Conditional Treatment Effect Analysis of Two Infusion Rates for Fluid Challenges in Critically Ill Patients: A Secondary Analysis of Balanced Solution versus Saline in Intensive Care Study (BaSICS) Trial.

Rationale: Optimal infusion rate for fluid challenges in critically ill patients is unknown. A large clinical trial comparing two different infusion rates yielded neutral results. Conditional average treatment effect (CATE) assessment may aid in tailoring therapy. Objectives: To estimate CATE in patients enrolled in the BaSICS trial and to assess the effects of receiving CATE model-recommended treatment in terms of hospital mortality. Methods: Post hoc analysis of the BaSICS trial assessing the effect of two infusion rates for the fluid challenge (fast, 999 ml/h, control group; vs. slow, 333 ml/h, intervention group) on hospital mortality. CATE was estimated as the difference in outcome for treatment arms in counterfactuals obtained from a Bayesian model trained in the first half of the trial adjusted for predictors hypothesized to interact with the intervention. The model recommended slow or fast infusion or made no recommendation in the second half. A threshold greater than 0.90 probability of benefit was considered. Results: A total of 10,465 patients were analyzed. The model was trained in 5,230 patients and tested in 5,235 patients. A recommendation could be made in the test set in 19% of patients (14% were recommended the control group and 5% the treatment group); for 81% of patients, no recommendation could be made. Slow infusion was more frequently recommended in cases of planned admissions in younger patients; fast infusion was recommended for older patients with sepsis. Slow infusion rate in the subgroup of patients in the test set in which slow infusion was recommended by the model was associated with an odds ratio of 0.58 (95% credible interval of 0.32-0.90; 0.99 posterior probability of benefit) for hospital mortality. Fast infusion in the subgroup in which the model recommended fast infusion was associated with an odds ratio of 0.72 (credible intervals from 0.54 to 0.91; probability of benefit >0.99). Conclusions: Estimation of CATEs from counterfactual probabilities in data from BaSICS provided additional information on trial data. Agreement between treatment recommendation and actual treatment was associated with lower hospital mortality. Clinical trial registered with clinicaltrials.gov (NCT02875873).

Efeitos da solução balanceada em desfechos de curto prazo em pacientes com traumatismo craniencefálico: uma análise secundária do ensaio clínico randomizado BaSICS / Effects of balanced solution on short-term outcomes in traumatic brain injury patients: a secondary analysis of the BaSICS randomized trial

RESUMO Objetivo: Descrever os efeitos do uso de soluções balanceadas nos desfechos de curto prazo de pacientes com traumatismo craniencefálico incluídos no estudo BaSICS. Métodos: Os pacientes foram randomizados para receber solução salina 0,9% ou solução balanceada durante a internação em unidade de terapia intensiva. O desfecho primário foi mortalidade em 90 dias, já os desfechos secundários foram dias de vida e sem internação em unidade de terapia intensiva aos 28 dias. O desfecho primário foi avaliado por regressão logística bayesiana. O desfecho secundário foi avaliado usando regressão beta-binomial inflada de zeros bayesiana. Resultados: Incluímos 483 pacientes (236 no braço de solução salina 0,9% e 247 no braço de solução balanceada). Foram incluídos 338 pacientes (70%) com pontuação na escala de coma de Glasgow ≤ 12. A probabilidade geral de que soluções balanceadas estivessem associadas a maior mortalidade em 90 dias foi de 0,98 (RC de 1,48; ICr95% 1,04 - 2,09). Esse aumento de mortalidade foi particularmente perceptível em pacientes com pontuação na escala de coma de Glasgow abaixo de 6 no momento da inclusão (probabilidade de dano de 0,99). Soluções balanceadas foram associadas a -1,64 dia de vida e sem internação em unidade de terapia intensiva aos 28 dias (ICr95% -3,32 - 0,00) com probabilidade de dano de 0,97. Conclusão: Houve alta probabilidade de que soluções balanceadas estivessem associadas a alta mortalidade em 90 dias, menos dias de vida e sem internação em unidade de terapia intensiva aos 28 dias. ClinicalTrials.gov:NCT02875873

