Hypoalbuminemia as a Predictor of Adverse Outcome in Critically Ill Children: A Prospective Cohort Study

Background hypoalbuminemia is a common nding in critically ill patients associated with a high risk of mortality, but there is lack of data on its role in pediatric patients. The aim of this study is to investigate the effect of low albumin levels in pediatric patients on poor prognosis and high risk of mortality in the pediatric intensive care unit (PICU). Methods This was a prospective cohort study conducted at the PICU at El-Bagour hospital from November 2018 to November 2020. The aim was to evaluate low albumin level as a predictor of poor prognosis and clinical outcome in 150 critically ill children aged one month up to 18 years. ROC curve was used to assess the discriminatory ability of scoring systems for patients’ mortality. Results 148 patients were included in the nal where the of in the 1st 48-h postadmission was 44.6% with an overall mean serum albumin level of 3.34 ± 0.78. Hypoalbuminemia was an independent factor of mortality prediction. Moreover, we found children with hypoalbuminemia had higher mortality rate (p-value < 0.001), higher PICU stays (p-value = 0.016), lower galscow coma score (GSC) (p-value = 0.0017), and more need of mechanical ventilation (p-value < 0.001).


Introduction
Albumin represents the most abundant protein in plasma with more than two-third of plasma protein composition, thus it contributes about 75% or higher of the colloid osmotic pressure of plasma [1]. Also, albumin plays an important role in the transport and binding of many molecules such as bilirubin, bile salts, hormones and even drugs [2]. About two-thirds of albumin remains in the extra-vascular space with only one-third in the intra-vascular space as it is highly water-soluble [2].
Hypoalbuminemia is a complex disease characterized by either lack of synthesis in malnutrition, malabsorption, and even hepatic dysfunction or excessive loss, which happens in nephropathy, or proteinlosing enteropathy [3]. In critical illness, the permeability of capillaries increases much caused by pro-in ammatory mediators such as histamine, or bradykinin or by damage to the integrity of capillaries structures so that they may become leakier. Thereby there is an exchange between albumin in the extravascular and intra-vascular compartments so hypoalbuminemia is a common nding in critical ill patients [4].
A recent meta-analysis study, has been conducted on critically ill patients, showed that hypoalbuminemia was associated with higher mortality rate, higher length of PICU stay along with the higher need of mechanical ventilation [5]. It also showed that hypoalbuminemia is anchored with adverse outcome in adults [6]. There is a paucity of data regarding the incidence and signi cance of hypoalbuminemia in critically ill children, but show con icting results [7][8][9]. Therefore, the aim of this study is to evaluate the incidence of hypoalbuminemia as a predictor of clinical outcome in critically ill pediatric patients.

Study Design:
This was a prospective observational cohort study conducted at the Pediatric intensive care unit (PICU) of Meno a teaching hospital from November 2018 to November 2020. The study protocol was approved by the Ethical committee of Meno a Hospital under the code of 9114485, as well as a written con rmed consent was gained from guardians before the inclusion process after explanation of the study.

Inclusion Criteria:
Our inclusion criteria were children who were critically ill and admitted to the PICU aged one month up to 18 years. We also excluded children in whom hypoalbuminemia was expected to be a result of preexisting diseases such as severe protein-energy malnutrition characterized by either weight or height < 3rd centile according to the WHO guidelines in 2007 [10]. Also, children who had chronic diseases such as chronic liver disease and chronic kidney disease. Children who experienced second and third burn degrees, or who had received blood product or albumin within the last 4 weeks before admission were excluded too.

