Malnutrition and undernutrition (UN) are commonly used interchangeably, although they are not synonyms. According to the World Health Organization (WHO), malnutrition is described as an imbalance in someone's energy and nutrient intake, which can occur at either end of the weight spectrum (1). In contrast, UN is a term that refers to nutritional inadequacies in an individual's energy and nutrient intake and absorption (2). There are four main types of UN: wasting, stunting, underweight, and micronutrient deficiencies (3). Wasting is characterized by low weight for height. It frequently implies rapid weight reduction, although it can also be sustained. It usually occurs when an individual has not consumed enough or has been sick frequently (3). If left untreated, wasting in children increases the chance of mortality. Stunting is recognized as a short height for age. It is the outcome of chronic or repeated malnutrition, which is frequently connected with poverty, poor prenatal health and nutrition, frequent illness, and/or improper early life feeding and care. Children who are stunted cannot realize their full physical and cognitive capabilities. Underweight is characterized as having an abnormally low weight for one's age. Underweight children may be stunted, wasted, or both. Micronutrient deficiencies are a deficiency of vitamins and minerals that are necessary for the body to operate properly, including the production of enzymes, hormones, and other compounds essential for growth and development (3).

Undernutrition is more prevalent in women, infants, children, and adolescents (3). Children who are severely ill are also in danger of nutritional inadequacy due to the disease itself and the failure to deliver nutrients (4, 5). Although UN is widespread among hospitalized children, especially those admitted to pediatric intensive care units (PICUs), it is underreported (6). The reported prevalence of UN in hospitalized children ranges from 2.5 to 51% (7). It varies depending on the population investigated, clinical settings, characteristics, and categorization systems (7). In addition, this discrepancy stems from the fact that there is no universally accepted definition of pediatric UN (7). There has been a link established in a number of studies between UN and increased mortality and hospitalization duration and an increased number of organ dysfunctions and complications (8, 9). Pediatric patients who are malnourished and admitted to PICUs are at an increased risk of infection and death (10). Moreover, the UN is a growing concern due to its association with poor PICU outcomes (4, 5, 7, 11). Underweight is linked explicitly with an increased incidence of death (4, 7, 8), length of stay (LOS) (9), and duration of mechanical ventilation (MV) (5). Given that UN upon admission or worsening of the nutritional status during hospitalization has a detrimental effect on clinical outcomes and increases healthcare expenses, better identification and documentation of the impact of UN on critically ill children is warranted.

To date, the effect of malnutrition on critically ill children has been studied by only a few previous systematic studies (12). The study conducted by Costa et al. (13) investigated the relationship between UN and PICU outcomes. It revealed that undernourished patients had a longer MV duration. However, the study found inconclusive evidence of a connection between prolonged PICU LOS and mortality (13). Alipoor et al. undertook a systematic evaluation of observational data and a meta-analysis in 2019 for their research into obesity in critically ill children. Compared to normal-weight pediatric patients, they found that obese pediatric patients had a higher risk of mortality and a longer stay in the hospital. They also report a non-statistically significant connection between prolonged PICU LOS and decreased MV length in the obese pediatric patients' group, which they attribute to a lack of statistical significance (14). A more recent review defined the total impact of malnutrition in critically unwell children using PICU admission body mass index (BMI). They evaluated mortality, LOS, and MV length in underweight and overweight PICU patients. They also assessed the impact of BMI on PICU outcomes across nations with varying socioeconomic levels (as defined by the World Bank). However, previous studies characterized both undernutrition and overnutrition by combining anthropometric parameters such as weight for age, BMI, and skin folds with laboratory data (e.g., albumin and C-reactive protein) or by focusing primarily on PICU entrance BMI (12). To the best of our knowledge, there are limited studies that focus on the association between UN in PICU only and outcomes in critically ill children. To address this gap in the literature, we undertook this study to update and improve the evidence foundation regarding the association between UN and children's PICU outcomes, including mortality incidence, LOS in the PICU, the necessity for MV, and duration of MV use. A thorough examination of the currently available data was also revealed.

Moher et al. (15) recommended using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart to identify evidence-based research protocols in the context of a systematic review and meta-analysis.

In our systematic review, we found a slightly significant risk for UN children to stay longer in critical care units by 7% and a mild significant risk of prolonged MV usage (13%) compared to NN children. Prolonged MV usage trend was also observed similarly in all subgroups analyzed. When we focused on pooled studies of both developing countries and younger children's samples, we found that the highest risk needs MV odds in UN patients relative to NN.

However, in contrast to earlier findings, significant RD evidence of mortality incidence was detected between both nutritional status groups. However, we cannot rely on this result as the heterogeneity was high. Therefore, we excluded studies with a non-significant result to test the sensitivity analysis, which were studies by Leite et al. (23), Ward et al. (27), Anton-Martin et al. (30), Costa et al. (28), and Xiong et al. (37). Surprisingly, we found that mortality incidence in UN PICU was 5% higher than in the NN on a homogeneous sample. The five excluded studies had only limited power because most of the studies were small.

The association between UN and inferior PICU outcomes might be explained by a depleted metabolic store with a high catabolic state, low nutritional intake or decreased absorption efficacy (38, 39), loss of muscle mass and strength affecting respiratory function (40, 41), as well as impaired immunity and high oxidative stress associated with delayed wound healing and increased infection risks (40, 42). Thus, in future studies nutrition states must be evaluated during the whole PICU period rather than at admission.