ABSTRACT Objective: To describe the effects of balanced solution use on the short-term outcomes of patients with traumatic brain injury enrolled in BaSICS trial. Methods: Patients were randomized to receive either 0.9% saline or balanced solution during their intensive care unit stay. The primary endpoint was 90-day mortality, and the secondary outcomes were days alive and free of intensive care unit stay at 28 days. The primary endpoint was assessed using Bayesian logistic regression. The secondary endpoint was assessed using a Bayesian zero-inflated beta binomial regression. Results: We included 483 patients (236 in the 0.9% saline arm and 247 in the balanced solution arm). A total of 338 patients (70%) with a Glasgow coma scale score ≤ 12 were enrolled. The overall probability that balanced solutions were associated with higher 90-day mortality was 0.98 (OR 1.48; 95%CrI 1.04 - 2.09); this mortality increment was particularly noticeable in patients with a Glasgow coma scale score below 6 at enrollment (probability of harm of 0.99). Balanced solutions were associated with -1.64 days alive and free of intensive care unit at 28 days (95%CrI -3.32 - 0.00) with a probability of harm of 0.97. Conclusion: There was a high probability that balanced solutions were associated with high 90-day mortality and fewer days alive and free of intensive care units at 28 days. ClinicalTrials.gov:NCT02875873

Association between Type of Fluid Received Prior to Enrollment, Type of Admission, and Effect of Balanced Crystalloid in Critically Ill Adults: A Secondary Exploratory Analysis of the BaSICS Clinical Trial.

Rationale: The effects of balanced crystalloid versus saline on clinical outcomes for ICU patients may be modified by the type of fluid that patients received for initial resuscitation and by the type of admission. Objectives: To assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. Methods: Secondary post hoc analysis of the BaSICS (Balanced Solution in Intensive Care Study) trial, which compared a balanced solution (Plasma-Lyte 148) with 0.9% saline in the ICU. Patients were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). The association between 90-day mortality and the randomization group was assessed using a hierarchical logistic Bayesian model. Measurements and Main Results: A total of 10,520 patients were included. There was a low probability that the balanced solution was associated with improved 90-day mortality in the whole trial population (odds ratio [OR], 0.95; 89% credible interval [CrI], 0.66-10.51; probability of benefit, 0.58); however, probability of benefit was high for patients who received only balanced solutions before enrollment (regardless of admission type, OR, 0.78; 89% CrI, 0.56-1.03; probability of benefit, 0.92), mostly because of a benefit in unplanned admissions due to sepsis (OR, 0.70; 89% CrI, 0.50-0.97; probability of benefit, 0.96) and planned admissions (OR, 0.79; 89% CrI, 0.65-0.97; probability of benefit, 0.97). Conclusions: There is a high probability that balanced solution use in the ICU reduces 90-day mortality in patients who exclusively received balanced fluids before trial enrollment. Clinical trial registered with www.clinicaltrials.gov (NCT02875873).

Association Between Hyponatremia and Maintenance Intravenous Solutions in Critically Ill Children: A Retrospective Observational Study.

Objetive: We sought to determine the association between maintenance intravenous solutions and the presence of hyponatremia in children in pediatric intensive care (PICU). Materials and Methods: An analytical observational study in children hospitalized in the PICU between January 2015 and December 2018. Patients who received maintenance fluids within the first 48 h after admission and who had at least two serum sodium levels drawn during this time were included. Measurements and Main Results: A total of 1,668 patients were admitted to the PICU during the study period, 503 of whom met the inclusion criteria. The median age was 24 months (IQR 8-96) and 50.9% were female. Altogether, 24.1% of the children developed hyponatremia; it was more frequent in those who received hypotonic solutions (63 vs. 37%; OR 1.41 95% CI 0.92, 2.15 p = 0.106), who also had a longer hospital stay (20 vs. 14 days, difference in means 8 days, 95% CI 2.67, 13.3, p = 0.001). Children who received loop diuretics and those who were post-operative had a greater risk of developing hyponatremia if they received hypotonic solutions (aOR 2.1 95% CI 1.41, 3.0, p = 0.000). Those with balanced isotonic solutions had a lower risk of developing hyponatremia (aOR 0.59 95% CI 0.35, 0.99, p = 0.004) and hyperchloremia (aOR 0.51 95% CI 0.34, 0.77, p = 0.000), adjusted for disease severity. A greater risk of death was found in the group with severe hyponatremia <130 mEq/L (aOR 9.75 95% CI 1.64-58.15; p = 0.01). Conclusions: Hyponatremia associated with the use of hypotonic maintenance solutions occurs in one out of four children in intensive care. The use of these solutions is associated with a longer hospital stay, and the main risk groups are post-operative patients and those who receive loop diuretics. Clinical studies are needed to determine which maintenance solutions have the greatest efficacy and safety in critically ill children.

Fluids in ARDS: more pros than cons.

