2021 : Volume 1, Issue 1

PICU Chronic Lung Disease Mortality and Morbidity (PLUM)

Author(s) : Gayathri Subramanian 1 , Claire Nissenbaum 2 , Mia Kahvo 3 and Catherine Fullwood 4

1 Consultant Intensivist , Manchester University NHS Foundation Trust , England

2 Faculty of Medicine , Manchester University NHS Foundation Trust , England

3 Regional Newborn Intensive Care Unit , St Michael's Hospital , Manchester University NHS Foundation Trust , England

4 Research Fellow , St Michael's Hospital , Manchester University NHS Foundation Trust , England

Open J Pediatr Neonatol

Article Type : Research Article

Abstract

Background: Children with Bronchopulmonary dysplasia (BPD) have increased incidence of respiratory illness, often necessitating Pediatric ICU admission. Little is known about the outcome of these admissions.

Aim: This study aimed to determine clinical and demographic data of this cohort and determine factors affecting mortality and length of ICU stay. Oxygen requirement following a year after ICU admission was determined.

Methods: Retrospective case-note review was performed. Patients with congenital cardiac abnormalities or chronic respiratory conditions like cystic fibrosis were excluded. Data were presented as descriptive statistics. Predictors of death and LOS were determined using Fisher’s exact test and univariate regression analyses.

Results: Small numbers of deaths prohibited strong conclusions. Inotrope use (p<0.001), blood transfusion (p<0.001), use of inhaled nitric oxide (p=0.003) and a diagnosis of sepsis (p=0.004) were related to mortality. Age at admission, gestational age at birth, weight, oxygen requirement prior to admission or length of stay did not increase the odds of mortality. Inotrope usage (p=0.027), transfusion requirements (p=0.044) and a sepsis diagnosis (p=0.005) were significantly associated with length of ICU stay >7 days. More than half the patients, who were followed up, had an oxygen requirement at 6-month and 12-month follow up.

Conclusion: Patients admitted with chronic lung disease to PICU with pulmonary hypertension and sepsis has long ICU stay and more odds of dying. More than half of the children who survive to 6-month and 12-month follow up have ongoing oxygen requirement. Studies in larger populations of children with BPD will help in more accurate prognostication following PICU admission.

Keywords: Pediatric; Critical Care; Bronchopulmonary Dysplasia; Respiration; Artificial; Mortality; Morbidity

Introduction

Bronchopulmonary dysplasia (BPD) is seen in approximately 40% of infants born <28 weeks gestation and rates receiving positive pressure ventilation have largely remained unchanged [1, 2]. Older definitions of BPD were limited to children with oxygen requirement and radiological changes in lungs at 28 days of life [3]. Current definition grades BPD as mild, moderate, and severe and considers total duration of oxygen administration, gestational age, need for positive pressure ventilation and oxygen dependency at 36 weeks of corrected gestational age (CGA) [1-4]. Extremely preterm babies are resuscitated at birth with new strategies like less surfactant use being practiced for the prevention and treatment of BPD [5]. Prevalence of infants with life limiting conditions admitted to PICU’s across UK is increasing, with perinatal causes being the second highest reason for this increase [6]. Children with BPD have poorer lung function, greater respiratory morbidity and increased incidence of respiratory illnesses [1, 2, 7-9]. However, there is paucity of data to define their course following PICU admission after discharge from neonatal units. We therefore sought to study this cohort of patients admitted to a tertiary PICU in view of paucity of admission and outcome data.

Aim

In patients admitted to Pediatric ICU with bronchopulmonary dysplasia to:
1. Study clinical and demographic data.
2. Identify potential predictors of mortality and length of stay (LOS) in ICU.
3. Evaluate oxygen requirement at 6 months and 12 months following discharge.

Methods

Single-center, retrospective observational cohort study through case note review using search terms CLD, chronic lung disease, BPD, bronchopulmonary dysplasia and prematurity. Children with prior diagnosis of CLD as defined by oxygen requirement at 36 weeks gestation and admitted to PICU between January 2016 and end December 2017 were included. Those with structural cardiac anomaly or other chronic respiratory diagnoses e.g. Cystic Fibrosis were excluded (Figure 1). Predictors for mortality and ICU Length of stay (LOS) were studied. Follow up at 6- and 12-months post discharge was obtained from the electronic patient records (EPR). Ethical approval was gained from Greater Manchester West Ethics Committee (IRAS 245832).