Study Process:
All children had done the admission albumin level test within the rst 48 hours of admission. The exact estimation of the albumin level in plasma was done according to the guidelines (dye-binding method) [11]. We de ned hypoalbuminemia based on the guidelines as serum albumin level < 2.5 g/dl for children < 7 months in age and < 3.4 g/dl for whom age are > 7 months [12].
The data collected from children were age, sex, weight, height, diagnosis categorized regarding the organ system, complete blood count (CBC), C-reactive protein (CRP), GCS, blood glucose, Na, K, urea Creatinine, SGOT, SGPT &blood culture.
Children were allocated into two groups based on their albumin level to hypoalbuminemic group (children with low level of albumin) and Normo-albuminemic group (children with normal albumin level). Based on the purpose of analysis, children were also assigned to two sub-groups regarding the age into (< 7 months and > 7 months). Children who were discharged against medical advice were excluded from the nal analysis of outcome.

Outcomes:
Our primary outcomes were the length of PICU stay, the need for mechanical ventilation, and the fate of patients in PICU. Pediatric Risk of mortality 2 (PRISM2), Pediatric Logistic Organ Dysfunction 2 (PELOD2), and Pediatric Index of Mortality 2 (PIM2) scoring systems were used to assess the severity of illness at admission.

Statistical analysis:
SPSS software version 25.0 was used to perform the analysis. All continuous data were expressed as mean ± standard deviation and dichotomous data were expressed as frequency (percentage).
Independent sample t-test and Fisher's exact test were used to compare albumin levels with PDR and duration of PICU stay. Mortality risk scores were analyzed using Pearson's Chi-square test.
The area under curve (AUC) of the receiver operating characteristics (ROC) was also carried out using SPSS to measure discrimination. P value less than 0.05 along with a 95% con dence interval (CI) was considered to be signi cant. The incidence of hypoalbuminemia was found in 67 children (44.6%) out of 150 children. When the children were allocated regarding their age, it was found that 13 out of 36 (36.1%) children in the younger group were hypoalbuminemic whereas 54 out of 114 (47.4%) in the older group were hypoalbuminemic making the incidence of hypoalbuminemia in children older than 7 months signi cantly higher (p-value = 0.26, RR = 0.76). The incidence of hypoalbuminemia in children with PDR > 5% (55.4%) was higher than the incidence observed in children with PDR calculated by PIM2 < 1% (23%) (p < 0.001, RR = 2.399)

Baseline
[ Table 1]. Mean ± SD was used for continuous data, and frequency (percentage) was used for dichotomous data.

Diagnostic Categories:
The diagnostic categories of 150 children showed that the incidence of hypoalbuminemia in the neurological disease category was higher than other illnesses (20 out of 40) followed by the respiratory disease category (20 out of 43), while in Normo-albuminemic group, the respiratory disease category has the highest number of pediatric patients (23 out of 43) then the neurological disease category (20 out of 40) [ Table 2].   Pearson's Chi-square test, MD = mean difference, CI = Con dence interval.

Mean ± SD was used for continuous data
Univariate binary logistic regression was performed to check whether hypo-albuminemia at admission was considered to be independently in relation to mortality. We assessed any factor that could be associated with mortality such as age < 1 year at admission, GCS < 8, PIM2 score, and the need for mechanical ventilation. GCS < 8, PIM2 score, and need for mechanical ventilation were signi cantly associated with mortality at admission (p-value < 0.001), except age < 1 year which wasn't signi cantly associated (p-value = 0.2) [ Table 5].

Statistical relations:
We measured the correlation between albumin level and other parameters to assess the strength of the relationship between this variable and other parameters [ Table 6]. A non-signi cant correlation was found between Serum Albumin level and GCS < 8, and PRISM2 score (Rho=-0.128, 0.105 respectively, p-value > 0.05), and a positive correlation between Serum Albumin level and PIM2 score, PELOD2 score, need for mechanical ventilation, the mortality rate, and length of PICU stay (Rho = 0.216, 0.306, 0.351, 0.31, and 0.235 respectively, p-value < 0.05).

