Murtaza Ali Gowa  ( Department of Pediatric Critical Care Medicine, National Institute of Child Health, Karachi, Pakistan. )
Usman Tauseef  ( Department of Pediatric Medicine, National Institute of Child Health, Karachi, Pakistan. )
Syed Habib Ahmed  ( Department of Pediatric Oncology, National Institute of Child Health, Karachi, Pakistan. )

Objective: To determine the frequency of hypoalbuminaemia in critically ill children, and to assess the association of low serum albumin with clinical deterioration and outcome.

 

Method: The prospective, descriptive study was conducted from September 1, 2020, to October 31, 2021, at the National Institute of Child Health, Karachi, and comprised critically ill children of either gender aged between 3 months and 16 years admitted to the paediatric intensive care unit. Serum albumin values were documented at 2 hours post-admission and at 24 hours. Paediatric Index of Mortality 2 score, Vasoactive Inotropic Score, and Paediatric Sequential Organ Failure Assessment scores were calculated. Hypoalbuminaemia was defined as serum albumin ≤3.3gdl. Data was analysed using SPSS 27.

 

Results: Of the 110 patients, 70(63.6%) were boys and 40(36.4%) were girls. The overall mean age was 46.72±43.28 months. Hypoalbuminaemia at 24 hours was found in 74(67.3%) subjects compared to 60(54.5%) at 2 hours, and mean serum albumin was lower at 24 hours compared to 2 hours post-admission (p<0.05). Patients with hypoalbuminaemia had significant relation with Paediatric Index of Mortality 2 score, Vasoactive Inotropic Score, Paediatric Sequential Organ Failure Assessment score, and outcome (p<0.05). The risk of mortality was 4.1 times higher in patients with hypoalbuminaemia (p=0.001).

 

Conclusion: The incidence of hypoalbuminaemia was found to be higher in children in intensive care settings, and hypoalbuminaemia was a significant independent predictor of mortality in a critically ill child.

 

Key Words: hypoalbuminaemia, Serum albumin, Critically ill, Children, PICU, Prognosis.

(JPMA 73: 1034; 2023) DOI: 10.47391/JPMA.7465

 

Submission completion date: 06-08-2022 — Acceptance date: 28-01-2023

 

Introduction

 

Albumin is the most abundant serum protein. In addition to its physiological role of maintaining the colloid osmotic pressure and preventing fluid leaking into the extravascular space, albumin acts as a low-affinity, high-capacity carrier for many exogenous and endogenous compounds. Albumin maintains the storage and intravascular transportation of hormones, like cortisol, thyroxin and testosterone. It is also a carrier for noxious compounds, like bilirubin, bile acids, fatty acids, cations like Fe+2, Ca+2, Cu+2, and Zn+2, and several drugs. Albumin can bind toxins, and, quantitatively, it is the primary extracellular antioxidant which constitutes three-fourths of the plasma antioxidant capacity. Besides, albumin acts as a plasma buffer and helps maintain the acid-base balance in the blood. Albumin is synthesised exclusively in the liver hepatocytes as pre-proalbumin and proalbumin, which is converted to albumin by the Golgi apparatus. The final product secretes into circulation at a rate of about 10-15gm per day. About 40% of the albumin remains in circulation, while a fraction moves to the interstitial space. Factors that stimulate albumin synthesis include the action of hormones, such as insulin and growth hormone. Most of the clearance of albumin occurs by catabolism (84%) and the remaining through gastrointestinal (10%) and renal clearance (6%)^1,2.

The average plasma albumin value range varies with age. At birth, it ranges from 1.8-3.0g/dl in premature babies on the first day of life, 2.5-3.4g/dl at <6 days in a full-term case, and its usual range is 1.9-4.9g/dl in infants <1 year. After the first year of life, the normal range of albumin is 3.4-4.2g/dl for a child <3 years and 3.5-5.6g/dl in children aged 4-19 years. But beyond infancy, any value of plasma albumin <3.3g/dl is considered hypoalbuminaemia irrespective of age^3,4.

hypoalbuminaemia can be caused by physiological states, like growth, menstruation, second and third trimester of pregnancy, lactation, or female gender. Pathologically, it can be a result of decreased intake as in protein-calorie malnutrition, kwashiorkor, decreased production as in liver diseases, increased loss in the urine as in nephrotic syndrome, or in the stool as in protein-losing enteropathy, vascular endothelial growth factor (VEGF) up regulation as in cancers, or secondary to the more complex mechanisms, like trauma, surgery, infection or mono-organ failure^5,6.