Figure 1: Inclusion of children in the study.

Statistics

Statistical analyses were conducted in SPSS v25. The demographic and follow-up data were presented using descriptive statistics (mean, median and percentage). The proportion of deaths was reported with 95% binomial confidence intervals. Predictors of death and LOS were explored using Fisher’s exact test and univariate regression analyses. Univariate logistic regression was also used to explore any significant characteristics of patients leading to multiple admissions.

Results

Clinical and demographic data
66 admissions (from 43 patients) were identified (Figure 1) in 2 years. This constitutes 3.7% of PICU admissions annually (average annual admissions= 1000). Twelve patients were readmitted 2-6 times in study period. Neonatal data was available for 20 patients. Seven patients died during their PICU admission and three within a year of admission giving a PICU mortality rate of 23.26% (95% CI 11.76-38.63). Death was secondary to respiratory failure in 8, out of hospital cardiac arrest in one and acute surgical emergency in one patient. Overall median PICU LOS was 7 days (IQR 2 - 18) with 48.5% (32/66) of admissions (95% CI 35.99-61.12) having >7 day PICU stay. 57.9% (21/38) of patients were born <28 weeks of gestation (data available only for 38 patients). 56% patients were male and 42% were Caucasian. Median age at PICU admission was 17.5 months (IQR 4.2 – 64.4) and mean weight was 11.9kg (SD ±10.6). Comorbidities included gastro-oesophageal reflux (35%), ventriculo-peritoneal shunts (14%), pulmonary hypertension (12%) and cerebral palsy (9%). 60% (40/66) required oxygen or assisted ventilation prior to PICU admission and 30% (20/66) had a tracheostomy. Sildenafil therapy prior to PICU admission was identified in 6.

76% (50/66) were invasively ventilated. None received renal replacement therapy. Nitric oxide was used in 16.2% (10/66) and systemic steroids in 19% (12/ 66) in their PICU stay. Predictors of mortality and LOS>7 days are summarised in Table 1 and Table 2. Unless specified, all data is analysed as a proportion of admissions rather than patients.


Summary statistics

Odds ratio (95% CI)

p-value

Died (N=7)

Survived (N=59)

Gestational age at birth (weeks) (mean, SD)

25.8 (±2.2), (n=5)

27.1 (±3.3), (n=49)

0.85 (0.56-1.16)

0.378

Age at admission to ICU (months) (median, IQR)

15.0 (4.5-77.4)

20.0 (4.5-60.9)

1.01 (0.99-1.02)

0.367

ICU stay (days) (median, IQR)

23.0 (13.0-24.0)

7.0 (2.0-14.0)

1.04 (0.98-1.09)

0.16

ICU stay > 7 days (n, %)

5 (71.4%)

27 (45.76%)

2.96 (0.59-21.86)

0.215

Oxygen required prior to admission (n, %)

3 (42.9%)

41 (69.5%)

0.33 (0.06-1.64)

0.173

PIM score (median, IQR)

0.04 (0.01-0.07)

0.04 (0.01-0.07), (n=52)

7.81 (0.12-275.68)

0.252

Inotrope used

6 (85.7%)

5 (8.5%)

64.8 (8.86-1364.37)

<0.001

Blood transfusion

5 (71.4%)

3 (5.1%)

46.67 (7.19-453.72)

<0.001

Inhaled nitric oxide used

4 (57.1%)

5 (8.5%)

14.40 (2.54-93.84)

0.003

Sepsis

5 (71.4%)

9 (15.3%)

13.89 (2.58-108.28)

0.004

Airway malacia

0 (0.0%)

13 (22.0%)

0 (0.00-2.84) *

0.329



Table 1: Potential factors affecting Mortality.