In acute respiratory distress syndrome (ARDS), increased pulmonary vascular permeability makes the lung vulnerable to edema. The use of conservative as compared to liberal fluid strategies may increase the number of ventilator-free days and survival, as well as reduce organ dysfunction. Monitoring the effects of fluid administration is of the utmost importance; dynamic indexes, such as stroke volume and pulse pressure variations, outperform static ones, such as the central venous pressure. The passive leg raise and end-expiratory occlusion tests are recommended for guiding fluid management decisions. The type of intravenous fluids should also be taken into consideration: crystalloids, colloids, and human albumin have all been used for fluid resuscitation. Recent studies have also shown differences in outcome between balanced and non-balanced intravenous solutions. In preclinical studies, infusion of albumin promotes maintenance of the glycocalyx layer, reduces inflammation, and improves alveolar-capillary membrane permeability. Fluids in ARDS must be administered cautiously, considering hemodynamic and perfusion status, oncotic and hydrostatic pressures, ARDS severity, fluid type, volume and infusion rate, and cardiac and renal function. Of note, no guideline to date has recommended a specific fluid composition for use in ARDS; most physicians currently follow recommendations for sepsis.

Plano de análise estatística para o estudo Balanced Solution versus Saline in Intensive Care Study (BaSICS) / Statistical analysis plan for the Balanced Solution versus Saline in Intensive Care Study (BaSICS)

RESUMO Objetivo: Relatar o plano de análise estatística (primeira versão) para o estudo Balanced Solutions versus Saline in Intensive Care Study (BaSICS). Métodos: O estudo BaSICS é um ensaio multicêntrico fatorial e randomizado que avaliará os efeitos da administração dos fluidos Plasma-Lyte 148 em comparação com solução salina 0,9% como fluido de escolha em pacientes críticos, assim como os efeitos de uma velocidade de infusão lenta (333mL/hora) em comparação com uma velocidade de infusão rápida (999mL/hora) durante desafios com volume, em importantes desfechos do paciente. O tipo de fluido será mantido cego para os investigadores, pacientes e nas análises. Não será possível, entretanto, ocultar dos investigadores a velocidade de infusão, mas os procedimentos de análise serão mantidos cegos quanto a esse aspecto. Resultados: O estudo BaSICS terá como parâmetro primário a mortalidade em 90 dias, que será testada com utilização de modelos de risco proporcional de Cox de efeitos mistos, considerando os centros de estudo como variável randômica (modelos de fragilidade) ajustada por idade, disfunção de órgãos e tipo de admissão. Os parâmetros secundários importantes incluem terapia de substituição renal até 90 dias, insuficiência renal aguda, disfunção de órgãos nos dias 3 e 7 e dias sem ventilação mecânica em 28 dias. Conclusão: Este artigo fornece detalhes referentes à primeira versão do plano de análise estatística para o estudo BaSICS e orientará a análise do estudo após a conclusão do seguimento.

Abstract Objective: To report the statistical analysis plan (first version) for the Balanced Solutions versus Saline in Intensive Care Study (BaSICS). Methods: BaSICS is a multicenter factorial randomized controlled trial that will assess the effects of Plasma-Lyte 148 versus 0.9% saline as the fluid of choice in critically ill patients, as well as the effects of a slow (333mL/h) versus rapid (999mL/h) infusion speed during fluid challenges, on important patient outcomes. The fluid type will be blinded for investigators, patients and the analyses. No blinding will be possible for the infusion speed for the investigators, but all analyses will be kept blinded during the analysis procedure. Results: BaSICS will have 90-day mortality as its primary endpoint, which will be tested using mixed-effects Cox proportional hazard models, considering sites as a random variable (frailty models) adjusted for age, organ dysfunction and admission type. Important secondary endpoints include renal replacement therapy up to 90 days, acute renal failure, organ dysfunction at days 3 and 7, and mechanical ventilation-free days within 28 days. Conclusion: This manuscript provides details on the first version of the statistical analysis plan for the BaSICS trial and will guide the study's analysis when follow-up is finished.

