Modelagem PK/PD na terapia antimicrobiana com carbapenêmico em pacientes sépticos críticos grandes queimados. " Estudo da efetividade do meropenem administrado através de infusão intermitente versus estendida " / PK/PD modelling in antimicrobial therapy with carbapenem in critically burn septic patients. " Study of the effectiveness of meropenem administered by intermittent versus extended infusion "

O meropenem é um carbapenêmico de amplo espectro e alta potência, largamente prescrito para tratamento de infecções graves causadas por bactérias sensíveis gram-negativas em pacientes críticos internados em Unidades de Terapia Intensiva. O objetivo do presente estudo foi avaliar a efetividade do antimicrobiano em pacientes grandes queimados, recebendo a dose recomendada 1 g q8h através da infusão intermitente de 0,5 hora que ocorreu até 2014 (grupo 1) comparada a infusão estendida de 3 horas que ocorreu após esse período (grupo 2). Investigaram-se 25 pacientes sépticos de ambos os sexos (6F/19M), 26 (21-34) anos, medianas (interquartil), 70 (60-75) kg, superfície corporal total queimada (SCTQ) 35 (16-42)%, SAPS 3: 55 (45-59) e Clcr 129 (95-152) ml/min que foram distribuídos em dois grupos. Registrou-se trauma térmico pelo fogo em 19/25 e trauma elétrico no restante dos pacientes (6/25), lesão inalatória (17/25), intubação orotraqueal e a necessidade de vasopressores em 18/25 pacientes. Duas amostras de sangue foram coletadas (3ª e 5ª horas) para dosagem sérica do meropenem por cromatografia líquida no período precoce do choque séptico. A farmacocinética foi investigada pela aplicação do modelo aberto de um compartimento e a abordagem PK/PD foi realizada com base no novo índice recomendado 100%fΔT>CIM. Evidenciou-se aumento do PCR 224 (179-286) versus 300 (264-339) mg/L, p=0,0411 e neutrofilia: 12 (8-17) versus 8 (2-15) células/mm3, p=0,1404, respectivamente nos grupos de infusão estendida versus infusão intermitente. Os níveis séricos obtidos mostraram diferença significativa entre grupos (p<0,0001) tanto para o pico 21 (21-22) mg/L versus 44 (42-45) mg/L, como para o vale 7,8 (7,3-9,5) mg/L versus 3,0 (2,6-3,7) mg/L. A farmacocinética mostrou-se alterada nos dois grupos frente aos dados de referência reportados em voluntários sadios. Significativa alteração ocorreu em diferentes proporções pela comparação entre os grupos relativamente à constante de eliminação 0,190 (0,157-0,211) versus 0,349 (0,334-0,382) h-1; meia-vida biológica 3,6 (3,3-4,4) versus 2,0 (1,8-2,1) h; depuração total corporal 8,6 (8,2-8,9) versus 5,3 (5,2-5,4) L/h; volume de distribuição 41,8 (39,9-44,5) versus 15,4 (14,1-16,2) L (p<0,0001). A infecção de ferida foi a mais prevalente nos dois grupos com 47% versus 38% dos isolados, sendo a Klebsiella pneumoniae, a principal enterobactéria. A abordagem PK/PD para patógenos CIM 1 a 4 mg/L mostrou cobertura até CIM 4 mg/L para a infusão estendida e até CIM 2 mg/L para infusão intermitente. Em conclusão, demonstrou-se a superioridade da infusão estendida decorrente de alterações na farmacocinética do meropenem em pacientes grandes queimados. O aumento do volume de distribuição contribuiu para o prolongamento da meia-vida e dos altos níveis de vale registrados, o justifica o impacto na cobertura antimicrobiana após infusão estendida e controle das infecções com cura desses pacientes

Meropenem is a broad-spectrum agent widely prescribed for the treatment of septic shock caused by gram-negative susceptible strains in critically ill patients from the Intensive Care Units. Subject of the present study was to evaluate the drug effectiveness in critically ill septic burn patients in SIRS at the early period of septic shock receiving the recommended dose of Meropenem 1 g q8h by intermittent 0.5 hour infusion or the extended 3 hour infusion. Twenty-five septic patients were: (6F/19M), 26 (21-34) years, medians (quartiles), 70 (60-75) kg, total burn body surface (SCTQ) 35 (16-42) %, SAPS 3: 55 (45-59) and Clcr 129 (95-152) ml/min. Thermal trauma was registered in 19/25 and electrical trauma in the remaining patients (6/25), inhalation injury (17/25), orotracheal intubation and vasopressor requirement in 18/25 patients. Patients were distributed in two groups on the basis of the duration of drug infusion that occurred for the patients of group 1 (1g q8h 0.5 hr) until 2014, December in the hospital. In addition, the extended 3 hours infusion occurred after that period for patients enrolled afterwards (group 2). Pharmacokinetics was investigated after blood sampling at the third (3rd) hour and the fifth (5th) hour of starting the meropenem infusion. Serum drug measurement was done by liquid chromatography. A one compartment open model was applied and kinetic parameters were estimated. PK/PD approach based on the new recommended index of drug effectiveness 100% fΔT>MIC was performed, on the basis on PK parameters and the minimum inhibitory concentration, PD parameter. It was demonstrated a significant difference between groups (p <0.0001) related to the trough levels 7.8 (7.3-9.5) mg/L versus 3.0 (2.6-3.7) mg/L, respectively after extended infusion or intermittent infusion. Concerning the pharmacokinetics, it was shown profound changes on meropenem kinetic parameters in both groups of burn patients by comparison with the reference data reported in healthy volunteers. In addition, it is important to highlight that significant changes occurred also by comparison of PK data between groups of patients related to the parameters: elimination constant 0.190 (0.157-0.211) versus 0.349 (0.334-0.382) h-1; biological half-life 3.6 (3.3-4.4) versus 2.0 (1.8-2.1) hr; total body clearance 8.6 (8.2-8.9) versus 5.3 (5.2-5.4) L/hr; volume of distribution 41.8 (39.9-44.5) versus 15.4 (14.1-16.2) L. Concerning the inflammatory biomarker an increase of C-reactive protein was registered in both groups of septic patients in SIRS: 224 versus 300 mg/L, p = 0.0411, after the extended infusion versus intermittent infusion, respectively. Wound and bone were the most prevalent sites of infection in those patients of both groups. It was shown in the isolates the prevalence of Gram-negative strains 54/83 (65%) that were distributed in Enterobacteriaceae, K. pneumoniae 7/30 (23%), and Non-Enterobacteriaceae, P. aeruginosa 13/54 (24%) followed by Acinetobacter baumannii 11/54 (20%). Drug effectiveness against susceptible strains was demonstrated by PK/PD approach up to 4 mg/L over 2 mg/L, after the extended infusion or after intermittent infusion, respectively. In conclusion, the superiority of the extended infusion in septic burn patients at the earlier period of septic shock was demonstrated, once considerable increases on volume of distribution impacted the drug effectiveness of these patients. Cure was obtained by meropenem monotherapy in 22/25 patients; only three patients (3/25) received meropenem - colistine combined therapy due to Acinetobacter baumannii isolated

Reclassificando o espectro de pacientes septicos com o uso do lactato: sepse grave, choque criptico, choque vasoplegico e choque disoxico / Reclassifying the spectrum of septic patients using lactate: severe sepsis, cryptic shock, vasoplegic shock and dysoxic shock

Objetivo: A definição atual de sepse grave e choque séptico inclui um perfil heterogêneo de pacientes. Embora o valor prognóstico de hiperlactatemia seja bem estabelecido, ela está presente em pacientes com ou sem choque. Nosso objetivo foi comparar o prognóstico de pacientes sépticos estratificando-os segundo dois fatores: hiperlactatemia e hipotensão persistente. Métodos: Este estudo é uma análise secundária de um estudo observacional conduzido em dez hospitais no Brasil (Rede Amil - SP). Pacientes sépticos com valor inicial de lactato das primeiras 6 horas do diagnóstico foram incluídos e divididos em 4 grupos segundo hiperlactatemia (lactato >4mmol/L) e hipotensão persistente: (1) sepse grave (sem ambos os critérios); (2) choque críptico (hiperlactatemia sem hipotensão persistente); (3) choque vasoplégico (hipotensão persistente sem hiperlactatemia); e (4) choque disóxico (ambos os critérios). Resultados: Foram analisados 1.948 pacientes, e o grupo sepse grave constituiu 52% dos pacientes, seguido por 28% com choque vasoplégico, 12% choque disóxico e 8% com choque críptico. A sobrevida em 28 dias foi diferente entre os grupos (p<0,001), sendo maior para o grupo sepse grave (69%; p<0,001 versus outros), semelhante entre choque críptico e vasoplégico (53%; p=0,39) e menor para choque disóxico (38%; p<0,001 versus outros). Em análise ajustada, a sobrevida em 28 dias permaneceu diferente entre os grupos (p<0,001), sendo a maior razão de risco para o grupo choque disóxico (HR=2,99; IC95% 2,21-4,05). Conclusão: A definição de pacientes com sepse inclui quatro diferentes perfis, se considerarmos a presença de hiperlactatemia. Novos estudos são necessários para melhor caracterizar pacientes sépticos e gerar conhecimento ...

Objective: The current definition of severe sepsis and septic shock includes a heterogeneous profile of patients. Although the prognostic value of hyperlactatemia is well established, hyperlactatemia is observed in patients with and without shock. The present study aimed to compare the prognosis of septic patients by stratifying them according to two factors: hyperlactatemia and persistent hypotension. Methods: The present study is a secondary analysis of an observational study conducted in ten hospitals in Brazil (Rede Amil - SP). Septic patients with initial lactate measurements in the first 6 hours of diagnosis were included and divided into 4 groups according to hyperlactatemia (lactate >4mmol/L) and persistent hypotension: (1) severe sepsis (without both criteria); (2) cryptic shock (hyperlactatemia without persistent hypotension); (3) vasoplegic shock (persistent hypotension without hyperlactatemia); and (4) dysoxic shock (both criteria). Results: In total, 1,948 patients were analyzed, and the sepsis group represented 52% of the patients, followed by 28% with vasoplegic shock, 12% with dysoxic shock and 8% with cryptic shock. Survival at 28 days differed among the groups (p<0.001). Survival was highest among the severe sepsis group (69%, p<0.001 versus others), similar in the cryptic and vasoplegic shock groups (53%, p=0.39), and lowest in the dysoxic shock group (38%, p<0.001 versus others). In the adjusted analysis, the survival at 28 days remained different among the groups (p<0.001) and the dysoxic shock group exhibited the highest hazard ratio (HR=2.99, 95%CI 2.21-4.05). Conclusion: The definition of sepsis includes four different profiles if we consider the presence of hyperlactatemia. Further studies are needed to better characterize septic patients, to understand the etiology and to design adequate targeted treatments. .

Shock séptico en pediatría I: enfoque actual en el diagnóstico y tratamiento / Septic shock in pediatrics I: current approach in diagnosis and therapeutics

El shock séptico es una de las principales causas de mortalidad infantil a nivel mundial y representa una compleja y progresiva vía inflamatoria secundaria a una enfermedad infecciosa, la cual origina disfunción cardiovascular aguda, no necesariamente hipotensión arterial, condicionando disoxia tisular y eventualmente falla celular y orgánica. Los paquetes de medidas de resucitación propuestos enfatizan el reconocimiento clínico y un tratamiento precoz. Estas intervenciones se basan en la pronta y agresiva resucitación con fluidos intravenosos para una adecuada perfusión tisular, administración de antibióticos, remoción del foco infeccioso y el uso de drogas vasoactivas en caso de ser necesario. La terapia debe evaluarse permanentemente según la normalización de metas clínicas y de laboratorio. En la presente publicación se actualiza el conocimiento de las características epidemiológicas y fisiopatológicas de la sepsis, una puesta al día en definiciones operacionales, campañas internacionales y referentes a las iniciativas propuestas para disminuir su morbimortalidad. Se aborda el enfoque terapéutico inicial en el servicio de urgencia. El objetivo de este artículo es dar a conocer el estado actual del conocimiento en el diagnóstico y tratamiento del paciente con shock séptico especialmente en su fase inicial previo al ingreso a UCI.

Septic shock is a major cause of infant mortality worldwide and represents the progressive underlying inflammatory pathway secondary to an infectious disease, which causes acute cardiovascular dysfunction, not necessarily hypotension, tissue dysoxia and eventually cellular and organ failure. Standard resuscitative measures emphasize clinical recognition and early treatment. These interventions are based on early and aggressive resuscitation with intravenous fluids to optimize tissue perfusion, antibiotics, removal of the source of infection and the use of vasoactive drugs if necessary. Therapy should be permanently evaluated according to the standardized laboratory and clinical targets. This publication is an update on the epidemiology and pathophysiology of sepsis, operational definitions, current international campaigns and initiatives concerning proposals to decrease the morbidity and mortality of this condition. It also addresses initial therapeutic approaches in the emergency room. The aim of this study is to present the current state of knowledge in the diagnosis and treatment of patients with septic shock especially in the initial phase before admissions to intensive care units.

Clasificación PIRO en sepsis grave y shock séptico pediátrico: Nuevo modelo de estratificación y su utilidad en pronóstico / PIRO classification in pediatric severe sepsis and septic shock: A new model for staging and its potential usefulness in prognoses

Background: Sepsis is a dynamic process that involves complex interactions between the pathogenic micro-organisms and the host. The understanding of this heterogeneous disease has led to the development of a new system for stratification of septic patients: the PIRO system: Predisposition (P) -Insult/Infection (I) -Response (R) -Organ disfunction (O), a classification aimed to determine the risk of death in patients with sepsis. Only a few studies have validated this classification system in children. Objective: To empirically test the accuracy of the PIRO system in pediatric patients with septic shock and severe sepsis and associate its individual components to predict mortality. Patients and Method: A retrospective chart review was performed in a 13 bed PICU during 24 months (January 2006 to December 2007) Demographic, clinical and microbiological data were recorded in all patients with a diagnosis of septic shock and severe sepsis during the study period. For all patients the PIRO classification system was applied by one of four authors using paramethers measured at admission. Results: Atotal of 42 patients were included with a mean age of 11 months (range 3.25-58.3) of which 52 percent were male. Overall mortality was 19 percent and variables associated with mortality for each category were: (P) Chronic illness (OR: 7 IC95 percent 0.95-51) and Immunodeficiency (OR: 6.2; IC95 percent 1.1-35.2); (R) leucopema (OR 9; IC95 percent: 1.96-41.72); (O) more thanthree dysfunctional organs (OR: 6.1; IC95 percent: 1.22-31). None of the (I) variables were associated with mortality. Conclusions: The PIRO classification system identified factors associated with a fatal outcome in our population. The test is relatively simple to apply but cross-sectional studies are required to define variables associated with death that should then be prospectivelly validated.

Introducción: La compresión de la sepsis como un proceso dinámico, resultado de la interacción entre hospedero y agente infeccioso, ha llevado al sistema de estratificación "PIRO" (P) Predisposición, (I) Injuria/ Infección, (R) Respuesta y (O) disfunción de Órganos, clasificación orientada a predecir la muerte en pacientes con sepsis, a ganar adeptos. Sin embargo, faltan estudios clínicos que lo validen. Objetivo: Evaluar la certeza de la clasificación "PIRO" en sepsis grave y shock séptico para predecir mortalidad. Pacientes y Método: Estudio retrospectivo efectuado en una UCI pediátrica de 13 camas durante 24 meses (enero 2006 a diciembre 2007). Uno de los cuatro autores registró las características demográficas, clínicas y microbiológicas de la totalidad de pacientes ingresados con diagnóstico de sepsis grave y shock séptico, agrupándolos según sobrevida. Fueron clasificadas estas variables según sistema PIRO Se evaluó la asociación de estas variables con la mortalidad. Resultados: 42 pacientes, edad 11 meses (3,2-58) y mortalidad 19 por ciento. Las variables asociadas a mortalidad fueron: (P) antecedente de patología crónica (OR: 7; IC95 por ciento 0,95-51) e inmunodeficiencia (6,2; 1,1-35,2); (R) leucopenia (9; 1,96-41,72); (O) disfunción de 3 o más órganos (6,1; 1,22-31). Ninguna de las variables (I) se asoció a mortalidad. Conclusiones: El sistema "PIRO" es un modelo en desarrollo para una clasificación individual, de fácil aplicación. Permite reconocer factores asociados a un resultado fatal, en la presente casuística dado por inmunodeficiencia, leucopenia y fallo de tres o más sistemas. Es importante realizar estudios transversales para definir una etapificación PIRO consensuada y luego validarla prospectivamente.

Reanimación protocolizada del shcok séptico / Protocolized reanimation of septic shock

Severe sepsis and septic shock are pathologies with an increasing incidence in the world. Annually, in the USA 200.000 people die because of severe sepsis, the same number that die because of a myocardial infarction, being this last disease much more common. In Chile, a multicentric study found a 40 percent of prevalence of severe sepsis in critically ill patients, with amortality of 27 percent. In this scenario, it becomes of great importance the appropriate and integral management of this condition, by means of an early diagnosis and the implementation of anaggressive protocolized resuscitation, guided by clear goals. During the first stage of the resuscitation cristalloids and/ or colloids can be used, in order to expand the intravascular space, searching for CVP around 8 to 12 mmHg. In case of hypotension refractory to the administration of fluids, it is recommended to start with increasing doses of norepinephrin untila MAP of 65 - 75 mmHg is achieved. The intensity of the septic shock can be stratified according to the requirements of norepinephrine. It is of great importance to obtain blood cultures of the patients and to start with empiric antibiotic therapy as soon as possible. The initial metabolic goal must be the normalization of the central venous oxygen saturation. The implementation of the resuscitation bundle during the first six hours, since the diagnose of severe sepsis is done, increases the chances of surviving. Protocols of sedation and analgesia, and the use of protective mechanical ventilation is highly recommended. The use of hydrocortisone and human recombinant protein C in selected patients, may have a beneficial result in the outcome.Vasopressin, terlipressin and high-volume hemofiltration can be used as rescue measures for the most severe patients.

Fulminant hepatitis in dengue infection.

Eight cases of liver failure and encephalopathy were observed among twenty cases of grade 3 and grade 4 dengue hemorrhagic fever/dengue shock syndrome admitted to the Department of Pediatrics, University Hospital, Kuala Lumpur from January 1990 to December 1991. All patients with deterioriation in mental status showed a marked increase in liver enzymes (aspartate and alanine aminotransaminases) and severe coagulopathy. Six patients needed cerebral protection, including ventilation, intravenous sedation and muscle relaxants. There was one death during the period of study and one case of residual hemiparesis in a boy who had, in addition, intracerebral hemorrhage. All other survivors had complete recovery of liver and neurological function.