World Journal Of Pediatrics-articles

Author Affiliations: Department of PICU, Beijing Children's Hospital of Capital Medical University, No. 56 Nan Li Shi Road, Beijing 100045, China (Li Y, Wang Q, Chen H, Gao HM, Qian SY); Department of Nuclear Medicine, Dongzhimen Hospital affiliated to Beijing University of Traditional Chinese Medicine, Beijing 100700, China (Zhou T)

Corresponding Author: Su-Yun Qian, MD, Department of PICU, Beijing Children's Hospital of Capital Medical University, No. 56 Nan Li Shi Road, Beijing 100045, China (Tel: +86-010- 59612765; Fax: +86-010-59718726; Email: syqian@yahoo.com.cn)

Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) represents a devastating complication observed in critical care medicine. The purpose of this study is to investigate the epidemiological aspects of ALI/ARDS in pediatric intensive care unit (PICU) and risk factors of mortality.

Methods: Patients with ALI/ARDS in PICU of Beijing Children's Hospital, a tertiary medical center from November 1, 2005 to October 31, 2006 were included in this prospective study. We identified the risk factors for underlying diseases and mortality during a 3-month follow-up using multivariate logistic regression analysis.

Results: In 562 critically ill patients admitted to PICU of Beijing Children's Hospital, there were 15 ALI-non ARDS patients and 29 ARDS patients, resulting in an incidence of 7.8% (44/562). The mortality rate of ARDS was 24.1% (7/29) and that of ALI/ARDS was 18.2% (8/44). At a 3-month follow-up, 12 patients died after being discharged from PICU and the total mortality rate was 45.5% (20/44). ALI/ARDS patients with pulmonary disease had better outcomes than those with extra-pulmonary involvements (P<0.05). Discharge against medical advice, low PaO₂/FiO₂ during hospital stay and high PaCO₂ on PICU admission were risk factors of mortality.

Conclusions: ARDS has a high mortality rate in PICU, especially in those with extra-pulmonary diseases. In addition to aggressive medical management of comorbidity, lung protection and avoidance of discharge against medical advice will decrease the mortality.

Key words: acute lung injury; acute respiratory distress syndrome; children; epidemiology; risk factor

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains the ultimate challenge in pediatric intensive care unit (PICU). As the disease process evolving, ALI/ARDS is defined as acute hypoxic respiratory failure resulting from pulmonary or extra-pulmonary causes except cardiogenic factors. ARDS has recently been recognized as one of the most common causes of death because of severe acute respiratory syndrome and high pathogenic avian influenza infection. ARDS has posed great threats to public health, and deserves more study in pediatric critical care community. Clinical research into ALI/ARDS is dominated by studies in adult patients. Pediatric ALI/ARDS cases have been reported in the literature since 1967.^[1]Here, we report a one-year prospective survey of ALI/ARDS in PICU of Beijing Children's Hospital to describe the epidemiology and risk factors for ALI/ARDS.

All critically ill children admitted for ALI/ARDS in PICU of Beijing Children's Hospital between November 1, 2005 and October 31, 2006 were screened. The recruited children met the following inclusion criteria: (1) age between 29 days and 18 years; and (2) domestic pediatric critical index score (PCIS) ≤90 or fulfilling the American Guidelines for Admission of Pediatric Intensive Care Units (PICUs). Exclusion criteria were: (1) patients younger than 29 days or older than 18 years (Premature infants with corrected gestational age less than 43 weeks were also excluded); (2) patients with PCIS >90 and failed to meet the American Guidelines for Admission of PICU; (3) patients with central respiratory failure, neuromuscular diseases, cyanotic congenital heart disease or signs of cardiogenic pulmonary edema (Echocardiography within 24 hours after admission indicated ejection fraction <50% or fractional shortening <30% and left atria or ventricle enlargement). ALI/ARDS was defined according to the criteria of the American European Consensus Conference (1994).^[2]

Data were collected from the patients who met the inclusion criteria, which included age, gender, height, weight, contact information, diagnosis of primary disease, oxygenation index, PCIS, and modified lung injury score (LIS).^[3] Data concerning laboratory test, chest radiography, length of hospital stay, duration of mechanical ventilation, and ventilator setting were also recorded until transfer or discharge of patients. All laboratory tests were carried out according to the clinical indications.