Soluciones balanceadas: cloro el «nuevo villano¼ / Balanced solutions: chlorine the «new villain¼ / Soluções equilibradas: cloro «o novo vilão¼

Resumen: Las consecuencias de la reanimación con líquidos por lo regular se han minimizado y aceptado como un «mal necesario¼. En la mayoría de los casos su origen es iatrogénico. En años recientes se ha prestado mucha atención a las soluciones balanceadas, las cuales poseen una cantidad de electrolitos más parecida al plasma humano que otro tipo de soluciones. El objetivo de esta revisión es conocer aspectos fisiopatológicos y la evidencia actual respecto al uso de soluciones balanceadas en los pacientes críticamente enfermos, resaltar los efectos deletéreos de la hipercloremia y su asociación a malos resultados. Para comprender cómo funcionan las soluciones balanceadas debe conocerse el modelo de Stewart para las alteraciones ácido-base. El interés por la hipercloremia se debe a que la administración de soluciones es la maniobra más común en medicina crítica y a su vez la solución salina al 0.9% es el líquido que principalmente se administra. La solución salina al 0.9% puede convertirse en un «problema¼ y no en una «solución¼ si no se selecciona al paciente correcto. Las soluciones balanceadas son una opción, pero no la misma solución para los diferentes casos de pacientes críticamente enfermos.

Abstract: The consequences of resuscitation with liquids are usually minimized and accepted as a «necessary evil¼, in most cases their origin is iatrogenic. Recently much attention has been paid to balanced solutions which have a quantity of electrolytes more similar to human plasma than other types of solutions. The objective of this review is to know the pathophysiological aspects and current evidence regarding the use of balanced solutions in critically ill patients. Highlight the deleterious effects of hyperchloremia and its association with poor results. To understand how balanced solutions work we must know the Stewart Model for acid-base alterations. The interest in hyperchloremia is due to the fact that the administration of solutions is the most common maneuver in acute medicine and in turn the saline solution 0.9% the liquid mostly administered. The saline solution 0.9% can become a «problem¼ and not a «solution¼ if we do not select the right patient. Balanced solutions are an option, but not a solution in different populations of critically ill patients.

Resumo: As consequências da reanimação com líquidos são normalmente minimizadas e aceitas como um «mal necessário¼, na maioria dos casos é de origem iatrogênica. Recentemente se presta muita atenção nas soluções equilibradas que possuem uma quantidade de eletrólitos mais similares ao plasma humano do que outras soluções. O objetivo desta revisão é conhecer aspectos fisiopatológicos e a evidência atual sobre o uso de soluções equilibradas em pacientes em estado crítico. Destacar os efeitos deletérios da hipercloremia e sua associação com resultados desfavoráveis. Para compreeder como funcionam as soluções equilibradas devemos conhecer o modelo de Stewart para as alterações ácido-base. O interesse pela hipercloremia é pelo fato de que a administração de soluções é o procedimento mais comum na medicina aguda e a solução salina a 0.9% é o liquido mais administrado. A solução salina 0.9% pode se tornar um «problema¼ e não uma «solução¼ se não selecionamos o paciente correto. As soluções equilibradas são uma opção, mas não uma mesma solução para os diferentes casos de pacientes em estado crítico.

Abordaje fisicoquímico del estado ácido-base en pacientes críticamente enfermos después de la infusión de siete diferentes tipos de soluciones balanceadas / A physicochemical approach to acid-base balance in critically ill patients after infusion of seven different types of balanced fluids / Enfoque físico-químico do estado ácido-básico em pacientes em estado crítico depois da infusão de sete diferentes tipos de soluções balanceadas

Resumen: Introducción: El método simplificado de Fencl-Stewart puede ser empleado a la cabecera del paciente y es más exacto para la evaluación del balance ácido-base. Omron desarrolló un modelo fisicoquímico del cambio en el exceso de base posterior a la infusión de cristaloides con diferencia de iones fuertes (DIF) diferente; sin embargo, fue un trabajo experimental bajo condiciones controladas. Objetivo: Describir el cambio en el estado ácido-base inicial y a las 24 horas en personas críticamente enfermas tras la infusión de siete diferentes tipos de soluciones balanceadas. Material y métodos: Se realizó un estudio retrospectivo, observacional y descriptivo en una terapia intensiva de tercer nivel. Se incluyeron individuos mayores de 18 años de enero de 2015 a julio de 2016. Se evaluaron los efectos en el estado ácido-base a través del modelo fisicoquímico de Fencl-Stewart modificado al inicio y a las 24 horas de la infusión de cristaloides balanceados con DIF de 27 a 154 mEq/L. Se analizaron los gases arteriales a través del gasómetro ABL800 Flex y GEM Premier 3500. El análisis de electrolitos séricos se realizó a través de Architec plus c16,000. El análisis estadístico fue descriptivo a través del programa SPSS v21.0. Resultados: Se incluyeron 198 sujetos. Las soluciones utilizadas con mayor frecuencia fueron Hartmann y H25, en 27.8 y 26.3%, respectivamente. En general, al analizar la totalidad de la población estudiada, todos los parámetros relacionados con acidosis metabólica tuvieron mejoría a las 24 horas. Conclusiones: El uso de soluciones con DIF > 24 mEq/L mejora el estado ácido-base, sin mayor incidencia de hipercloremia a las 24 horas.