Albumin production may be inhibited by pro-inflammatory mediators, such as interleukin-6 (IL-6), IL-1, and tumour necrosis factor (TNF). So, it is considered a marker of nutritional status and disease severity, particularly in chronic and critically ill patients. Lower serum albumin levels are linked pathologically to inflammation in several aspects. Inflammation increases capillary permeability due to the release of inflammatory cytokines, such as TNF-alpha and IL-6, chemokines, and the action of prostaglandins, and complement components as well as endotoxins from gram-negative bacteria also cause escape and redistribution of albumin from vascular to interstitial space, leading to expansion of interstitial space and increasing the distribution volume of albumin. The rate of synthesis is also decreased in inflammation as a consequence of the increase in gene transcription for positive acute-phase proteins, such as C-reactive protein (CRP), and a decrease in the rate of transcription of albumin messenger ribonucleic acid (mRNA). On the other hand, albumin has a short half-life, and all of these factors lead to lower albumin levels despite increased fractional synthesis rates in the plasma^5,7.

The incidence of hypoalbuminaemia in critically ill children is reported to be >50%, and a significant relationship between lower albumin levels and mortality risk in children with critical illness has been established^4,8. Low serum albumin levels with a persisting positive fluid balance are associated with increased mortality and prolonged illness course in a critically ill or severely septic patient, and a shift to a negative fluid balance (polyuria) with rising serum albumin levels herald recovery in a critically ill child^4,5,9,10.

Hypoalbuminaemia on admission was found to be associated with prolonged paediatric intensive care unit (PICU) stay, higher Paediatric Risk of Mortality scores, more need for assisted respiratory support in the form of mechanical ventilation, higher progression to multi-organ dysfunction, and remarkably higher morbidity and mortality^11-14.

However, data from local studies is still scanty in this regard. The current study was planned to document the incidence of hypoalbuminaemia in critically ill children, and to find out its correlation with clinical deterioration and outcome.

 

Patients and Methods

 

The prospective, descriptive, cross-sectional, analytical study was conducted from September 1, 2020, to October 31, 2021, at the National Institute of Child Health (NICH), Karachi, which is a tertiary care hospital and a regional referral site. After approval of the institutional ethics review committee (ERC), the sample size was calculated using OpenEpi¹⁵ with 99% confidence interval (CI) while assuming the prevalence of hypoalbuminaemia on admission to be 56.7%⁴. The probability simple random sampling technique was used. Those included were critically ill children of either gender aged between 3 months and 16 years admitted to the 13-bed NICH PICU. Patients diagnosed with nephrotic or nephritic syndrome or protein-losing enteropathy, cardiac failure, or patients who were there after cardiac surgery and those who came with burns were excluded. Also excluded were patients who received albumin solution at any time during the admission or were on total parenteral nutrition (TPN).

A proforma (Appendix 1) was used as the data-collection instrument filled out by the researchers. Socio-demographic characteristics of the patients, hospital registration number, age, gender, weight, height and the diagnosis were recorded. Serum albumin levels at 2 hours and 24 hours post-admission were noted. Quantitative measurement of serum albumin was performed by photometric colour test (Beckman Coulter analyser). Hypoalbuminaemia was defined as serum albumin ≤3.3g/dl.

In addition, mortality risk assessed by calculating Paediatric Index of Mortality 2 (PIM2) score¹⁶, Vasoactive Inotropic Score (VIS)^17,18, and Multiple Organ Dysfunction Score (MODS) Paediatric Sequential Organ Failure Assessment (pSOFA) score¹⁹ (Appendices 2-4). Parameters required for calculating theses scores, like PaO2, FiO2, base excess, SO2, platelet count, bilirubin count, and serum creatinine were recorded. The need of mechanical ventilation (MV), MV duration, and the duration of PICU stay were recorded. The outcome was noted in terms of survived or expired. The institutional ERC waived parental consent as all sampling and monitoring was going on as part of routine management. The anonymity of the patients was, however, maintained throughout the study.