In patients who required mechanical ventilation, low-tidal-volume ventilation setting was implemented (Normal tidal volume ranged from 6 to 8 mL/kg, maximizing at 10 mL/kg).

Proportion was used as descriptive statistics for categorical variables, mean ± standard deviation for normally distributed continuous variables, and median (interquartile range) for non-normally distributed continuous variables. For normally distributed quantitative data, Student's t test was applied to evaluate the difference between the two groups. Qualitative data were tested with the Chi-square test. Wilcoxon's rank-sum test was used for analysis of non-normally distributed quantitative data. To analyze mortality, a backward stepwise logistic regression model was used to choose variables that were associated with mortality and considered clinically important. Consequently, age, sex, PaO₂/FiO₂ ratio, initial lung injury score, and arterial carbon dioxide tension were included. The SPSS 12.0 software was used for all statistical analyses, and a two-sided P<0.05 was considered statistically significant.

In 562 critically ill patients admitted to PICU of Beijing Children's Hospital, a total of 44 patients met the inclusion criteria. Among them, 15 patients had ALI-non ARDS (34.1%) and 29 had ARDS (65.9%). Their gender and age at the first clinical visit are presented in the Table. Among 30 patients of 0-3 years old, 15 were ARDS patients. All the patients of 3-7 years old (n=2) and those of more than 7 years old (n=12) were diagnosed with ARDS.

The most common causes of ALI/ARDS were pneumonia (52%) and sepsis (36%), followed by multiple trauma (5%), lung contusion (5%) and drowning (2%). Sepsis was associated with leukemia, congenital immunodeficiency disease, lymphoma, systemic lupus erythematosus, etc.

According to the causes, ALI/ARDS patients were divided into a pulmonary disease group (direct lung damage, n=26) and an extra-pulmonary disease group (indirect lung damage, n=18). The survival rate was higher in the pulmonary disease group than in the extra-pulmonary disease group (69.2% vs. 33.3%).

Eight ALI/ARDS patients died during hospital stay and 36 survived at discharge. In-hospital mortality was 18.2% (8/44) for patients with ALI/ARDS, and 24.1% (7/29) for patients with ARDS. The prevalence rate of self-discharge against medical advice was 50% (22/44), which was attributed to socioeconomic factors (63.6%, 14/22), uncontrollable diseases (27.3%, 6/22) and other factors (9.1%, 2/22).

The primary causes of hospital mortality included multiple organ failure (50%, 4/8), respiratory failure (25%, 2/8) and uncontrollable diseases (25%, 2/8). The uncontrollable diseases included malignant diseases (leukemia, lymphoma) and congenital diseases (metabolic disease, immunodeficiency disease).

Among the 36 patients who survived after discharge from the hospital, 21 patients survived, 12 died within 28 days after discharge, and 3 were lost to follow-up. The lost 3 patients were considered survivors because of the improvement of their clinical manifestations and no requirement of mechanical ventilation at the time of discharge. The total mortality rate at the end of the follow-up was 45.5% (20/44). Thus there were 20 patients in the non-survival group and 24 in the survival group. There was no significant difference in age and sex between the two groups (P=0.320 and 0.457, respectively).

Variables with a significant difference between the ALI/ARDS survivors and non-survivors included PaCO₂ on PICU admission (P=0.008), LIS (P=0.036), minimum PaO₂/FiO₂ during the hospital stay (P=0.010) and self-discharge against medical advice (P<0.001). In the risk factors of mortality identified, discharge against medical advice (OR=87.651, 95%CI=7.300-1052.494), low PaO₂/FiO₂ during the hospital stay (OR=0.967, 95%CI=0.941-0.994), and high PaCO₂ on PICU admission (OR=1.093, 95%CI=1.009-1.184) were the most significant ones shown by multivariate stepwise logistic regression analysis.