Summary Statistics

Odds ratios (95% CI)

p-value

LOS ? 7 days (N=34)

LOS > 7 days (N=32)

Gestational age at birth (weeks) (mean, SD)

27.0 (3.5), (n=30)

27.0 (2.9), (n=24)

1.01 (0.85-1.20)

0.931

Age at admission to ICU (months) (median, IQR)

11.5 (4.0-48.0)

22.0 (5.0-72.0)

1.01 (1.00-1.02)

0.276

Oxygen required prior to admission (n, %)

22 (64.7%)

22 (68.8%)

1.02 (0.43-3.40)

0.728

PIM score (median, IQR)

0.03 (0.01-0.06), (n=32)

0.05 (0.02-0.08), (n=27)

0.47 (0.01-11.69)

0.652

Inotrope use

2 (5.9%)

9 (40.9%)

6.26 (1.45-43.67)

0.027

Blood transfusions

1 (2.9%)

7 (21.9%)

9.24 (1.51-178.61)

0.044

Inhaled nitric oxide use*

0 (0.0%)

9 (28.1%)

0.00*

<0.001

Sepsis

2 (5.9%)

12 (37.5%)

9.60 (2.31-65.98)

0.005

Airway malacia

6 (20.6%)

7 (18.8%)

1.31 (0.38-4.56)

0.667



Table 2: Factors potentially affecting length of stay >7 days.

Small numbers of deaths prohibited strong conclusions, but higher proportions of inotrope use (p<0.001), blood transfusions (p<0.001), inhaled nitric oxide (p=0.003) and a diagnosis of sepsis (p=0.004) were related to mortality. Age at admission, gestational age at birth, weight, oxygen requirement prior to admission or length of stay did not significantly increase the odds of mortality.

Inotrope usage (p=0.027), transfusion requirements (p=0.044) and a sepsis diagnosis (p=0.005) were significantly associated with LOS >7 days. Although not statistically significant, this cohort tended to be older at admission, was on oxygen prior to admission and needed inhaled nitric oxide in their PICU admission. Due to the low numbers involved our conclusions are exploratory. Readmission was more common in those children requiring oxygen (75%) or long-term ventilation prior to admission. Univariate logistic regression analysis demonstrated a significant association between readmission and a diagnosis of airway malacia – 33.3% vs 6.5% (p=0.038, odds ratio=7.25), however again we note the small numbers involved.


Follow-up data (Figure 2)



Figure 2: Follow up data.

Data were available for 27 children at 6-months and 23 for 12-months follow up. 63% (17/27) and 61% (14/23) of these children respectively were on supplemental oxygen therapy at 6- and 12-months following ICU discharge.

Discussion

Bronchopulmonary dysplasia is strongly associated with adverse long-term health outcomes [2, 10]. Over half of infants with a diagnosis of BPD will require admission to hospital at some stage in early childhood with respiratory distress and lower respiratory tract infections causing maximum admissions as seen in our cohort [1-3]. Although gestation at birth, NICU course, oxygen requirement are often used to predict severity of BPD [1, 8], neither these factors nor the premorbid state of the child prior to PICU admission were found to affect mortality, readmission or ICU LOS in our cohort. Larger studies are needed for generalizability of this data. We found that children with blood transfusion requirement were more likely to die. This is in keeping with other studies where blood transfusion has been found to be an independent predictor of ICU LOS and mortality [11]. This is independent of the severity of illness. A transfusion threshold of haemoglobin 70gm/L was used as a departmental guideline in the period of study. In children with oxygen requirement of >0.6% FiO2 and haemodynamic instability, the departmental guideline recommends transfusion at a threshold of 10gm/L- this is however assessed on a case-to-case basis. We were unable to determine the reason for transfusion as there was inconsistent documentation.

We also found that inhaled nitric oxide use, a surrogate for PHT, was associated with higher mortality. High inotrope usage in our cohort was often used as a clinical strategy in the background of pulmonary hypertension to drive higher systemic pressures. Children with inotrope requirement were more likely to die. Association of PHT with death is in keeping with other literature where mortality for children with pulmonary hypertension is as high as 53% (+/-11%) 2 years after diagnosis [12]. PHT is common in BPD because of dysmorphic vasculature and dysgenesis [2, 7, 8, 12, 13]. The documentation of sildenafil usage prior to PICU admission was poor and hence sildenafil usage prior to PICU admission was not used as a variable to determine association with LOS or mortality. LOS was longer in children with PHT, inotrope usage and blood transfusion requirement. Readmission was common as seen with other longitudinal studies [10]. Readmission rates were higher in those with airway malacia possibly because of increased deterioration with respiratory illness. Surveillance and prompt management of airway malacia could potentially address this issue.