Abstract: Introduction: Acid-base status in a body fluid is physically determined by several independent variables. These are: pCO2, the «strong ion difference¼ (SID), all the strong anions (among them is Cl-), and concentrations of nonvolatile weak acids (ATOT). Normal acid-base status is achieved when the independent variables have normal (empirically established) values. The simplified Fencl-Stewart's method can be used at the bedside of the patient and is more accurate in the assessment of acid-base balance. Omron developed a physicochemical model of the projected change in standard base excess (SBE) as a consequence of infused crystalloid solutions of common use (isotonic saline and balanced fluids); unfortunately this was a clinical simulation at standard physiological state. In addition, Kaplan evaluated acid-base balance after the administration of balanced fluids in trauma patients. Nevertheless, to our knowledge, there are no other clinical trials that evaluate the administration of other types of balanced fluids. Objective: To assess the acid-base status of critically ill patients after the infusion of seven different types of balanced solutions. Material and methods: This was a retrospective, observational and descriptive study conducted in an intensive care unit of a tertiary care hospital. We included all patients 18 years and older admitted to this department from January 2015 to July 2016. We evaluated the effects on acid-base balance after the infusion of seven different solutions: 1) Hartmann + 17.8 mEq/L sodium bicarbonate (NaHCO3) (SID 45.8), 2) Hartmann + 8.9 mEq/L NaHCO3 (SID 36.9), 3) Hartmann + 15 mEq/L NaHCO3 (SID 43), 4) Hartmann + 25 mEq/L NaHCO3 (SID 53), 5) Hartmann (SID 28), 6) normal saline 0.45% + 77 mEq/L NaHCO3 (SID 75), and 7) dextrose solution 5% + 154 mEq/L NaHCO3 (SID 154). Arterial blood gases, serum electrolytes, and proteins were measured in the same blood sample. Also SIDa, SEDe, SIG, ATOT, pCO2, change in standard base excess (SBE), pH, [HCO3], [Na]p and SOFA were calculated. pH, SBE and pCO2 were estimated with the ABL8000 FLEX blood gas analyzer. Data are mean ± SD or percents. We used the data analysis package SSPS. Results: One hundred ninety-eight patients were included. Of these, 54% were women and 45% men. The solutions most used were Hartmann (25%), Hartmann + 8.9 mEq/L NaHCO3 (21%), and Hartmann + 25 mEq/L NaHCO3 (18%). Before the infusion, SIDe was under 30 mEq/L in 30% of the patients and above in 23% of them. The effect on the SIDe was significant before the infusion of different solutions (p 0.01), SIDe > 30 ± 8 mEq/L. No metabolic alkalosis or greater decrease of SIDa/SIDe was observed. Conclusions: This study assesses additional varieties of fluids that have a different SID in the clinical setting. No major acid-base disturbances were observed.

Resumo: Introdução: O método simplificado de Fencl-Stewart pode ser usado no leito do paciente e é mais preciso para a avaliação do equilíbrio ácido-básico. Omron desenvolveu um modelo físico-químico da mudança do excesso de base após a infusão de cristalóide com DIF diferente; No entanto, foi um estudo experimental sob condições controladas. Objetivo: Descrever a mudança no estado ácido-básico inicial e às 24 horas em pacientes em estado crítico após a infusão de sete tipos diferentes de soluções equilibradas. Material e métodos: Realizou-se um estudo retrospectivo, observacional e descritivo em uma terapia intensiva. Incluiram-se pacientes maiores de 18 anos de janeiro de 2015 a julho de 2016. Avaliamos os efeitos no estado ácido-básico através do modelo físico-químico de Fencl-Stewart modificado no início e às 24 horas após a infusão de cristalóides equilibrados com DIF 27 a 154 mEq/L. Analizaram-se gases arteriais através do Gasômetro ABL800 Flex e GEM Premier 3500. A análise dos eletrólitos séricos foi feita através de Architec plus C16,000. A análise estatística foi descrita através do programa SPSS v21.0. Resultados: 198 pacientes. As soluções usadas com mais frecuência eram Hartmann e H25, com 27,8 e 26,3%, respectivamente. Em geral, ao analisar toda a população estudada, todos os parâmetros relacionados com acidose metabólica apresentou melhoria às 24 horas. Conclusão: O uso de soluções com DIF 24 mEq/L melhoraram o estado ácido-básico, sem maior incidência de hipercloremia em um intervalo de 24 horas.