Title:Mental and physical wellbeing following admission to paediatric intensive care.

Word count: 3798

Authors:Lorraine C Als PhD1, Maria D Picouto PhD LMS2, Sau-Ming Hau BSc1, Simon NadelFRCP3, Mehrengise Cooper FRCPCH FFICM3, Christine M Pierce FRCPCH4, TamiKramer MBBCh MRCPsych1, M Elena Garralda MD FRCPsych FRCPCH1

From the 1Centre for Mental Health, Imperial College London, London; 2 Department of Child and Adolescent Psychiatry and Psychology, Sant Joan de Déu Hospital, Universitat de Barcelona, Barcelona; 3Department of Paediatric Intensive Care, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London; and 4Department of Paediatric Intensive Care, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Trust, London.

The work was carried out at Imperial College Academic Health Science Centre andGreat Ormond Street Hospital for Children.

Corresponding Author:Dr Lorraine C. Als, Centre for Mental Health,Imperial College London, Hammersmith Hospital Campus, 7th Floor Commonwealth Building, Du Cane Road, London, UK, W12 0NNEmail: l.als@imperial.ac.ukTelephone: +44 208 383 4161

Reprints:No reprints are requested.

Financial Support:The grant support for this study was provided by the Meningitis Research Foundation of the United Kingdom. The funder had no role in the study design, execution, analysis, or manuscript preparation. This research was undertaken at Imperial College Academic Health Science Centre and Great Ormond Street Hospital for Children NHS Trust, both of which are supported by the National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Dr Maria D Picouto was supported by funding from the Alicia Koplowitz Foundation.

Conflicts of interest:None declared.

Key Words: PICU; sepsis; wellbeing; post-traumatic stress symptoms.

Publication Details:Pediatric Critical Care Medicine:June 2015 - Volume 16 - Issue 5 - p e141–e149doi: 10.1097/PCC.0000000000000424Online Clinical Investigations

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Abstract:

Objective: To assess mental and physical wellbeing in school-aged children

following admission to paediatric intensive care (PIC) and to examine risk

factors for worse outcome.

Design: A prospective cohort study.

Setting: Two paediatric intensive care units (PICUs).

Subjects: A consecutive sample of 88 patients aged 5-16 years (median age

10.00; interquartile range 6.00-13.00), admitted to PICU 2007-2010 with

septic illness, meningo-encephalitis, or other critical illnesses were assessed

a median of 5 months following discharge and outcomes compared with 100

healthy controls.

Interventions: None.

Measurements and Main Results: Parents completed questionnaires

documenting child mental and physical wellbeing, including the Strengths and

Difficulties Questionnaires (SDQ), Chalder fatigue scale, and Child Sleep

Habits Questionnaire (CSHQ). Children over 8 years completed the Impact of

Event Scale (IES-8). The children admitted to PICU scored worse on all

measures in comparison to the healthy controls, with 20% scoring at risk for

psychiatric disorder, 34% with high levels of post-traumatic stress symptoms,

38% at risk for fatigue disorder, and 80% scoring at risk for sleep disturbance.

In the PICU group, multivariable regression analyses identified septic illness

as an independent predictor of post-traumatic stress symptoms, and family

status, past child health problems and PICU length of stay as predictors of

reduced general mental wellbeing.

2

Conclusions: Our findings indicate a significant minority of school-aged

children admitted to PICU are at risk for reduced mental and physical

wellbeing in the short term. Symptoms of poor mental wellbeing were linked to

both vulnerability factors and critical illness factors.

3

Introduction

The development of paediatric intensive care (PIC) has led to major

improvements in the management and outcome of critical illness in children.

Between January 2010 and December 2012, there were 57,949 children

admitted to PIC units (PICUs) in the United Kingdom and Ireland, and of

these, 96% survived (1). In recent years, research on the mental health of

PICU survivors, has gathered momentum (2-6). The most commonly

assessed conditions have been post-traumatic stress disorder (PTSD) and

major depression (7, 8). Rees et al., (4) found increased rates of PTSD in

children following admission to PICU compared with admission to a general

paediatric ward, which suggests a link between critical illness and

psychopathology. However, it remains unclear as to whether these after-

effects are primarily related to specific disease states commonly seen in

PICU. Indeed, high rates of sequelae have been identified in children

following infectious disease, such as meningococcal infection (9-14).

Reduced physical wellbeing in PICU survivors, manifested through

fatigue and sleep difficulty, has received less attention. Fatigue encompasses

feelings of psychological and/or physical tiredness and can be extremely

debilitating. The majority of research has focused on chronic fatigue states

(15) and fatigue in conditions such as rheumatic disease, multiple sclerosis,

malignancy and diabetes (16,17). With regards to sleep, although research

suggests children experience disruption whilst on PICU (18-20), less is known

about sleep quality following critical illness. There is anecdotal evidence from

paediatricians suggesting that sleep problems occur, but as far as we are

aware, no study has sought to assess disturbance post PICU.

4

The primary aim of this study was to establish a comprehensive profile

of short term mental and physical wellbeing in school-aged children following

admission to PICU. The secondary aim was to ascertain risk factors

associated with worse outcome, including the role of severe infection (i.e.,

meningo-encephalitis and septicaemia). Our a priori hypotheses were that

wellbeing would be reduced in children after PICU admission (compared with

healthy controls), and that severe infections, would be linked with worse

outcome among PICU-admitted children.