In this study, ALI/ARDS patients accounted for 7.8% (ARDS for 5.2%) of all patients admitted to the PICU of Beijing Children's Hospital. This finding is consistent with the average ALI/ARDS incidence in PICU reported elsewhere.^[4-9] The reported ARDS prevalence is about three times higher than that of China in 2004,^[10] and the relatively higher ALI/ARDS prevalence may be correlated to a higher percentage of severe cases in PICU.

The reported mortality rates of ARDS varied from 34% to 70%^[11-14] because of different inclusion criteria and mortality calculation. The mortality in our study was 45.5%. Interestingly, there were striking differences between the reported data and ours. The in-hospital mortality rates were 18.2% and 24.1% for ALI and ARDS respectively, which are considerably lower than those reported previously,^[15-21] but consistent with those reported by other four studies published after 2000.^[9,13,22,23] This wide disparity in mortality could be related to many factors including medical referral system, admission and discharge criteria of PICU, severity of illness, socioeconomic status of patients, quality of patient care, and resource availability. Notably, our findings differ significantly from those mentioned above in that some patients had to abandon treatments for reasons that made the in-hospital mortality different from 28-day mortality. It is possible that the factors influencing the mortality of in-hospital vs. 28-day are the coverage of medical insurance and the capability to afford medical expenses.

This study revealed that pneumonia was the main cause of ALI/ARDS. The second cause of ALI/ARDS was non-pneumonia related sepsis, accounting for approximately 10% of the patients. Since most pneumonia cases also met the diagnostic criteria for pulmonogenic sepsis, we came to the conclusion that sepsis is the leading cause of ALI/ARDS. Risk factors of ALI/ARDS include sepsis, chronic liver disease, extra-pulmonary organ failure, low PaO₂/FiO₂, hypoalbuminemia and old age.^{[7-9,16,19,24-26]} In our study the principal risk factor of ALI/ARDS mortality was discharge against medical advice, followed by low PaO₂/FiO₂ and high PaCO₂ on PICU admission.

No coverage of medical insurance and low socioeconomic status of patients contributed to delayed treatment or discharge against medical advice. Some patients with a great chance of survival who chose to terminate their treatment would make the mortality rate higher and the identification of risk factors difficult, for instance, multiple organ failure.

Limited by the low incidence of the disease and the small sample size, this study can only provide a preliminary conclusion and further investigation with a large sample is necessary. The prognosis of ALI/ARDS with pulmonary and extra-pulmonary origin is still unclear. In this study, ALI/ARDS patients with pulmonary disease had better outcome than those with extra-pulmonary involvement. The difference in prognosis was thought to be related to both the underlying diseases and the fact that most patients with extra-pulmonary disease also had other diseases such as leukemia, immune deficiency syndrome, and lymphoma, which caused immunocompromized conditions making sepsis patients susceptible to ARDS and even life-threatening multiple organ dysfunction syndrome (MODS). In cases of ALI/ARDS caused by pulmonary diseases, the lower incidence of severe complications or MODS was probably due to the improved survival rate. This indicated that MODS may be a morbidity-related risk factor for ALI/ARDS, but a definite conclusion still needs a large-sample study.

The authors are grateful to the staff in PICU of Beijing Children's Hospital for their support.

Ethical approval: This study was approved by the Ethics Committee of Beijing Children's Hospital, Capital Medical University.

Competing interest: There are no conflicts of interest with other organizations or persons.

Contributors: Yan L wrote the first draft of this paper. All authors contributed to the intellectual content and approved the final version. Qian SY is the guarantor.

1 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967;2:319-323.

2 Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. Intensive Care Med 1994;20:225-232.

3 Newth CJ, Stretton M, Deakers TW, Hammer J. Assessment of pulmonary function in the early phase of ARDS in pediatric patients. Pediatr Pulmonol 1997;23:169-175.

4 Goss CH, Brower RG, Hudson LD, Rubenfeld GD; ARDS Network. Incidence of acute lung injury in the United States. Crit Care Med 2003;31:1607-1611.