Data was analysed using SPSS 27. Data normality was assessed using Shapiro-Wilks test, and serum albumin values were found to be normally distributed at all points (coefficient 0.98, p=0.48). Mean and standard deviations were calculated for quantitative data, while frequencies and percentages were calculated for qualitative data. Comparison of mean values was done using dependent and independent t-test, as appropriate. Pearson’s coefficient of correlation was applied for determining the relationship among quantitative variables, and Chi-square/Fischer Exact test were utilised, as appropriate, for qualitative variables. McNemar’s test was applied to check the proportion difference at two different time frames. The odds ratio (OR) was calculated by univariate and multivariate binary logistic regression. P<0.05 was considered statistically significant.

 

Results

 

Of the 110 patients, 70(63.6%) were boys and 40(36.4%) were girls. The overall mean age was 46.72±43.28 months. Hypoalbuminaemia at 24 hours was found in 74(67.3%) subjects compared to 60(54.5%) at 2 hours (p=0.007). Of the total, 96(87.3%) patients required MV and 62(56.4%) required inotropic support. There were 48(43.6%) deaths; 40(36.4%) among those with hypoalbuminaemia, and 8(7.3%) among those with normal albumin level (Table 1).

 

 

Mean serum albumin was lower at 24 hours 3.20±0.54g/dl compared to 2 hours post-admission 3.31±0.57g/dl (p<0.05).

Patients with hypoalbuminaemia had significant relation with PIM2, VIS, pSOFA scores, and outcome (p<0.05). The risk of mortality was 4.1 times higher in patients with hypoalbuminaemia (p=0.001) Patients aged <60 months were 1.17 times more likely to have hypoalbuminaemia than patients aged >60 months (Table 2).(Page-70)

 

 

Discussion

 

The incidence of hypoalbuminaemia in children admitted to PICU (67.3%) was higher than reported earlier in a study (56.7%)⁴.

The pathophysiology of hypoalbuminaemia in a sick child is multifactorial, and this can occur as a consequence of decreased production by the liver during critical illness or due to malnutrition, or it can occur because of increased degradation and altered distribution caused by increased catabolism or capillary leakage and an altered distribution of albumin during inflammation and illness⁴.

Infants, children aged <6 years and malnourished children were more prone to develop hypoalbuminaemia compared to older and good-weight children in the current study. The mean serum albumin in patients who expired was lower (2.81g/dl) compared to those who survived (3.17g/dl). In contrast, a study reported that means albumin levels were similar between non-survivors and survivors⁴.

The current findings related to PIM2 and MODS pSOFA were consistent with earlier reports^11,20.

Mean Arterial Pressure (MAP) had no significant correlation with serum albumin (r=0.052), but the hypoalbuminaemia group had a slightly lower average MAP (78.04mHg) compared to the normoalbuminaemia group (83.14mmHg). The finding explains that hypoalbuminaemia is not the solitary culprit causing hypotension in a critically ill child, and a fall in MAP in such patients is multifactorial. There was a moderate negative correlation between serum albumin and VIS (r=-0.30, p=0.05). The mean VIS was higher in the hypoalbuminaemia group than in patients with normal albumin (12.15 vs. 6.69), and the odds of having VIS score >10 were 2.3 times higher in patients with hypoalbuminaemia than patients with normal albumin (p=0.07). The patients who needed inotropic support had low serum albumin, indicating the importance of intravascular albumin in maintaining blood pressure. Theoretically, albumin infusion as a volume expander should increase blood pressure, but the evidence of albumin infusion for hypotension is still lacking. In a double-blind Saline vs. Albumin Fluid Evaluation (DAFE) trial, the albumin infusion given to treat hypotension in adult patients failed to reduce mortality and morbidity in critical adult patients^21,22. As such, it more research is needed in this regard, especially in the paediatric population.

Patients with hypoalbuminaemia were more likely to require MV than patients with normal albumin in the current study (p=0.14). MV duration was also higher in the hypoalbuminaemia group, which is consistent with literature^8,22.

