The authors reply.

Pediatric Critical Care Medicine www.pccmjournal. org 585 on our sample considering 28-day mortality as outcome, the Cox regression final model did not change. Serum albumin, the Pediatric Index of Mortality 2 score, and lactate remained significantly associated with 28-day mortality in the adjusted analysis. The increase of 1.0 g/dL in serum albumin at admission resulted in a 64% reduction in the hazard for 28-day mortality (hazard ratio, 0.36; 95% CI, 0.20–0.65; p < 0.001). As in most cohort studies evaluating the effects of hypoalbuminemia on outcome of critically ill patients, in our study (5), we analyzed only admission serum albumin serum concentrations, which could be prone to change according to the clinical course during the ICU stay. In their letter, Zamberlan et al (1) cite a study in which serum albumin concentrations were examined at admission or at any time during PICU stay. However, in the cited study, the authors simply compared hypoalbuminemic with normoalbuminemic patients regarding clinical outcome (6). No adjustment for potential confounding variables was performed, and a number of patients received albumin infusion and fresh frozen plasma during the study period. Unfortunately, these methodological issues hamper the interpretation of the results. In addition, it is worth noting that admission serum albumin concentration has been included as one of the component variables in the Acute Physiology and Chronic Health Evaluation III and IV scores (7, 8). Human serum albumin functions probably go beyond its known and important roles in maintaining colloid osmotic pressure and transporting substances in the blood. The diversity of the structural details and new biological pleiotropic properties of human serum albumin in maintaining physiologic homeostasis are being increasingly understood and appreciated as biochemical and biophysical research studies explore the molecule of this protein (9, 10). From the clinician’s perspective, relevant questions that must be addressed include 1) which factors other than those already known modify the concentration of serum biomarkers, including albumin, 2) what is the prognostic value of hypoalbuminemia that develops during the ICU stay, and 3) whether administration of albumin solutions can influence the outcome and which patients are most likely to benefit from their use (11). New biomarkers of inflammation with potential to identify functional outcomes and mortality are being discovered, including metabolic profiling, micro-RNA, cell surface markers, and gut microbiota. In parallel, strategies for integrative analysis of all different genomic and phenotype data are being developed, such as “nutritional systems biology” (12). There is no doubt that these emerging markers and technologies look promising, but their link to outcome measures requires further exploration and validation. Theories have been confirmed and refuted throughout history. Research hypotheses should be tested in studies with ever more improved methodologies. This is how scientific knowledge progresses. To date, we understand that more welldesigned studies are necessary to refute the classical concept that hypoalbuminemia is a strong independent predictor of morbidity and mortality and that serum albumin represents a low-cost and reliable biomarker of many diseases. The authors reply: In response to the commentary by Zamberlan et al (1) who seem to contradict the concept that serum albumin is a strong outcome predictor, we would like to ponder on the two review studies cited to support their arguments. In the first one, a comprehensive review involving studies in different groups of critically ill children published up to June 2013, it was found that nutritional serum biomarkers were of limited value in predicting clinical outcome (2). However, among the studies that examined the association between serum albumin and clinical outcomes, some were not specifically designed for this purpose or were not adequately powered for the endpoints. Furthermore, a study that was not included in the cited review found admission hypoalbuminemia to be associated with morbidity and mortality in critically ill children (3). The second study, a systematic review by Ferrie et al (4), was actually designed to investigate the role of nutritional indicators in predicting favorable outcome after nutritional therapy intervention in adult ICU patients. Randomized clinical trials of any nutritional interventions in critically ill adult patients that reported any nutrition indicator after baseline and any clinically meaningful outcome variables were included in the review. Essentially, the authors verified the reliability of nutritional variables (including weight, plasma proteins, nitrogen balance, and lymphocytes) in monitoring response to nutritional support in the ICU. This is not the same as investigating biomarkers of poor clinical outcomes. With regard to the comments on our study (5), we agree that using 60-day mortality as outcome might be an overstretched time span to test the effect of serum albumin on mortality; however, when we repeated the statistical analysis Clínicas da Faculty of Medicine da Universidade de São Paulo, Department of Pediatrics, São Paulo, Brazil; Werther Brunow de Carvalho, MD, Department of Pediatrics of Faculty of Medicine/Universidade de Sao Paulo, São Paulo, Brazil, Instituto da Criança do Hospital das Clínicas da Faculty of Medicine/University of São Paulo, São Paulo, Brazil