5 Vincent JL, Sakr Y, Ranieri VM. Epidemiology and outcome of acute respiratory failure in intensive care unit patients. Crit Care Med 2003;31(4 Suppl):S296-S299.

6 Goh AY, Chan PW, Lum LC, Roziah M. Incidence of acute respiratory distress syndrome: a comparison of two definitions. Arch Dis Child 1998;79:256-259.

7 Walker TA. The acute respiratory distress syndrome in children: recent UMMC experience. J Miss State Med Assoc 1999;40:371-375.

8 Randolph AG, Meert KL, O'Neil ME, Hanson JH, Luckett PM, Arnold JH, et al. The feasibility of conducting clinical trials in infants and children with acute respiratory failure. Am J Respir Crit Care Med 2003;167:1334-1340.

9 Dahlem P, van Aalderen WM, Hamaker ME, Dijkgraaf MG, Bos AP. Incidence and short-term outcome of acute lung injury in mechanically ventilated children. Eur Respir J 2003;22:980-985.

10 Yu WL, Lu ZJ, Wang Y, Shi LP, Kuang FW, Qian SY, et al. The epidemiology of acute respiratory distress syndrome in pediatric intensive care units in China. Intensive Care Med 2009;35:136-143.

11 Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685-1693.

12 Bersten AD, Edibam C, Hunt T, Moran J; Australian and New Zealand Intensive Care Society Clinical Trials Group. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002;165:443-448.

13 Flori HR, Glidden DV, Rutherford GW, Matthay MA. Pediatric acute lung injury: prospective evaluation of risk factors associated with mortality. Am J Respir Crit Care Med 2005;171:995-1001.

14 Erickson S, Schibler A, Numa A, Nuthall G, Yung M, Pascoe E, et al. Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study. Pediatr Crit Care Med 2007;8:317-323.

15 Paret G, Ziv T, Augarten A, Barzilai A, Ben-Abraham R, Vardi A, et al. Acute respiratory distress syndrome in children: a 10 year experience. Isr Med Assoc J 1999;1:149-153.

16 Davis SL, Furman DP, Costarino AT. Adult respiratory distress syndrome in children: associated disease, clinical course, and predictors of death. J Pediatr 1993;123:35-45.

17 Norrashidah AW, Azizi BH, Zulfiqar MA. Acute respiratory distress syndrome in a paediatric intensive care unit. Med J Malaysia 1999;54:225-229.

18 Ben-Abraham R, Moreh O, Augerten A, Vardi A, Harel R, Barzilay Z, et al. Adapting prognostic respiratory variables of ARDS in children to small-scale community needs. J Crit Care 1999;14:120-124.

19 Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with adult respiratory distress syndrome. J Pediatr 1991;119:896-899.

20 Rivera RA, Butt W, Shann F. Predictors of mortality in children with respiratory failure: possible indications for ECMO. Anaesth Intensive Care 1990;18:385-389.

21 Redding GJ. Current concepts in adult respiratory distress syndrome in children. Curr Opin Pediatr 2001;13:261-266.

22 Wang JD, Wang TM, Chi CS. Clinical spectrum of acute respiratory distress syndrome in a tertiary pediatric intensive care unit. Acta Paediatr Taiwan 2003;44:202-207.

23 Zimmerman JJ, Akhtar SR, Caldwell E, Rubenfeld GD. Incidence and outcomes of pediatric acute lung injury. Pediatrics 2009;124:87-95.

24 Swaniker F, Kolla S, Moler F, Custer J, Grams R, Barlett R, et al. Extracorporeal life support outcome for 128 pediatric patients with respiratory failure. J Pediatr Surg 2000;35:197-202.

25 Peters M, Tasker R, Kiff K, Yates R, Hatch DJ. Acute hypoxemic respiratory failure in children: case mix and the utility of respiratory severity indices. Intensive Care Med 1998; 24:699-705.

26 O'Brien JM Jr, Phillips GS, Ali NA, Lucarelli M, Marsh CB, Lemeshow S. Body mass index is independently associated with hospital mortality in mechanically ventilated adults with acute lung injury. Crit Care Med 2006;34:738-744.