced expression of inhibitory receptors and ligands suggests clinically relevant immunosuppression
- ORGAN-SPECIFIC EFFECTS OF SEPSIS — The cellular injury described above, accompanied by the release of proinflammatory and antiinflammatory mediators, often progresses to organ dysfunction. No organ system is protected from the consequences of sepsis; those listed included in this section are the organ systems that are most often involved. Multiple organ dysfunction is common. Circulation — Hypotension due to diffuse vasodilation is the most severe expression of circulatory dysfunction in sepsis. It is probably an unintended consequence of the release of vasoactive mediators, whose purpose is to improve metabolic autoregulation (the process that matches oxygen availability to changing tissue oxygen needs) by inducing appropriate vasodilation. Mediators include the vasodilators prostacyclin and nitric oxide (NO), which are produced by endothelial cells. NO is believed to play a central role in the vasodilation accompanying septic shock, since NO synthase can be induced by incubating vascular endothelium and smooth muscle with endotoxin [44,45]. When NO reaches the systemic circulation, it depresses metabolic autoregulation at all of the central, regional, and microregional levels of the circulation. In addition, NO may trigger an injury in the central nervous system that is localized to areas that regulate autonomic control [46]. Another factor that may contribute to the persistence of vasodilation during sepsis is impaired compensatory secretion of antidiuretic hormone (vasopressin). This hypothesis is supported by a study that found that plasma vasopressin levels were lower in patients with septic shock than in patients with cardiogenic shock (3.1 versus 22.7 pg/mL), even though the groups had similar systemic blood pressures [47]. It is also supported by numerous small studies that demonstrated that vasopressin improves hemodynamics and allows other pressors to be withdrawn [48-51]. (See "Use of vasopressors and inotropes", section on 'Vasopressin and analogs'.) Vasodilation is not the only cause of hypotension during sepsis. Hypotension may also be due to redistribution of intravascular fluid. This is a consequence of both increased endothelial permeability and reduced arterial vascular tone leading to increased capillary pressure. In addition to these diffuse effects of sepsis on the circulation, there are also localized effects: In the central circulation (ie, heart and large vessels), decreased systolic and diastolic ventricular performance due to the release of myocardial depressant substances is an early manifestation of sepsis [52,53]. Despite this, ventricular function may still be able to use the Frank Starling mechanism to increase cardiac output, which is necessary to maintain the blood pressure in the presence of systemic vasodilation. Patients with preexisting cardiac disease (eg, elderly patients) are often unable to increase their cardiac output appropriately. In the regional circulation (ie, small vessels leading to and within the organs), vascular hyporesponsiveness (ie, inability to appropriately vasoconstrict) leads to an inability to appropriately distribute systemic blood flow among organ systems. As an example, sepsis interferes with the redistribution of blood flow from the splanchnic organs to the core organs (heart and brain) when oxygen delivery is depressed [54]. The microcirculation (ie, capillaries) may be the most important target in sepsis. Sepsis is associated with a decrease in the number of functional capillaries, which causes an inability to extract oxygen maximally (figure 2) [55,56]. Techniques including reflectance spectrophotometry and orthogonal polarization spectral imaging have allowed in vivo visualization of the sublingual and gastric microvasculature [57,58]. Compared to normal controls or critically ill patients without sepsis, patients with severe sepsis have decreased capillary density [58]. This may be due to extrinsic compression of the capillaries by tissue edema, endothelial swelling, and/or plugging of the capillary lumen by leukocytes or red blood cells (which lose their normal deformability properties in sepsis). At the level of the endothelium, sepsis induces phenotypic changes to endothelial cells. This occurs through direct and indirect interactions between the endothelial cells and components of the bacterial wall. These phenotypic changes may cause endothelial dysfunction, which is associated with coagulation abnormalities reduced leukocytes, decreased red blood cell deformability, upregulation of adhesion molecules, adherence of platelets and leukocytes, and degradation of the glycocalyx structure [59]. Diffuse endothelial activation leads to widespread tissue edema, which is rich in protein. Microparticles from circulating and vascular cells also participate in the deleterious effects of sepsis-induced intravascular inflammation [60]. Lung — Endothelial injury in the pulmonary vasculature during sepsis disturbs capillary blood flow and enhances microvascular permeability, resulting in interstitial and alveolar pulmonary edema [61,62]. Neutrophil entrapment within the lung's microcirculation initiates and/or amplifies the injury in the alveolocapillary membrane. The result is pulmonary edema, which creates ventilation-perfusion mismatch and leads to hypoxemia. Such lung injury is prominent during sepsis, likely reflecting the lung's large microvascular surface area. Acute respiratory distress syndrome is a manifestation of these effects. (See "Acute respiratory distress syndrome: Epidemiology; pathophysiology; pathology; and etiology".) Gastrointestinal tract — The circulatory abnormalities typical of sepsis may depress the gut's normal barrier function, allowing translocation of bacteria and endotoxin into the systemic circulation (possibly via lymphatics, rather than the portal vein) and extending the septic response [61-64]. This is supported by animal models of sepsis, as well as a prospective cohort study that found that increased intestinal permeability (determined from the urinary excretion of orally administered lactulose and mannose) was predictive of the development of multiple organ dysfunction syndrome [65]. Liver — The reticuloendothelial system of the liver normally acts as the first line of defense in clearing bacteria and bacteria-derived products that