The average PICU stay was almost similar in both groups (p=0.38) in the current study, which was in contrast to Tiwari et al⁸.

Finally, there was also a significant relation between hypoalbuminaemia and patient outcome (p=0.001), and the mean serum albumin was lower in non-survivors than the survivors (p=0.001), which is contrary to the findings of Durward et al⁴, who reported that mean serum albumin was similar in both groups. The overall risk of mortality was 4.1 times higher in patients with hypoalbuminaemia in the current study, highlighting low serum albumin as a crucial independent predictor of mortality in critically ill children. The finding is also in contrast to that of Durward et al⁴.

The major limitation of the current study was that it did not look for the response of albumin infusion in increasing blood pressure and decreasing mortality and morbidity. In terms of strength, the current study is the first to establish a relation between serum albumin level and MODS pSOFA score.

 

Conclusion

 

The findings provided supportive evidence to the literature about the frequent incidence of hypoalbuminaemia among critically ill patients. A significant relationship between low serum albumin was established with mortality and morbidity.

 

Acknowledgement: We are grateful to the participating families and the staff of the paediatric intensive care unit (PICU).

 

Disclaimer: None.

 

Conflict of Interest: None.

 

Source of Funding: None.

 

References

 

1       Soeters PB, Wolfe RR, Shenkin A. Hypoalbuminemia: Pathogenesis and Clinical Significance. JPEN J Parenter Enteral Nutr. 2019; 43:181-193.doi: 10.1002/jpen.1451.

2.      Doucette K, Percival ME, Williams L, Kandahari A, Taylor A, Wang S, et al. Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia. Hematol Oncol. 2021; 39:697-706.doi: 10.1002/hon.2925

3.      Kliegman R, Geme JST. Nelson textbook of pediatrics. Edition 21st. Kliegman R, Geme JST, eds. Philadelphia, PA: Elsevier, 2020.

4.      Durward A, Mayer A, Skellett S, Taylor D, Hanna S, Tibby SM, et al. Hypoalbuminaemia in critically ill children: incidence, prognosis, and influence on the anion gap. Arch Dis Child. 2003; 88:419-22.doi: 10.1136/adc.88.5.419.

5.      Qian SY, Liu J. [Relationship between serum albumin level and prognosis in children with sepsis, severe sepsis or septic shock]. Zhonghua Er Ke Za Zhi. 2012; 50:184-7.

6.      McLean TW, Stewart RM, Curley TP, Dewsnup MY, Thomas SG, Russell TB, et al. Hypoalbuminemia in children with cancer treated with chemotherapy. Pediatr Blood Cancer. 2020; 67:e28065. doi: 10.1002/pbc.28065.

7.      Cobeñas CJ, Lombardi LL, Pereyra P, De Rose E, Gogorza MJ, Spizzirri AP, et al. Hypoalbuminemia: a risk factor in patients with STEC-associated hemolytic uremic syndrome. Pediatr Nephrol. 2021; 36:2739-46. doi: 10.1007/s00467-021-05017-8.

8.      Tiwari LK, Singhi S, Jayashree M, Baranwal AK, Bansal A. Hypoalbuminemia in critically sick children. Indian J Crit Care Med. 2014; 18:565-9.doi: 10.4103/0972-5229.140143.

9.      Wiedermann CJ. Hypoalbuminemia as Surrogate and Culprit of Infections. Int J Mol Sci. 2021; 22: 4496. doi: 10.3390/ijms22094496.

10.    Loffredo L, Campana A, Olivini N, Cotugno N, Palma P, Oliva A, et al. Hypoalbuminemia and clinical adverse events in children with COVID-19. J Med Virol. 2021; 93:2611-3.doi: 10.1002/jmv.26856.

11.    Kittisakmontri K, Reungrongrat S, Lao-Araya M. Hypoalbuminaemia at admission predicts the poor outcomes in critically ill children. Anaesthesiol Intensive Ther. 2016; 48:158-61.doi: 10.5603/AIT.a2016.0028.

12.    Yanni GN, Lubis M, Ali M. The Influence of Albumin Level in Critically Ill Children to Length of Stay and Mortality in Paediatric Intensive Care Unit. Open Access Maced J Med Sci. 2019; 7:3455-8. doi: 10.3889/oamjms.2019.445.

13.    Duan L, Hu GH, Jiang M, Zhang CL, Duan YY. [Association of hypoalbuminemia with acute kidney injury in children after cardiac surgery]. Zhongguo Dang Dai Er Ke Za Zhi. 2018; 20:475-80.doi: 10.7499/j.issn.1008-8830.2018.06.009.

14.    Gelfand Y, De la Garza Ramos R, Nakhla JP, Echt M, Yanamadala V, Yassari R. Predictive value of hypoalbuminemia and severe hypoalbuminemia in oncologic spine surgery. Clin Neurol Neurosurg. 2021; 210:107009.doi: 10.1016/j.clineuro.2021.107009.

15.    Sullivan KM, Dean A, Soe MM. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep. 2009; 124:471-4. doi: 10.1177/003335490912400320.

16.    Slater A, Shann F, Pearson G, for the PIMSG. PIM2: a revised version of the Paediatric Index of Mortality. Intensive Care Medicine. 2003; 29:278-85. Intensive Care Med. 2003; 29:278-85.doi: 10.1007/s00134-002-1601-2.

17.    McIntosh AM, Tong S, Deakyne SJ, Davidson JA, Scott HF. Validation of the Vasoactive-Inotropic Score in Pediatric Sepsis. Pediatr Crit Care Med. 2017; 18:750-7. doi: 10.1097/PCC.0000000000001191.

18.    Kumar M, Sharma R, Sethi SK, Bazaz S, Sharma P, Bhan A, et al. Vasoactive Inotrope Score as a tool for clinical care in children post cardiac surgery. Indian J Crit Care Med. 2014; 18:653-8. doi: 10.4103/0972-5229.142174.

19.    Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the sepsis-3 definitions in critically ill children. JAMA Pediatr. 2017; 171:e172352. doi: 10.1001/jamapediatrics.2017.2352.

20.    Leite HP, Rodrigues da Silva AV, de Oliveira Iglesias SB, Koch Nogueira PC. Serum Albumin Is an Independent Predictor of Clinical Outcomes in Critically Ill Children. Pediatr Crit Care Med. 2016; 17:e50-7. doi: 10.1097/PCC.0000000000000596.

21.    Chen CB, Hammo B, Barry J, Radhakrishnan K. Overview of Albumin Physiology and its Role in Pediatric Diseases. Curr Gastroenterol Rep. 2021; 23:11. doi: 10.1007/s11894-021-00813-6.

22.    Horowitz IN, Tai K. Hypoalbuminemia in critically ill children. Arch Pediatr Adolesc Med. 2007; 161:1048-52. doi: 10.1001/archpedi.161.11.1048.

 

 

 

 

Appendix 1: The study proforma

 

PROFORMA                                Date: ___________

BIODATA:

Name(optional): ________________     Age: ____     Gender:  M/F     Height: ____cm       Weight: ____Kg

Provisional Diagnosis: ________________   Hospital Registration No: ___________

Date of Admission: _________    Date of Discharge/Death: ________     Final Diagnosis:________________

Serum Albumin levels:

At 2 hours: _________     At 24 hours: _______

PIM 2 (Pediatric Index of Mortality 2) Score(Error! Reference source not found.): ____________

Systolic BP: _____ mmHg       PaO2: _____ mmHg      FIO2 at the time of PaO2:  ______     Base excess: _____ mmol/l

Pupillary reactions to bright light:  >3 mm and both fixed/other/unknown

Mechanical ventilation at any time during the first hour in ICU:  No/Yes   Elective admission to ICU:  No/Yes

Recovery from surgery or a procedure is the main reason for ICU admission: No/Yes

Admitted following cardiac bypass No/Yes   High risk diagnosis:

Vasoactive Inotropic Score(VIS)(Error! Reference source not found.): _____________

Dopamine dose: ____ (μg/kg/min)          Dobutamine dose: _____ (μg/kg/min)         Epinephrine dose: _______(μg/kg/min)           Milrinone dose: ______(μg/kg/min)       Vasopressin dose: _____(U/kg/min)        Norepinephrine dose: ______ (μg/kg/min)

Length of PICU stay: ________ days

Length of Mechanical Ventilation:  ____________ days

MODS(pSOFA-Pediatric Sequential Organ Failure Assessment Score)(Error! Reference source not found.): ______

PO2: _____   FiO2: _____   P/F ratio: _____   SO2: _____    S/F Ratio: ______

Platelet count: _______ x 10⁵uL    Bilirubin levels: _____mg/dl     Creatinine: _______ mg/dL

Mean Arterial Pressure: _______mmHg    Inotropic Support: ____________ at dose : ________

Glasgow Coma Score : _______

Outcome: survived/expired/LAMA/Step Down/Discharge/other: ___________

Remarks: ____________________________________________________________________________          

 

 

 

 

 

 

Appendix 2: Paediatric Index Of Mortality Score

 

 

Coding rules. These rules must be followed carefully for PIM2 to perform reliably:

1.Record SBP as 0 if the patient is in cardiac arrest, record 30 if the patient is shocked and the blood pressure is so low that it cannot be measured.

2.Pupillary reactions to bright light are used as an index of brain function. Do not record an abnormal finding if this is due to drugs, toxins or local eye injury.

3.Mechanical ventilation includes mask or nasal CPAP or BiPAP or negative pressure ventilation.

4.Elective admission. Include admission after elective surgery or admission for an elective procedure (e.g. insertion of a central line), or elective monitoring, or review of home ventilation. An ICU admission or an operation is considered elective if it could be postponed for more than 6 h without adverse effect.

5.Recovery from surgery or procedure includes a radiology procedure or cardiac catheter. Do not include patients admitted from the operating theatre where recovery from surgery is not the main reason for ICU admission (e.g. a patient with a head injury who is admitted from theatre after insertion of an ICP monitor; in this patient the main reason for ICU admission is the head injury).

6.Cardiac bypass. These patients must also be coded as recovery from surgery.

7.Cardiac arrest preceding ICU admission includes both in-hospital and out-of-hospital arrests. Requires either documented absent pulse or the requirement for external cardiac compression. Do not include past history of cardiac arrest.

8.Cerebral haemorrhage must be spontaneous (e.g. from aneurysm or AV malformation). Do not include traumatic cerebral haemorrhage or intracranial haemorrhage that is not intracerebral (e.g. subdural haemorrhage).

9.Hypoplastic left heart syndrome. Any age, but include only cases where a Norwood procedure or equivalent is or was required in the neonatal period to sustain life.

10.Liver failure acute or chronic must be the main reason for ICU admission. Include patients admitted for recovery following liver transplantation for acute or chronic liver failure.

11.Neuro-degenerative disorder. Requires a history of progressive loss of milestones or a diagnosis where this will inevitably occur.

12.Bronchiolitis. Include children who present either with respiratory distress or central apnoea where the clinical diagnosis is bronchiolitis.

13.Obstructive sleep apnea. Include patients admitted following adenoidectomy and/or tonsillectomy in whom obstructive sleep apnoea is the main reason for ICU admission (and code as recovery from surgery).

Note: For the sake of convenience PIM 2 score will be calculated using online calculator available at OPENPediatrics https://www.openpediatrics.org/assets/calculator/pediatricindex-mortality-2

 

 

 

 

Appendix 3: Vasoactive Inotropic Score (VIS)

 

 

VIS = [IS] + 10 X Milrinone dose (μg/kg/min) +10,000 × Vasopressin dose (U/kg/min) + 100 × Norepinephrine dose (μg/kg/min)

[Wernowsky IS] = [Dopamine dose (μg/kg/min) + Dobutamine dose (μg/kg/min) +100 × epinephrine dose (μg/kg/min)]

A score of < 10 will be assigned as low, 10-20 as moderate and >20 as high.

 

 

 

 

Appendix 4: Paediatric Sequential Organ Failure Assessment (pSOFA) Score

 

 

The sum of sub-scores will result in pSOFA score (ranging from 0-24 points; higher scores indicate a worse outcome. Risk of mortality interpreted from pSOFA score of 0-6 is 80% and 15-24 is > 90% respectively.