Most children with BPD will outgrow their oxygen needs. However, more than 50% patients who were discharged on oxygen from PICU and survived to a year after discharge required home oxygen therapy. The numbers are too small to show any association with duration on ventilator and oxygen requirement to determine if this effect was secondary to ventilator induced lung injury. However, given the need for oxygen a year after discharge, it does raise a case for considering the special healthcare needs of these children at discharge, involving necessary community support for parents and families and considering a multi-disciplinary approach to PICU discharge in this cohort of patients. This approach has also been advocated in other reviews [2]. Mortality rates of patients with BPD are around 10% of total PICU deaths, this rate is higher than those children dying from PHT but lesser than those dying from multi-organ failure in PICU.

Our data is limited by its retrospective nature and small sample size. Although an attempt was made to collect data like sildenafil/bosentan usage prior to PICU admission, steroids in neonatal period or duration of ventilation in the neonatal period; authors were not able to use these variables for analysis because of the poor data quality and inconsistent reporting. Some patients were lost to follow up. This study was carried out in a single center and inter-center variability of managing such patients exists - hence are findings are not wholly generalizable. Multivariable relationships were not considered due to the small sample size. The authors have chosen to use proportion of admissions rather than actual patient numbers to analyze the results. This is with the rationale that admission specific parameters are reflected accurately. As seen in the results, a proportion of children were readmitted with different severity of illness and course of stay at each admission.

Conclusion

Mortality rates of patients with BPD admitted to PICU are high. Longitudinal studies are needed at a national level in multiple sites and centers to inform prognostication and determine factors related to increased mortality, LOS and long-term oxygen requirement in patients with BPD.

Acknowledgements

Dr Clare S Murray, MD, MBChB, MRCPCH for her valuable inputs for study design and protocol.
Dr Mamata Jalisatgi for her support in scoping for the study and study design.

Statement regarding reprints: The authors confirm that a reprint will not be ordered.

Conflicts of interest: No financial, institutional, consultant or other conflicts of interest.

References


2. Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary Dysplasia. Nat Rev Dis Primers. 2019;51:78.

3. Northway WH, Jr., Rosan RC, Porter DY. Pulmonary Disease Following Respirator Therapy of Hyaline-Membrane Disease. Bronchopulmonary Dysplasia. N Engl J Med. 1967;276:357-68.

4. Jobe AH, Bancalari E. Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163:1723-9.

5. Sweet DG, Carnielli V, Greisen G, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update. Neonatology. 2019;115:432-50.

6. Fraser LK, Parslow R. Children with Life-Limiting Conditions in Pediatric Intensive Care Units: A National Cohort, Data Linkage Study. Arch Dis Child. 2018;103:540-7.

7. Hwang JS, Rehan VK. Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment. Lung. 2018;196:129-38.

8. El Mazloum D, Moschino L, Bozzetto S, et al. Chronic Lung Disease of Prematurity: Long-Term Respiratory Outcome. Neonatology. 2014;105:352-6.

9. Hong T, Bolisetty S, Bajuk B, et al. A Population Study of Respiratory Rehospitalisation in Very Preterm Infants in the First 3 Years of Life. J Paediatr Child Health. 2016;52:715-21.

10. Lodha A, Ediger K, Rabi Y, et al. Does Chronic Oxygen Dependency in Preterm Infants with Bronchopulmonary Dysplasia at NICU Discharge Predict Respiratory Outcomes at 3 Years of Age?. J Perinatol. 2015;35:530-6.

11. Rajasekaran S, Kort E, Hackbarth R, et al. Red Cell Transfusions as an Independent Risk for Mortality in Critically Ill Children. J Intensive Care. 2016;4:2.

12. Khemani E, McElhinney DB, Rhein L, et al. Pulmonary Artery Hypertension in Formerly Premature Infants with Bronchopulmonary Dysplasia: Clinical Features and Outcomes in the Surfactant Era. Pediatr. 2007;120:1260-9.

13. Ivy D. Pulmonary Hypertension in Children. Cardiol Clin. 2016;34:451-72.

CORRESPONDENCE & COPYRIGHT

Corresponding Author: Dr Gayathri Subramanian, PICU Offices, Royal Manchester Children’s Hospital, Oxford Road. M13 9WL, UK.

Copyright: © 2021 All copyrights are reserved by Gayathri Subramanian, published by Coalesce Research Group. This This work is licensed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Support Links

Track Your Article

Twitter Tweets