Children in the critical care unit are at risk of having their nutritional status deteriorating due to their disease or barriers to nutrient delivery (43), further worsening their prognosis (42). Appropriate nutritional interventions for UN patients can decrease their incidence of mortality, which is similarly found in the study by Sharma et al. (33); the intervention group had a decreased mortality incidence as a result of appropriate nutritional interventions.

The lack of differences in clinical outcomes demonstrated in our review differs from a systematic review conducted by Costa et al. (13) and a meta-analysis review conducted by Toh et al. (12). These prior reviews either did not demonstrate the association or non-significant association between mortality, PICU LOS, and admission nutrition status. This is likely due to the high heterogeneity within studies and differences in the classification of UN in their included studies. However, the significant results in our review may possibly be due to verified heterogeneity analysis and a more restricted methodology. Only three of the included studies utilized upper z-score cutoffs than our a priori z-score cutoffs, which were based on different growth reference studies (27, 31, 34). The remaining studies used either BMI percentiles or a priori z-score cutoffs that we adopted from WHO (17).

We were only able to analyze PICU LOS and extended MV in UN individuals in ≦ −2 z_score and ≦ −1 z_score pooled due to the minimal variability in nutrition status definitions across studies. UN children are at risk of staying longer in PICU compared to NN children when UN defined from < -1 z_score by 4% than UN standard classification. This may indicate a classification overlap. In most of the studies, a patient who was between the −1 and −2 SD line would have been classified as NN, but Ward et al. (27), Irving et al. (31), and Afonso et al. (34) counted them as UN patients. Given that our sensitivity analysis found discrepancies in results, it appears that we, as a research community, need to standardize the classification of critically ill children's nutritional status.

However, there was significant heterogeneity in defining upper accepting age range subgroup and mortality incidence, MV need, and PIC LOS. But, when the ≦16 years patient cohorts were analyzed alone, we revealed lower mortality odds in UN patients relative to NN. In contrast, the risk of using MV outcome was mildest higher in UN compared to NN children. The explanation of that significant moderate heterogeneity was still even after subgroup the define upper accepting age range is a reflection of the growth cycle. As in infants, toddlers, and the last 2 years of adolescent ages, the body composition especially muscle mass can be fluctuating (44); besides, evidence suggests that when low muscle mass is present, the risk of death in critically ill patients is increased (45). This led us to the hypothesis that subgroups must be categorized according to narrowing age, i.e., infancy, toddler, childhood, and adolescence.

We further explored this influence by heterogeneity analysis including mixed patient cohorts, which revealed a 7% higher risk of MV usage in UN compared to NN patients. It was logical to exclude the Anton-Martin et al. (30) study to get a sensitivity analysis as it was focused only on ventilated patient population (ECMO cases). However, exclusion was impossible in this situation as the specific diagnosis group contained only Anton-Martin et al. (30) and Ross et al. (24). As a result, we can rule out the possibility of heterogeneous research populations having an impact on our major findings. In certain research, chronic diseases are known to cause UN (46); therefore, it is important to know the patient's diagnostic history and frequency of hospitalization.

In addition, it was analyzed to explore the prospective influence of economical country status on the effect of the UN on PICU outcomes. Analyzing mortality incidence in both developing and developed countries showed no significant RD, which was relatively higher in UN compared to NN patients. In contrast, the estimated RD of MV usage incidence in UN patients were ten time higher in developing countries than in developed countries. Thus, we can hypothesize that the lack of impact distinction is due to a lack of literature undertaken in underdeveloped countries (47). Furthermore, poorer results in lower-income nations may be due to differences in PICU resources between countries (48, 49), which may not have been apparent in the papers we reviewed.

The last heterogeneity analysis in our review was the number of days to define long period even in PICU staying. When we compared the pooled results from studies that used ≦3 days as a cutoff to describe their sample longer stay in PICU to ≦7 days pooled result, we found that UN had the highest risk of prolonged stay in PICU than NN in ≦7 days group. Despite this, this meta-analysis of the stay prolonged in MV included RDs had only limited power because most of the subgroups have one study.

This systematic review established a significant association between UN status at PICU admission and clinical outcomes such as mortality incidence, need for MV, PICU LOS, and prolonged stay in MV. All studies examined were observational in nature and were consistent in their use of the nutritional assessment parameters (anthropometry, i.e., BMI and W/H) in the pediatric intensive care unit. However, there was considerable variance in the classification of the UN between studies. Sensitivity analysis revealed that an increased risk of PICU stay, MV usage, and duration on MV may be associated with UN at the time of PICU admission, as assessed by BMI z-score. Additionally, the data suggest that the primary diagnosis for PICU admission and economical country level may influence clinical outcomes. This may imply the necessity for standardization of UN status classification based on hospital or PICU admission status, stratified by patients' diagnosis subgroups at admission, to facilitate future research elucidating the relationship between nutritional status and clinical outcomes in PICU patients.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

MA designed the study, interpreted the data, and wrote the manuscript. KB takes responsibility for the integrity of the data and the accuracy of the data analysis. Both authors reviewed and contributed to the manuscript drafted by MA. Both authors have read the manuscript, took part in the discussion, and agreed the final version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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