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![Bibliografía
• Pediatric sepsis in the developing world, Kissoon, Niranjan, Journal of Infection, Volume 71, Supplement 1, S21-S26
• Angus DC, van der Poll T. Severe Sepsis and Septic Shock. New England Journal of Medicine. 2013;369(9):840-851. doi:10.1056/NEJMra1208623.
• Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
• Official UpToDate, Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis - This topic last updated: Oct 30, 2015
• Liñán-Ponce J, Clinical characteristics of the admitted patients with severe sepsis to an Intensive Care Unit, Rev Soc Peru Med Interna 2008; vol 21 (4)
• Mayorga M, Strategies for improving survival in patients with severe sepsis, Acta Med Per 27(4) 2010
• Bozza Fernando A, Bozza Patrícia T, Castro Faria Neto Hugo C. Beyond sepsis pathophysiology with cytokines: what is their value as biomarkers for disease severity?.
Mem. Inst. Oswaldo Cruz [Internet]. 2005 Mar [cited 2016 Jan 12] ; 100( Suppl 1 ): 217-221.
• Zou, Qi, Wei Wen, and Xin-chao Zhang. “Presepsin as a Novel Sepsis Biomarker.” World Journal of Emergency Medicine 5.1 (2014): 16–19. PMC. Web. 12 Jan. 2016.
• Swiss Med Wkly, Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia, 2012;142:w13542
• Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Mirjam Christ-Crain, Critical Care 2005, 9:R816-R824](https://image.slidesharecdn.com/sepsis-sepsissevera-shocksptico-160203040916/75/Sepsis-sepsis-severa-shock-septico-30-2048.jpg)
Subido porRicardo Falcón
Sepsis sepsis severa - shock séptico
Este documento presenta información sobre sepsis, sepsis severa y shock séptico. Define estos términos y describe los criterios diagnósticos. Explica la fisiopatología subyacente, incluida la respuesta inflamatoria sistémica y la disfunción de órganos. También cubre biomarcadores como la procalcitonina y la presepsina que pueden usarse para el diagnóstico. Finalmente, resume las tasas de incidencia y mortalidad reportadas de sepsis en diferentes países.
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Sepsis sepsis severa - shock séptico
- 1. Sepsis - SepsisSevera - Shock Séptico Ricardo Falcón Salinas Alumno 7° año de Medicina Humana UNMSM – San Fernando HCAB
- 2. Agenda • Introducción • Definición •Criterios Diagnósticos • Fisiopatología • Novedades en el Diagnóstico
- 3. Introducción 37% Sepsis 30% Sepsis Severa Mexico •27.3% Incidencia • 30.4% Mortalidad Carrillo-Esper R, Carrillo-Córdova JR, Carrillo-Córdova LD. Estudio epidemiológico de la sepsis en unidades de terapia intensiva mexicanas. Cirugía y Cirujanos de la Academia Mexicana de Cirugía 2009;77:301–8. Vincent J-L, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA: the journal of the American Medical Association 2009;302(21):2323–2329.
- 4. Gramm + Gramm - Mixtas Hongos Anaerobios Cultivos- • 25% • 25% • 15% • 3-15% • 2% • 25% Angus DC, van der Poll T. Severe Sepsis and Septic Shock. New England Journal of Medicine 2013;369(9):840-851.
- 5. Pulmón 50% Abdomen ypelvis 25% Urinario 10% Sangre 15%
- 6. Introducción • 750,000 personaspor año sufren de sepsis en USA; 210,000 de ellas morirán. • Sepsis es la 1° causa de mortalidad de áreas de cuidado crítico • La mortalidad de sepsis y shock séptico oscila entre 35 – 80%, los progresos en el conocimiento no se han traducido en progresos terapéuticos en esta patología. Medicrit 2005; 2(8):164-178 AN.MED. INTERNA (Madrid) Vol. 19, N.º 1, pp. 35-43, 2002
- 7. Perú Se reportó unafrecuencia de 48,6% de enfermedad infecciosa al momento de admisión, con una mortalidad global de 31,4%, siendo 39,4% en el caso de pacientes infectados versus 23,6% en pacientes no infectados al momento de la admisión El origen de la infección más frecuente fue abdominal (44%), seguido del respiratorio (40%), urinario (12%) y otros (4%). Dentro del periodo de estudio murieron 27 pacientes (25,2%) en la UCI y 31 pacientes (30%) dentro de los 28 días de seguimiento. Rev Soc Peru Med Interna 2008; vol 21 (4)
- 8. Agenda • Introducción • Definicióny Criterios Diagnósticos • Fisiopatología • Novedades en el Diagnóstico
- 9. Definiciones SEPSIS SEPSIS SEVERA SHOCK SEPTICO INFECCION+ SIRS SEPSIS + DISFUNCION DE ORGANOS SEPSIS + HIPOTENSION REFRACTARIA A CRISTALOIDES Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
- 10. Criterios Síndrome de RespuestaInflamatoria 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. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
- 11. Criterios SEPSIS Síndrome clínico queasocia 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. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
- 12. Criterios SEPSIS SEVERA Sepsis +al menos 1 signo de hipoperfusión o disfunción orgánica 1. Sepsis-induced hypotension 2. Lactate above upper limits of laboratory normal (> 2mmol/L) 3. Urine output <0.5 mL/kg/hr for more than two hours despite adequate fluid resuscitation 4. Acute lung injury with PaO /FIO <250 in the absence of pneumonia as infection source 5. Acute lung injury with PaO /FIO <200 in the presence of pneumonia as infection source 6. Creatinine >2 mg/dL (176.8 micromol/L) / Creatinine increase >0.5 mg/dL 7. Bilirubin >4 mg/dL (70 micromol/L) 8. Platelet count <100,000 microL–1 9. Coagulopathy (INR >1.5) 10. Ileus (absent bowel sounds) Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis - This topic last updated: Oct 30, 2015 - Official reprint from UpToDate
- 13. Criterios SEPSIS SEVERA Sepsis +al menos 1 signo de hipoperfusión o disfunción orgánica 1. Áreas de piel moteada 2. Llenado capilar ≥3 seg 3. Cambios abruptos en el estado mental 4. Electroencefalograma (EEG) anormal 5. Coagulación Intravascular diseminada 6. Lesión pulmonar aguda (ALI) o síndrome de distrés respiratorio(ARDS) 7. Disfunción cardíaca por ecocardiografía o medición directa del índice cardíaco Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
- 14. Criterios 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 (infusion of 30 mL/kg of crystalloids). 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. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
- 15. Criterios SHOCK SÉPTICO REFRACTARIO Presentalos siguientes criterios: 1. Presión Arterial Media (PAM) <60 mmHg (ó <80 mmHg si el paciente es hipertenso) a pesar de la resucitación con líquidos (infusion of 30 mL/kg of crystalloids). 2. Mantener 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. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1.
- 16. Disfunción orgánica progresiva + Primaria + Secundaria PO2/FiO2 CreatininaSérica Conteo plaquetario Escala de Glasgow Bilirrubina Sérica Fc ajustada a la presión, (Fc x PVC/PAM) Primaria: A result of a well-defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself (eg, renal failure due to rhabdomyolysis) Secndaria: Organ failure that is not in direct response to the insult itself, but is a consequence of the host’s response (eg, acute respiratory distress syndrome in patients with pancreatitis) Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis - This topic last updated: Oct 30, 2015 - Official reprint from UpToDate
- 17.
- 18. Agenda • Introducción • Definicióny Criterios Diagnósticos • Fisiopatología • Novedades en el Diagnóstico
- 19.
- 20. The peptidoglycan ofGram-positive bacteria binding to TLR-2 on host immune cells. The lipopolysaccharide of Gram-negative bacteria binding to TLR-4 and/or lipopolysaccharide-binding protein (CD14 complex) on host immune cells. Polymorphonuclear leukocytes (PMNs) become activated and express adhesion molecules that cause their aggregation and margination to the vascular endothelium. This is facilitated by the endothelium expressing adherence molecules to attract leukocytes. The PMNs then go through a series of steps (rolling, adhesion, diapedesis, and chemotaxis) to migrate to the site of injury. The release of mediators by PMNs at the site of infection is responsible for the cardinal signs of local inflammation: warmth and erythema due to local vasodilation and hyperemia, and protein-rich edema due to increased microvascular permeability.
- 21. 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 N O ↓ O2 Coagulación y Fibrinólisis
- 22. 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
- 23. Pathophysiology of sepsis-inducedorgan dysfunction. DAMPs, damage- associated molecular patterns; LPS, lipopolysaccharide; LTA, lipoteichoic acid; PAMPs, pathogen-associated molecular patterns. Cardiorenal Syndrome Ronco, Claudio, MD, PhD, Heart Failure Clinics, Volume 10, Issue 2, 251-280 Copyright © 2014 Elsevier Inc.
- 25. Agenda • Introducción • Definicióny Criterios Diagnósticos • Fisiopatología • Novedades en el Diagnóstico
- 26. Biomarcadores Procalcitonina • gene,Calc-1, waslocalized to chromosome 11p15.4 • Its promoter presents binding sites to transcription factors such as NFkB and AP-1. • It’s expressed in different cells and tissues such as a neurons, blood leukocytes, liver and brain after stimulation by cytokines (TNF e IL- 6) or LPS. • It’s rapidly secreted and can be measured in the plasma as early as 2 h after the beginning of the infection, peaking within 12-24 h. Normal values are usually bellow 0.5 ng/ml and can increase up to 2000 fold during severe infections. • Not usually elevated during viral infection Presepsina • Se genera a través de la molécula sCD14. • La Glicoproteína CD14, receptor para los lipopolisacáridos (LPS) en Gram negativas. • El complejo LPS-LBP se une al receptor CD14, y este complejo activa al receptor TLR4, con la consecuente liberación de citoquinas e interleukinas, produciendo la cascada inflamatoria contra los agentes infecciosos. El complejo LPS-LPBP-CD14 se libera a la circulación, formándose así el sCD14 y a través de la actividad de ciertas enzimas se genera el subtipo sCD14 (sCD14-ST) llamado Presepsina. • Gram positivas, es a través de la Fagocitosis y mediante enzimas como la Catalasa, se generaría el fragmento sCD14-ST conocido como Presepsina. • 15min Proadrenomedulina • Peptide with 52 amino acids, has immune modulating, metabolic and vascular actions • It is a potent vasodilator, and its widespread production in tissues helps to maintain blood supply to individual organs. • Bactericidal activity, which is further enhanced by its regulation and modulation of complement activity. • Not surprisingly, serum levels of ADM were shown to be increased in sepsis. • Quantification of ADM could be helpful in diagnosis and monitoring of sepsis and in prognostication. I • t is rapidly cleared from the circulation, it was identified in plasma of patients with septic shock.
- 29. Bibliografía • 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. • Schuetz P, Plebani M. Can biomarkers help us to better diagnose and manage sepsis? Diagnosis. 2015;2(2). doi:10.1515/dx-2014-0073 • Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. BMJ. 2007;335(7625):879-883. doi:10.1136/bmj.39346.495880.AE • J. L Vincent, Opal Steven M. Sepsis definitions: time for change. The Lancet 2013;387:774-75. • Sepsis, en Marik PE. Evidence-Based Critical Care. Cham: Springer International Publishing; 2015. • Carrillo-Esper R, Carrillo-Córdova JR, Carrillo-Córdova LD. Estudio epidemiológico de la sepsis en unidades de terapia intensiva mexicanas. Cirugía y Cirujanos de la Academia Mexicana de Cirugía 2009;77:301–8. • Vincent J-L, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA: the journal of the American Medical Association 2009;302(21):2323–2329. • Angus DC, van der Poll T. Severe Sepsis and Septic Shock. New England Journal of Medicine 2013;369(9):840-851 • Bosmann M, Ward PA. The inflammatory response in sepsis. Trends in Immunology. 2013;34(3):129-136. doi:10.1016/j.it.2012.09.004. • Kingsmore, Stephen F., Genomic and Personalized Medicine, Chapter 98, 1155-1172
- 30. Bibliografía • Pediatric sepsisin the developing world, Kissoon, Niranjan, Journal of Infection, Volume 71, Supplement 1, S21-S26 • Angus DC, van der Poll T. Severe Sepsis and Septic Shock. New England Journal of Medicine. 2013;369(9):840-851. doi:10.1056/NEJMra1208623. • Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Vol. 36, No. 1. • Official UpToDate, Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis - This topic last updated: Oct 30, 2015 • Liñán-Ponce J, Clinical characteristics of the admitted patients with severe sepsis to an Intensive Care Unit, Rev Soc Peru Med Interna 2008; vol 21 (4) • Mayorga M, Strategies for improving survival in patients with severe sepsis, Acta Med Per 27(4) 2010 • Bozza Fernando A, Bozza Patrícia T, Castro Faria Neto Hugo C. Beyond sepsis pathophysiology with cytokines: what is their value as biomarkers for disease severity?. Mem. Inst. Oswaldo Cruz [Internet]. 2005 Mar [cited 2016 Jan 12] ; 100( Suppl 1 ): 217-221. • Zou, Qi, Wei Wen, and Xin-chao Zhang. “Presepsin as a Novel Sepsis Biomarker.” World Journal of Emergency Medicine 5.1 (2014): 16–19. PMC. Web. 12 Jan. 2016. • Swiss Med Wkly, Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia, 2012;142:w13542 • Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Mirjam Christ-Crain, Critical Care 2005, 9:R816-R824
- 31.
Notas del editor
- #20 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].
- #22 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
- #23 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].
- #27 La procalcitonina (PCT), una proteína que consta de 116 aminoácidos, es el precursor del péptido de la calcitonina, una hormona que se sintetiza por las células C parafoliculares de la glándula tiroides y participa en la homeostasis del calcio. La Glicoproteína CD14, presente en la membrana de los macrófagos y monocitos, sirve como receptor para los lipopolisacáridos (LPS) presentes en la pared de las bacterias Gram negativas. El complejo LPS-LBP se une al receptor CD14, y este complejo activa al receptor TLR4, con la consecuente liberación de citoquinas e interleukinas, produciendo la cascada inflamatoria contra los agentes infecciosos. El complejo LPS-LPBP-CD14 se libera a la circulación, formándose así el sCD14 y a través de la actividad de ciertas enzimas se genera el subtipo sCD14 (sCD14-ST) llamado PRESEPSINA La adrenomedulina (ADM) es un péptido con actividad inmunomoduladora, metabólica y vasodilatadora. Además, se eleva en procesos infecciosos independientemente de la etiología (bacteriana, viral o fúngica). Su vida media es muy corta por lo que medirlo en sangre es difícil. MidRange-Proadrenomedulina (MR-ProADM) es la fracción medial del precursor de la ADM que puede ser utilizada como sustituto de esta.