Diagnostic Accuracy:
The optimal cut-off PIM2 score was at > 1.6%, with 92.9% sensitivity and 75.5% speci city and area under ROC curve of 0.78 (p-value < 0.001). The optimal cut-off PRISM2 score was at > 4.5 with 92.9% sensitivity and 72.6% speci city and area under ROC curve of 0.73 (p-value < 0.001). Also, the optimal cut-off PELOD2 score was at > 1.5 with 95.2% sensitivity and 84.9% speci city and area under ROC curve of 0.844 (p-value < 0.001) that yielded a good discrimination on predicting mortality and morbidity in the PICU [ Table 7]. Level of signi cant is 0.5

Discussion
Despite of the availability of many severity scores systems that can predict the mortality, there were only few studies that assess the mortality and morbidity in PICU in critically ill patients presented with hypoalbuminemia. This study focused on the incidence of hypoalbuminemia in PICU in critically ill pediatrics, as hypoalbuminemia is a common problem associated with higher mortality and morbidity rate [13]. In critical illness, the permeability of blood vessels increases much by the action of in ammatory mediators, as a result, there is a dramatic change in albumin level between extra-vascular and intra-vascular. There is about 300% rise in albumin escape rate as a result of albumin balance alteration. Also, there is a huge decrease in albumin synthesis in liver by the effect of these in ammatory mediators especially IL-6 and TNF-alpha [7,14].
The incidence of hypoalbuminemia in this study was 44.6% of children admitted to the PICU and this comes with the alignment of a study by (Horowitz and Tai 2007) that mentioned the incidence of hypoalbuminemia which was about 33% at admission [8]. (Durward et al. 2003) found that hypoalbuminemia was 57% at admission but after 1 day, it was progressed to 76% [7]. The frequency of hypoalbuminemia in another study by (Tiwari et al. 2014) was 21% at admission, then it increased to 34% after one week, and about 37% during the rest of the PICU stay [14]. We couldn't perform repeated serum albumin to all children due to the lack of commitment from guardians, so we measured only the incidence of hypoalbuminemia at admission.
We used PIM2, PRISM2 and PELOD2 scores to assess the severity of illness 48-h postadmission [15][16][17]. Pediatric Index of Mortality 2 (PIM2) was found in a previous study by (Qureshi et al. 2007) to be the most effective pediatric scoring system with the highest accuracy rate among all other scores [17]. Pediatric Risk of mortality 2 (PRISM2) and Pediatric Logistic Organ Dysfunction 2 (PELOD2) were also used to assess the severity of illness and give the highest accuracy rate in assessing the risk mortality as well.
There was a strong relation between hypoalbuminemia and mortality rate as PRISM2 score was much higher in the hypoalbuminemic group rather than the normal albumin level group ( . So overall these three scores rendered good discriminative relation between survivors and non-survivors and further it may be used as a tool for prognostic evaluation beside their use in assessing the risk of mortality.

Limitations and Recommendations:
This study had several limitation. It was a single-center study with a small number of participants in each group. Also we couldn't perform repeated serum albumin so we can assign the incidence of hypoalbuminemia in whole study duration. We recommend further high number of participants and multicenter studies to be approached, so we can conclude a better evaluation of such disease. We also recommend prospective studies and randomized controlled trials to be performed not retrospective, so we can get the highest possible accuracy.

Conclusion
There is a strong relation between hypoalbuminemia in PICU and high mortality and morbidity rates as patients with hypoalbuminemia tend to have bad adverse outcomes and hence giving that high mortality rates.

Declarations
Ethics approval and consent to participate: The study was approved by the Ethical committee of Meno a Hospital. A written consent of participation was obtained from guardians after discussing the measures of the study and its importance. All Methods of the study were performed in accordance with Meno a Hospital guidelines and their regulations.
Consent for publication: Not applicable.
Availability of data and materials: • All data generated or analyzed during this study are included in this published article [and its supplementary information les].

Figure 1
Temporal Pro le of subject admitted to Pediatric intensive care unit

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. DataSheet.xlsx