have entered the portal system from the gut. Liver dysfunction can prevent the elimination of enteric-derived endotoxin and bacteria-derived products, which precludes the appropriate local cytokine response and permits direct spillover of these potentially injurious products into the systemic circulation [61,62]. Kidney — Sepsis is often accompanied by acute renal failure. The mechanisms by which sepsis and endotoxemia lead to acute renal failure are incompletely understood. Acute tubular necrosis due to hypoperfusion and/or hypoxemia is one mechanism [61,62]. However, systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, tumor necrosis factor), and activation of neutrophils by endotoxin and FMLP (a three amino acid [fMet-Leu-Phe] chemotactic peptide in bacterial cell walls) may also contribute to renal injury. (See"Pathogenesis and etiology of postischemic acute tubular necrosis".) The likelihood of death is increased in patients with sepsis who develop renal failure. It is not well understood why this occurs. One factor may be the release of proinflammatory mediators as a result of leukocyte-dialysis membrane interactions when hemodialysis is necessary. Use of biocompatible membranes can prevent these interactions and may improve survival and the recovery of renal function [66]. (See "Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure): Recovery of renal function and effect of hemodialysis membrane", section on 'Complement activation, membrane biocompatibility, renal recovery, and survival'.) Nervous system — Central nervous system (CNS) complications occur frequently in septic patients, often before the failure of other organs. The most common CNS complications are an altered sensorium (encephalopathy). The pathogenesis of the encephalopathy is poorly defined. A high incidence of brain microabscesses was noted in one study, but the significance of hematogenous infection as the principal mechanism remains uncertain because of the heterogeneity of the observed pathology. CNS dysfunction has been attributed to changes in metabolism and alterations in cell signalling due to inflammatory mediators. Dysfunction of the blood brain barrier probably contributes, allowing increased leukocyte infiltration, exposure to toxic mediators, and active transport of cytokines across the barrier [67]. Mitochondrial dysfunction and microvascular failure both precede functional CNS changes, as measured through somatosensory evoked potentials [68]. In addition to these neurological consequences of sepsis, there is growing recognition that the parasympathetic nervous system may be a mediator of systemic inflammation during sepsis. This is supported by numerous observations in various animal models. Afferent vagus nerve stimulation during sepsis increases the secretion of corticotropin-releasing hormone (CRH), ACTH, and cortisol; the last effect can be suppressed by subdiaphragmatic vagotomy [69,70]. Parasympathetic tone affects thermoregulation, as experimental vagotomy attenuates the hyperthermic response to IL-1 [70,71]. Efferent parasympathetic activity, mediated by acetylcholine, has an antiinflammatory effect on the cytokine profile, with decreased in vitro expression of the proinflammatory cytokines TNF, IL-1, IL-6 and IL-18 [72]. And, external vagal stimulation prevents the onset of shock following vagotomy [72], while an acetylcholine receptor agonist diminishes the pathologic response to sepsis [73].
- Desde el año 2002 surgió la iniciativa de parte de la Sociedad Americana de Medicina Crítica (SCCM), la Sociedad Europea de Medicina Crítica y Terapia Intensiva (ESICM), y el Foro Internacional de Sepsis (ISF) de crear e implementar mecanismos y herramientas que lograrán un mejor tratamiento de los pacientes con sepsis. Desde ese entonces surgió la “Campaña para la Supervivencia a la Sepsis Severa y el Shock Séptico” (SSC). Esta campaña fue diseñada en tres fases: La primera fue la información y divulgación de la idea en diferentes escenarios alrededor del mundo con el fin de que la comunidad médica conociera la problemática, a continuación en el año 2004 se elaboró y se publicó una guía basada en evidencia para el diagnóstico y tratamiento de la sepsis severa y el shock séptico, lo que constituyó la segunda fase de la campaña. Recientemente, a comienzos del año 2008, se publicó la actualización de estas guías. La elaboración de las guías clínicas basadas en la evidencia fue desarrollada por un diverso panel de expertos en el área de la sepsis en respuesta a una serie de estudios que contundentemente demostraron que algunos tratamientos para la sepsis lograron una reducción de la mortalidad. Los estudios mas notables incluyeron hallazgos tales como: La reanimación inicial temprana dirigida con metas logró reducir la mortalidad en un 16%, dosis bajas de hidrocortisona prolongaron la sobrevida en los pacientes con shock refractario e insuficiencia adrenal relativa en un 31%, la ventilación mecánica protectiva con volumen corriente bajo redujo la mortalidad en un 8,8%, la proteína C recombinante activada redujo la mortalidad de los pacientes con alto riesgo de mortalidad en un 13%, el uso de antibióticos apropiados redujo la mortalidad en un 14%. La tercera fase y quizás la mas importante de llevar a cabo es la de implementar y llevar a la práctica diaria toda la información contenida en las guías basadas en evidencia.
- ● Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source (1B) ● Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs (1C) Consider combination therapy in Pseudomonas infections (2D) Consider combination empiric therapy in neutropenic patients (2D) Combination therapy 3–5 days and de-escalation following susceptibilities (2D) ● Duration of therapy typically limited to 7–10 days; longer if response is slow or there are undrainable foci of infection or immunologic deficiencies (1D) ● Stop antimicrobial therapy if cause is found to be noninfectious (1D)
- ○ Critically ill patients: Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold of no greater than 180 mg/dL (10 mmol/L). Once insulin therapy is started, a glucose range of 140–180 mg/dL (7.8 to 10 mmol/L) is recommended for the majority of critically ill patients. (A) ○ More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L) may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. (C) ○ Critically ill patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia.