ATENCIN INICIAL

Constantes:

Frecuencia cardiaca y respiratoria Presin arterial Temperatura Saturacin de oxgeno Sondaje vesical con control de diuresis horaria

Canalizar 2 vas venosas en sepsis grave

Anlisis generales:

Protena C reativa (PCR) Procalcitonina: 2 ng/mL, riesgo de gravedad Lactato: > 4 mmol/L, alta mortalidad Fibringeno Calcio (Perfil de dolor torcico, pro-BNP, dmero-D) Anormales y sedimento de orina Gasometra arterial/venosa Pruebas cruzadas Hemocultivos Urinocultivo Cultivo del posible foco sptico Tincin de Gram

Electrocardiograma Radiografa de trax (Radiografa de abdomen, ecografa abdominal, TAC torcica o abdominal)

PCR:

Procalcitonina:

Gran sensibilidad como marcador de inflamacin sistmica, pero: No discrimina infeccin respecto a otros procesos (ciruga, traumatismo, pancreatitis, neoplasia, enfermedad inflamatoria) No diferencia infeccin vrica de bacteriana Pico a las 36-48 h

Se eleva en procesos infecciosos de etiologa bacteriana con afectacin sistmica, pero no en procesos locales

Pico a las 8 h, ms especfica que PCR, y mejor correlacin con la gravedad de la sepsis
Puede elevarse en procesos sistmicos no infecciosos En general, los gramnegativos presentan mayores elevaciones que los grampositivos Algunos agentes no provocan elevaciones:

Lactato:

Se eleva en sepsis grave/shock sptico, pero tambin en insuficiencia respiratoria, renal o heptica, convulsiones, cetoacidosis diabtica Predictor independiente de mortalidad, especialmente si > 4 mmol/L Puede ser el nico indicador de hipoperfusin en pacientes normotensos

Mycoplasma pneumoniae Mycobacterium tuberculosis Chlamydia Legionella Pneumocystis jirovecii

Biomarcadores y sospecha de infeccin en los servicios de urgencias P. Tudela et al / Med Clin (Barc). 2012;139(1):3337 Admission hyperlactatemia: Causes, incidence, and impact on outcome of patients admitted in a general medical intensive care unit Juneja D, Journal of Critical Care (2011) 26, 316320 Manual del Hospital 12 de Octubre, 7 edicin 2012

Biomarcadores y sospecha de infeccin en los servicios de urgencias P. Tudela et al / Med Clin (Barc). 2012;139(1):3337

 Oxigenoterapia para asegurar SatO2 90 % o PO2 60 mm Hg Fluidoterapia:

Suero fisiolgico al 09% 1000 mL en

Transfusin:
Hemoglobina < 7 g/dL Hemoglobina 7 g/dL si

cualquiera de:

30 min

Bolos adicionales segn respuesta, con

Sangrado activo Acidosis lctica Cardiopata isqumica

estimacin de volemia y tolerancia respiratoria:

Mantener glucemia < 150 mg/dL Evitar hipotermia

1500-2000 mL en la 1 hora Posteriormente 500-1000 mL/h

Valorar albmina 500 mL al 5%:

Especialmente si albuminemia < 2

g/dL

Teraputica Mdica en Urgencias 2012-2013 Garca-Gil D, Mensa J

 Si existe obstruccin de va urinaria o biliar, un absceso o

coleccin, tejido necrtico, un cuerpo extrao (incluyendo el catter vascular o una sonda urinaria) o perforacin de vscera hueca, son prioritarios, con independencia de la situacin hemodinmica del paciente:
Desobstruccin
Drenaje Desbridamiento quirrgico

Retirada del cuerpo extrao

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al.

TRATAMIENTO ETIOLGICO
Tratamiento antibitico:
Tras obtencin de hemocultivos, urinocultivo y cultivo del

posible foco sptico

En la 1 hora desde triaje si hipotensin o lactato > 4 mmol/L De amplio espectro segn agentes ms probables No es necesario ajustar la dosis de carga en insuficiencia

heptica o renal, pero s la dosis de mantenimiento

A las 48-72 h debe adecuarse a los hallazgos microbiolgicos

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al.

Manual de Protocolos y Actuacin en Urgencias Tercera edicin 2010 Complejo Hospitalario de Toledo

FACTORES DE RIESGO PARA MICROORGANISMOS ESPECIALES

Staphylococcus aureus resistente a meticilina (SARM):

Gramnegativo betalactamasa de espectro extendido (BLEE):

Antecedente de colonizacin por SARM Prevalencia de SARM comunitario elevada Si cumple 2 o ms de:

Ingreso en ltimo ao o procedencia de residencia geritrica o centro sociosanitario con endemia de SARM Tratamiento con quinolonas en 6 meses previos > 65 aos Insuficiencia renal en hemodilisis

Cateterismo urinario Tratamiento con cefalosporinas o quinolonas en 2 meses previos Colonizacin previa conocida

Candidiasis:

Pseudomonas aeruginosa:

Hospitalizados con antibioterapia prolongada, especialmente en UCI Inmunodeficiencia grave (neutropnicos) o inmunocompetentes con 2 o ms de:

Ingreso > 7 das en UCI con antibioterapia de amplio espectro Pancreatitis grave Ciruga abdominal reciente Colonizacin multifocal por Candida Presencia de catter venoso femoral Nutricin parenteral Insuficiencia renal en hemodilisis Tratamiento antibitico prolongado

> 90 aos Antibioterapia en mes anterior Presencia de catter venoso central (femoral) Catter urinario

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al. Tratamiento emprico de la sepsis. Medicine. 2010;10(49):3334-6

Clinigua 2011. Actualizacin de diagnstico y Teraputica

SEPSIS GRAVE DE ORIGEN DESCONOCIDO

Cualquiera de:

Meropenem 1-2 g/8 h I.V. Imipenem 1 g/6-8 h I.V. Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V.

Si la evolucin es favorable y no se identifica Pseudomonas aeruginosa, el aminoglucsido puede retirarse al 3-5 da

Tambin se puede retirar el antibitico activo contra el SARM si no se demuestra su participacin en la infeccin El tratamiento con betalactmico se mantiene 7-10 das, salvo que exista alguna complicacin sptica (osteitis, absceso no drenado, endocarditis) que justifique prolongarlo

Asociar Amikacina 1 g/da I.V.

Si riesgo de SARM, aadir uno de:

Daptomicina 8-12 mg/kg/da I.V. Linezolid 600 mg/12 h I.V.

Si riesgo de candidiasis aadir cualquiera de:

Caspofungina:

Dosis inicial: 70 mg I.V. Mantenimiento: 50 mg/da I.V.

Anidulafungina:

Dosis inicial: 200 mg I.V. Mantenimiento: 100 mg/da I.V.

Teraputica Mdica en Urgencias 2012-2013 Garca-Gil D, Mensa J Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al.

 En alrgicos a betalactmicos:
En caso de antecedente de exantema maculopapuloso, probablemente secundario a una

aminopenicilina, se pueden administrar:

Aztreonam Carbapenmicos Cefalosporina con cadena lateral diferente

Reacciones graves:

(Angioedema, broncoespasmo), anafilaxia, Stevens-Johnson, NET, sndrome de hipersensibilidad o DRESS

En el caso de reaccin grave, sustituir carbapenem por cualquiera de:

Aztreonam 2 g/8 h I.V. Ciprofloxacino 400 mg/8 h I.V. Tigeciclina: Dosis inicial: 100 mg I.V. Mantenimiento: 50 mg/12 h I.V.

En sepsis grave asociar Amikacina 1 g/da I.V. Valorar adicin de otros antibiticos si riesgo de SARM o candidiasis

Recomendaciones de tratamiento antimicrobiano en pacientes alrgicos a antibiticos betalactmicos Rev Esp Quimioter 2008;21(1):60-82

Antibiticos betalactmicos C. Surez, F.Gudiol/Enferm Infecc Microbiol Clin. 2009;27(2):116129

COMUNIDAD DE CADENAS LATERALES

Ampicilina, Cefalexina, Cefaclor, Cefadrina
Amoxicilina, Cefadroxilo Penicilina G, Cefalotina, Cefamandol, Cefaloridina Ceftazidima, Aztreonam

Cefepima, Cefotaxima, Ceftriaxona

Cefuroxima, Cefoxitina

SEPSIS DE PROBABLE ORIGEN RESPIRATORIO

Uno de los siguientes:

Ceftriaxona 1 g/12 h I.V. + Azitromicina 500 mg/da I.V. Levofloxacino 500 mg/12 h I.V.

Si sospecha de aspiracin, uno de:

Amoxicilina-cido clavulnico 2 g/8 h I.V. Ertapenem 1 g/da I.V.

Si sepsis grave o riesgo de Pseudomonas, uno de:

Meropenem 1-2 g/8 h I.V. Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V.

Si riesgo de Pseudomonas, aadir uno de:

Levofloxacino 500 mg/12 h I.V. Ciprofloxacino 400 mg/8-12 h I.V. Amikacina 1 g/da I.V.

Si riesgo de SARM, aadir uno de:

Vancomicina 1 g/12 h I.V. Linezolid 600 mg/12 h I.V.

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al. Gua Pneumologica 9 edicin 2012. Morell F

SEPSIS DE PROBABLE ORIGEN URINARIO

Cualquiera de:
Ceftriaxona 1-2 g/12 h I.V. Cefotaxima 1-2 g/6-8 h I.V.

Si grave o sospecha de gramnegativo BLEE,

cualquiera de:

Meropenem 1-2 g/8 h I.V. Imipenem 1 g/6-8 h I.V. Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V.

En sepsis grave asociar Amikacina 1 g/da I.V.

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al.

SEPSIS DE PROBABLE ORIGEN ABDOMINAL

Cualquiera de:
Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V. Meropenem 1-2 g/8 h I.V. Imipenem 1 g/6-8 h I.V.

O bien:
Metronidazol 500 mg/8 h I.V. Combinado con uno de:

Ceftriaxona 1 g/12 h I.V. Aztreonam 2 g/8 h I.V.

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al.

SEPSIS DE PROBABLE ORIGEN CUTNEO

Celulitis en pacientes sin enfermedad subyacente:

lceras por presin sacras (estadio III/IV):

Cualquiera de:

Cualquiera de:

Amoxicilina cido clavulnico 1-2/02 g/6 h I.V. Cloxacilina 1-2 g/4 h I.V. Clindamicina 600 mg/8 h I.V.

Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V. Ceftriaxona 1 g/12 h I.V. + Clindamicina 600 mg/8 h I.V.

En alrgicos a betalactmicos o si riesgo de SARM:

Fascitis, celulitis y miositis necrosante, pie diabtico muy grave:

Clindamicina 600 mg/8 h I.V. Linezolid 600 mg/12 h V.O. Daptomicina 6 mg/kg/da I.V.

Cualquiera de:

Celulitis con criterios de gravedad o en pacientes con enfermedad subyacente:

Piperacilina-Tazobactam 4 g-05 g/6 h I.V. Meropenem 1 g/6 h o 2 g/8 h I.V.

Junto a uno de:

Ancianos encamados Edema crnico en miembros inferiores Diabetes mellitus Cirrosis Otros tipos de inmunosupresin

Linezolid 600 mg/12 h I.V. Clindamicina 600 mg/6-8 h I.V. Daptomicina 8-12 mg/kg/da I.V.

Cefotaxima 1-2 g/8 h I.V. o Ceftriaxona 1-2 g/da I.V. Junto a uno de:

Cloxacilina 2 g/4 h I.V. Linezolid 600 mg/12 h V.O. o I.V. Daptomicina 6 mg/kg/da I.V.
Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al.

SEPSIS POR CATTER INTRAVENOSO

Retirada inmediata del catter en sepsis grave

Cubrir SASM con Cloxacilina 2 g/4 h I.V. sin cobertura emprica para SARM si:

Si riesgo de Pseudomonas o sepsis grave sustituir Cloxacilina por uno de:

Ausencia de: Sepsis grave, cardiopata de riesgo para desarrollo de endocarditis, prtsis endovascular Posibilidad de retirada del catter de forma precoz

Meropenem 1-2 g/8 h I.V. Imipenem 1 g/6-8 h I.V. Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V. Cefepima 1-2 g/8-12 h I.V.

Cubrir Staphylococcus coagulasa negativo (SCN) y SARM con uno de:

Si sepsis grave con riesgo de Candida, uno de:

Caspofungina:

Daptomicina 10-12 mg/kg/da I.V.

Dosis inicial: 70 mg I.V. Mantenimiento: 50 mg/da I.V.

De eleccin en:

Sepsis grave/shock sptico Colonizacin previa por SARM Incidencia elevada de SARM con CMI de Vancomicina >1 Imposibilidad para retirar catter Existencia de material protsico

2 lnea: Anfotericina B liposomal 3 mg/kg/da I.V.

Vancomicina 1 g/8-12 h I.V. 2 lnea: Linezolid 600 mg/12 h I.V.

Documento de consenso sobre infecciones relacionadas con catteres vasculares Sociedad Andaluza de Enfermedades Infecciosas Octubre 2011

SEPSIS DE PROBABLE ORIGEN EN EL SNC

Tratamiento/profilaxis del edema cerebral:

Cubrir Listeria con Ampicilina 2 g/4 h

I.V. si:

Inmediatamente antes o a la vez que la 1 dosis de antibitico Dexametasona 8-10 mg/6 h I.V. durante 2-4 das

Cualquiera de:

> 50 aos Enfermedades crnicas debilitantes Clnica de romboencefalitis:

Ceftriaxona 2 g/12 h I.V. Cefotaxima 300 mg/kg/da I.V. en 6 dosis (mximo 24 g/da)

Ataxia Nistagmo Afectacin de pares craneales

Junto a uno de:

Si sospecha de infeccin herptica

aadir Aciclovir 10 mg/kg/8 h I.V tratamiento tuberculosttico:

Vancomicina 1 g/8-12 h I.V. Linezolid 600 mg/12 h I.V.

Si evolucin subaguda aadir

En inmunodeprimidos:

Meropenem 2 g/8 h I.V. + Ampicilina 2 g/4 h I.V. Junto a cualquiera de:

Rifampicina 10 mg/kg/da + Isoniacida 5 mg/kg/da + Etambutol 15-25 mg/kg/da + Pirazinamida 25 mg/kg/da

Vancomicina 1 g/8-12 h I.V. Linezolid 600 mg/12 h I.V.

Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al. Teraputica Mdica en Urgencias 2012-2013 Garca-Gil D, Mensa J

SEPSIS EN NEUTROPNICOS

Cualquiera de:

Valorar adicin de un antifngico:

Meropenem 1-2 g/8 h I.V. Imipenem 1 g/6-8 h I.V. Piperacilina-Tazobactam 4 g-05 g/6-8 h I.V.

Si sepsis grave, y de forma precoz:

Caspofungina:

En sepsis grave asociar Amikacina 1 g/da I.V. + uno de:

Dosis inicial: 70 mg I.V. Mantenimiento: 50 mg/da I.V.

Daptomicina 10-12 mg/kg/da (salvo neumona) Vancomicina 1 g/8-12 h I.V. Linezolid 600 mg/12 h I.V.

Si fiebre persistente al 4-7 da de tratamiento o 2 episodio de fiebre:

Caspofungina:

Asociar Daptomicina o Vancomicina o Linezolid si cualquiera de los siguientes:

Dosis inicial: 70 mg I.V. Mantenimiento: 50 mg/da I.V.

Voriconazol: Sospecha de infeccin del catter Hipotensin u otros datos de afectacin hemodinmica o Dosis inicial: 6 mg/kg/12 h I.V. cardiovascular Mantenimiento: 4 mg/kg/12 h I.V. o V.O. Colonizacin conocida por cepas de Neumococo resistente a Penicilina o cefalosporinas o SARM Anfotericina B liposomal 3-5 mg/kg/da I.V. Resultados positivos del hemocultivo para grampositivos pendientes de identificar Quimioterapia con altas dosis de Citarabina Uso de fluorquinolonas en rgimen de profilaxis Gua de Teraputica Antimicrobiana 2012. Mensa J, Gatell J M et al. Mucositis grave

Enfoque clnico de los grandes sndromes infecciosos 4 edicin 2011. Gmez Gmez J Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients) (UpToDate)

SEPSIS EN ESPLENECTOMIZADOS
Cubrir grmenes encapsulados

con cualquiera de:

Ceftriaxona 2 g/12-24 h I.V. Cefotaxima 2 g/4-6 h I.V.

Cubrir Neumococo resistente a

Penicilina, SCN y SARM con:

Vancomicina 1 g/12 h I.V.

En sepsis grave asociar

Amikacina 1 g/da I.V.

Clinical features and management of sepsis in the asplenic patient (UpToDate)

Y DESPUS DE TANTO ANTIBTICO QU?

 Si tras fluidoterapia la presin arterial media

permanece < 65 mm Hg, administrar:

Noradrenalina:

Puede iniciarse antes si hipotensin grave Diluir 40 mg en 500 mL de suero glucosado al 5% Ritmo de perfusin de inicio en paciente de 70 kg: 26 mL/h Incrementar segn respuesta Mximo de 25 mcg/kg/min

Vasopresina 003 U/min:

Alternativa a la Noradrenalina Tambin se puede administrar junto a sta

Teraputica Mdica en Urgencias 2012-2013 Garca-Gil D, Mensa J

 Si tras ello la presin arterial media persiste < 65 mm Hg:

Contactar con UCI para monitorizacin hemodinmica ms precisa

(catter Swan Ganz, PiCCO, vigileo, ecocardiograma)

Si disfuncin de ventrculo izquierdo:

Dobutamina:

Diluir 500 mg en 250 mL de suero glucosado al 5% Ritmo de perfusin de inicio en paciente de 70 kg: 105 mL/h Incrementar dosis cada 10 min Mximo de 20 mcg/kg/min

Si hipoglucemia + hipotensin que no remonta con drogas vasoactivas, sospechar insuficiencia suprarrenal subyacente:

Hidrocortisona 50 mg/6 h (si no se ha administrado antes)

 Considerar medidas para reducir demanda de oxgeno:

Sedacin Analgesia Control de la fiebre

Si a pesar del oxgeno suplementario con mascarilla de

Venturi, PO2 < 60 mm Hg:

Ventilacin mecnica no invasiva

En caso de sepsis grave o shock sptico estreptoccico o

estafiloccico considerar empleo de inmunoglobulina:

1 g/kg I.V. el 1 da
05 g/kg I.V. el 2 y 3 da

 Considerar hemoperfusin a travs de cartucho con

polimixina si el paciente sigue empeorando:

gramnegativo (origen abdominal o urinario)

En caso de shock sptico con alta probabilidad de bacilo

A las 6-8 h del control quirrgico efectivo del foco Tras administracin de antibiticos efectivos, fluidoterapia y soporte vasopresor

En caso de oliguria (< 30 mL/h) persistente a pesar de

correccin de parmetros hemodinmicos:

Hemodilisis Hemofiltracin/hemodiafiltracin

 Si aparece ditesis hemorrgica en relacin con

coagulacin intravascular diseminada, considerar:

Plasma fresco
Plaquetas si < 10.000/mm Fibringeno si < 100 mg/dL Heparina:

Slo si fracasa el tratamiento sustitutivo La hemorragia no compromete rganos vitales (SNC, pericardio, regin peritraqueal) O predominan signos de trombosis (necrosis drmica, isquemia acra o tromboembolia venosa)

 Profilaxis de lceras de estrs con anti H2 o inhibidor de la bomba de

protones

Profilaxis de trombosis venosa profunda con heparina de bajo peso molecular salvo si:

Trombopenia Sangrado activo Hemorragia cerebral reciente Coagulopata grave

Iniciar nutricin enteral lo antes posible salvo contraindicaciones:

Isquemia mesentrica Obstruccin intestinal Ciruga abdominal reciente

CURIOSIDADES SOBRE ALGUNOS ANTIBITICOS

Ceftriaxona:

Imipenem:
Evitar en pacientes con epilepsia o trastornos del SNC Aumenta el riesgo de convulsiones, especialmente en insuficiencia renal

Se asocia con pseudolitiasis biliar, pudiendo dar lugar a clnica de colecistitis

Cefepima:

A menudo es efectiva contra cepas de Pseudomonas resistentes a Ceftazidima

Meropenem:

Aztreonam:

El nico carbapenem que se puede administrar en bolo I.V.

No cubre gram positivos Es seguro en alrgicos a betalactmicos

Ertapenem:
El nico carbapenem que no cubre Pseudomonas No cubre Enterococo (va biliar, infeccin del tracto urinario)

Amikacina:

Es el aminoglucsido con mayor actividad frente a Pseudomonas

Ciprofloxacino:

Es la quinolona con mayor riesgo de convulsiones Tiene menos actividad frente al Neumococo y el S. aureus que Levofloxacino o Moxifloxacino

Linezolid:

Es igual de eficaz por va oral que I.V. No se ajusta en insuficiencia renal porque su eliminacin es heptica

Daptomicina:

No cubre gram negativos Se inactiva por el calcio del surfactante, por lo que no es til como tratamiento de las neumonas

Tigeciclina:

Es segura en pacientes con alergia a Penicilina o Sulfamidas Debe evitarse en alrgicos a Tetraciclinas No se ajusta en insuficiencia renal porque su eliminacin es heptica No acta sobre el citocromo P450, por lo que es especialmente til en pacientes con VIH Tiene gran actividad frente a K. pneumoniae multirresistente
Antibiotic Essentials. Cunha BA. PhysiciansPress 2011

GRACIAS POR VUESTRA ATENCIN!

Tratamiento antibitico de la sepsis grave y shock sptico (UpToDate)

Sin riesgo de Pseudomonas:

Vancomicina + uno de: Cefotaxima o Ceftriaxona Betalactmico + inh. betalactamasa (Piperacilina- Tazobactam, Ticarcilina-Clavulnico) Carbapenem (Imipenem, Meropenem)

Riesgo de Pseudomonas:

Vancomicina + uno de: Cefalosporina antipseudomnica (Ceftazidima, Cefepima) Carbapenem antipseudomnico (Imipenem, Meropenem) Betalactmico + inh. betalactamasa (Piperacilina- Tazobactam, Ticarcilina-Clavulnico) Fluoroquinolona antipseudomnica (Ciprofloxacino) Aminoglucsido (Gentamicina, Amikacina) Monobactam (Atreonam)

Surviving Sepsis: New Fluid Resuscitation Recommendations

They gave a strong 1A recommendation for the use of crystalloids like normal saline as the initial fluid resuscitation for people with severe sepsis. They further advise that the initial fluid challenge should be 1L or more of crystalloid, and a minimum of 30 mL/kg of crystalloid (2.1 L in a 70 kg or 154pound person) in the first 4-6 hours. Incremental fluid boluses should be continued as long as patients continue to improve hemodynamically (in blood pressure, delta pulse pressure, or both) (Grade 1C). They weakly recommended adding albumin to initial fluid resuscitation with crystalloid for severe sepsis and septic shock (Grade 2B). Authors strongly recommended not using hetastarches/hydroxyethyl starches greater than 200 kDa in molecular weight (Grade 1B). They did not comment on the use of lower molecular weight hetastarches or the use of gelatins; trials are ongoing to evaluate these resuscitative agents.

Surviving Sepsis: New Recommendations for Vasopressors, Inotropes

Authors strongly recommend norepinephrine (Levophed) as

the first choice for vasopressor therapy (Grade 1B). Vasopressin 0.03 units / minute is an alternative to norepinephrine, or may be added to it (Grade 2A). When a second agent is needed, epinephrine is their weaklyrecommended vasopressor choice (Grade 2B). Dopamine was only recommended in highly selected patients whose risk for arrhythmias was felt to be very low and who had a low heart rate and/or cardiac output (Grade 2C). Dobutamine is strongly recommended (by itself or in addition to a vasopressor) for patients with cardiac dysfunction as evidenced by high filling pressures and low cardiac output, or clinical signs of hypoperfusion after achievement of restoration of blood pressure with effective volume resuscitation (Grade 1C).

 Corticosteroid Recommendations:
Authors suggest not providing intravenous corticosteroid therapy

to patients for whom fluid resuscitation and vasopressors can restore an adequate blood pressure. For those with vasopressor-refractory septic shock, they recommend IV hydrocortisone in a continuous infusion totaling 200 mg/24 hrs a weak Grade 2C.

Mechanical Ventilation for ARDS:

For patients with ARDS due to severe sepsis, the authors made several

suggestions based on consensus opinion/weak evidence:

Using higher levels of PEEP (Grade 2C); Recruitment maneuvers for patients with severe hypoxemia while receiving high PEEP and FiO2 (Grade 2C), Prone positioning for patients with PaO2/FiO2 ratios < 100 despite such maneuvers (Grade 2C).

Other New Surviving Sepsis Guidelines

Some of the Surviving Sepsis committees other weak

recommendations/suggestions included:
Using normalization of lactate levels as an alternate goal

in early goal-directed therapy for severe sepsis, if central venous oxygenation monitoring is not available (Grade 2C). For patients at risk for fungal infection as a source for severe sepsis, checking one of the newer assays for invasive candidiasis such as 1,3-beta-D-glucan, mannan, or antimannan ELISA antibody testing (Grade 2B/C). When no infection can be found during empiric antibiotic therapy, consider using a low procalcitonin level as a supportive tool for the decision to stop antibiotics (Grade 2C).

THERAPIES BEING INVESTIGATED (UpToDate)

Inhibition of innate immunity Infecting microbes display highly conserved macromolecules on their surface. When these macromolecules are recognized by pattern-recognition receptors (called Toll-like receptors [TLRs]) on the surface of immune cells, the hosts immune response is initiated. This may contribute to the excess systemic inflammatory response that characterizes sepsis. Inhibition of several TLRs is being evaluated as a potential therapy for sepsis:

Inhibition of TLR-4 with the antagonist, E5564 (Eritoran), is currently being tested in humans Inhibition of TLR-2 with a neutralizing antibody (anti-TLR-2) successfully prevented lethal septic shock in an experimental mouse model. Anti-TLR-2 has not been tested in humans

Talactoferrin is a glycoprotein that has anti-infective and anti-inflammatory properties, possibly by restoring the barrier properties of the gastrointestinal mucosa. In unpublished studies conducted using animal models, talactoferrin reduced mortality when given enterally up to 12 hours following the onset of sepsis. A randomized trial has been completed in humans with severe sepsis and another randomized trial in humans with severe sepsis is planned. Intravenous immunoglobulin It has been hypothesized that polyclonal intravenous immunoglobulin (IVIG) may benefit patients with sepsis by binding endotoxin. However, the data are conflicting.

The evidence is insufficient to recommend the administration of polyclonal IVIG to patients with sepsis. However, well-designed randomized trials are warranted to evaluate the impact of IgA- and IgMenriched IVIG.

Endotoxin inactivation or removal Strategies to improve sepsis by either inactivating or removing endotoxin have been investigated and some of the preliminary data appear promising:

Hemoperfusion through an endotoxin-avid column Polymyxin B is an antibiotic with a high affinity for endotoxin. Several studies have found that hemoperfusion through a column that contains polymyxin B may be beneficial to patients with sepsis. Plasma or whole blood exchange Case series and observational studies with historical controls reported favorable outcomes when endotoxin was removed by plasma or whole blood exchange, including lower plasma endotoxin concentrations and, possibly, lower mortality. Additional evidence is necessary before any of these strategies are routinely used in patients with sepsis

Interferon-gamma A decrease in monocyte function has been observed late in the course of sepsis, which may predispose patients to life-threatening secondary infections. This observation prompted a study in which patients with sepsis were administered interferon-gamma. The study found that interferon-gamma restored monocytic cell function. Controlled clinical trials measuring patientimportant outcomes in patients with sepsis have not been reported, although a trial evaluating the impact of interferon-gamma in candidemia is underway. Granulocyte-macrophage colony stimulating factor Granulocyte-macrophage colony stimulating factor (GM-CSF, sargramostim, molgramostim) is a cytokine that promotes maturation of the progenitor cells of granulocytes, erythrocytes, megakaryocytes, and macrophages, as well as mature neutrophils, monocytes, macrophages, dendritic cells, T-lymphocytes, and plasma cells. Its use in sepsis has been studied in several controlled clinical trials.

Larger controlled clinical trials are necessary to confirm the clinical effects reported in these trials and that GM-CSF should not be routinely used to treat sepsis until then.

 Augmentation of immunomodulation Antibodies directed against

macrophage migration inhibition factor (MIF) prevented death in a study that used a cecal puncture animal model of sepsis, even when administered up to eight hours after the onset of peritonitis. While it is known that elevated MIF levels correlate with poor outcomes in humans with sepsis, the impact of MIF inhibition has not been studied in humans.

Inhibition of proinflammatory gene expression A synthetic peptide has been developed that inhibits bacterial superantigen-induced expression of certain proinflammatory genes (interleukin-2, gamma interferon, and tumor necrosis factor-beta) by limiting T-cell activation. In one study, the peptide protected mice against lethal challenges with staphylococcal and streptococcal superantigen, when administered up to three hours after the superantigen. This peptide has not been tested in humans. Hemofiltration It has been proposed that hemofiltration may remove proinflammatory molecules that induce hemodynamic collapse in septic shock, improving outcomes. However, the data in humans are inconsistent.
There is insufficient data to support the use of hemofiltration in the absence of

renal failure.

Heparin Heparin has anti-thrombotic and immunomodulating effects, both of which have the potential to be beneficial in sepsis. In a retrospective cohort study of patients with septic shock, intravenous therapeutic heparin was associated with decreased mortality, discontinuation of vasoactive drug infusions, and liberation from mechanical ventilation. The risk of major hemorrhage or the need for transfusion was not increased. This study was followed by the HETRASE trial, which randomly assigned 319 patients with sepsis to receive low dose intravenous heparin (500 units per hour) or placebo for seven days. The trial found no improvement in any clinical outcome. It has been suggested that the conflicting results were due to the randomized trial using a low dose of heparin; as a result, a randomized trial comparing various doses of heparin in patients with septic shock is being conducted. Naloxone A meta-analysis of three randomized trials (61 patients) comparing naloxone to either placebo or no naloxone found that naloxone therapy led to hemodynamic improvement, but did not improve the case-fatality rate. Adverse effects that have been associated with naloxone therapy include pulmonary edema, hypertension, and seizures. Naloxone therapy is not warranted for patients with septic shock. Pentoxifylline Sepsis results in decreased red cell deformability and increased erythrocyte aggregation, effects that may be mitigated by pentoxifylline. Pentoxifylline also inhibits neutrophil adhesion and activation, and modulates endotoxin-induced expression of proinflammatory cytokines . In a trial of 51 surgical patients with severe sepsis who were randomly assigned to receive pentoxifylline or placebo, pentoxifylline improved the multiple organ dysfunction score and the arterial oxygen tension to fraction of inspired oxygen (PaO2/FIO2), but there was no improvement in the 28-day mortality. A trial is in progress comparing pentoxifylline to placebo in neonatal sepsis. Statins HMG CoA reductase inhibitors (statins) are in wide clinical use and have an established role in the management of hyperlipidemia and cardiovascular disease. Statins also appear to have beneficial antiinflammatory properties, such as suppression of endotoxin-induced up-regulation of TLR-4 and TLR-2. Several observational studies have suggested that statins are beneficial in patients with sepsis, although conflicting studies exist. No controlled trials evaluating statin therapy initiated after the development of sepsis have been reported, but several such studies are underway.

INEFFECTIVE THERAPIES (UpToDate)

Despite promising initial data, recombinant human activated protein C (rhAPC) has not been confirmed to improve survival in patients with severe sepsis or septic shock, prompting withdrawal of this drug from the market. Recombinant human activated protein C (also called drotrecogin alfa) promotes fibrinolysis and inhibits thrombosis. It was hypothesized that rhAPC may benefit patients with sepsis because it modulates the procoagulant response that is believed to contribute to multisystem organ dysfunction. This hypothesis was initially tested in the PROWESS trial, which reported that rhAPC improved 28-day mortality in patients with severe sepsis or septic shock, with its greatest benefit among patients with a high risk of death (ie, APACHE II score 25). However, conflicting data from subsequent studies eventually led to a new trial, the PROWESS-SHOCK trial. In this trial, 1696 patients with vasopressordependent septic shock were randomly assigned to receive rhAPC or placebo. Preliminary analyses done by the maker of the drug indicated that rhAPC did not improve 28-day mortality (26.4 versus 24.2 percent for placebo, RR 1.09, 95% CI 0.92-1.28).
Additional therapies that have proven ineffective include the following:

The TLR-4 antagonist, TAK 242 (Resatorvid) The human anti-endotoxin monoclonal antibody, HA-1A The human anti-Enterobacteriaceae common antigen (ECA) monoclonal antibody Alkaline phosphatase Granulocyte colony-stimulating factor (filgrastim, G-CSF) Anti-tumor necrosis factor monoclonal antibody Tumor necrosis factor receptor antagonist Interleukin-1 receptor antagonist Antithrombin (formerly known as antithrombin III) Recombinant human tissue factor pathway inhibitor (tifacogin) Ibuprofen N-acetylcysteine Nitric oxide inhibitors The bradykinin antagonist, deltibant Growth hormone

The increase of PCT remains unaffected by the administration of immunosuppressive therapy (specifically corticosteroids) when compared to other biomarkers such as CRP.

Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis S. Riedel / Diagnostic Microbiology and Infectious Disease 73 (2012) 221227