Materials and methods

Participants

We conducted a prospective cohort study of children admitted to PICU.

Eligible cases were children 5-16 years old admitted April 2007-March 2010 to

St Mary’s Hospital or Great Ormond Street Hospital for Children, UK. The

PICU cohort was categorised into three sub-groups: septic illness, meningo-

encephalitis, and other critical illnesses. Cases of sepsis and meningo-

encephalitis were classified on the basis of a primary clinical diagnosis, with

microbiological confirmation from culture or polymerase chain reaction where

appropriate. Since we were interested to ascertain whether PICU admission,

especially for infectious illness, was likely to impact mental wellbeing, we

excluded children with a medical history suggesting prior psychiatric,

neurological or developmental disorder and where a psychiatric problem (e.g.,

deliberate self-harm) or neurological injury (e.g., traumatic brain injury) was

the cause of the admission.

5

In order to try and match participants as closely as possible, healthy

controls were primarily recruited from the family and/or friends of patients

admitted to PICU. Children included in the control group had no previous

history of PICU admission.

All participants provided written informed consent (by parent/guardian)

and assent (if aged 8 years or older). Ethics approval was granted by the

Research Ethics Committee (REC) at Hammersmith Hospital.

Procedure

Families in the PICU group were recruited 3-6 months following PICU

discharge. If parents and children agreed to take part, a questionnaire pack

was posted to the family home. The pack contained a standardised

questionnaire covering socio-demographics and past medical history, as well

as measures of mental and physical wellbeing, including the Strength and

Difficulties Questionnaire (SDQ), the Impact of Events Scale (IES-8), the

Chalder Fatigue Scale, and the Children’s Sleep Habits Questionnaire

(CSHQ). Clinical data related to the admission were obtained from medical

records. A face-to-face appointment was also scheduled in order to conduct a

neuropsychological assessment (data reported elsewhere) (21). The healthy

control group were invited to complete the same series of assessments.

Questionnaires

Child-rated measures:

Child post-traumatic stress symptoms were measured with the IES-8

(22). This is an 8-item self-report questionnaire validated for use in children

6

over 8 years. Children are asked to recall the frequency of post-traumatic

stress symptoms occurring in the past seven days. Thus, providing an

indication as to whether they are actively experiencing PTSD

symptomatology. The questions are asked in reference to a specific event; in

this case, the child’s PICU admission. The scale provides a total score and

two sub-scale scores (i.e., avoidance and intrusions). Items are rated on a 4-

point scale (total scores 0-24, a score ≥17 indicating caseness/risk for PTSD)

(23).

Parent-rated measures:

Child general mental wellbeing was measured with the parent-rated

version of the SDQ (24). This is a 25-item questionnaire validated for use with

parents of children aged 4-16 year old. The questionnaire yields a total

difficulties score and five sub-scores (i.e., emotional, conduct, hyperactivity,

pro-social behaviour, and peer relationships). Items are rated on a 3-point

scale (total scores 0-50, scores ≥17 indicating caseness/risk for psychiatric

disorder). Parents were asked to review their child’s behaviour since

discharge from PICU/last 3-6 months.

Child fatigue was measured with a modified version of the Chalder

Fatigue scale (25), originally a self-report scale. The author gave permission

for its adaptation and use as a parent-rated scale (T. Chalder, personal

communication, 2007). The scale assesses fatigue severity and provides a

total score and two sub-scores (i.e., mental and physical fatigue). Items can

be rated on a likert 4-point scale (total scores 0-33) and a bimodal scale (total

scores 0-11). A bimodal score of ≥4 indicates caseness/risk for probable

7

fatigue disorder. Parents were asked to review their child’s behaviour since

discharge from PICU/last 3-6 months.

Child sleep difficulties were measured with the parent-rated CSHQ

(26), which contains 33 items. It yields a total score and eight sub-scores (i.e.,

bedtime resistance; sleep-onset delay; sleep duration; sleep anxiety; night

waking; parasomnias; sleep disordered breathing; and daytime sleepiness).

Items are rated on a 3-point scale (total scores 0-99, scores ≥41 indicating

caseness/risk of sleep disorder). Parents were asked to recall sleep

behaviours occurring during the past seven days/most recent typical week.

This questionnaire was introduced later in the study as a result of feedback

from paediatricians concerning parent reports of sleep difficulties in this

population. Thus not all families in the sample received a copy to complete. It

is validated for children 5-12 years old, but we delivered it to parents of

children aged 5-16 years old to maximise completion rates.

Statistical analysis

Analyses were carried out using IBM SPSS Statistics for Windows,

Version 20.0 (IBM Corp., Armonk,NY). Comparisons were two-tailed, and

significance was set at p≤.05 unless stated otherwise.

The data describing participant characteristics were analysed with

nonparametric methods, using Mann-Whitney U tests for continuous data and

chi-square for categorical data. Data are expressed as median [Mdn]

(interquartile range [IQR]) and frequency (percent), respectively. When

exploring clinical characteristics of the patient sub-groups, main effects were

explored with post-hoc tests using a manual bonferroni adjusted alpha value

8

of p<.02. As there were a large number of subgroup comparisons

administered, a further correction for testing of multiple comparisons was

applied (i.e., The False Discovery Rate Controlling Procedure; 27).

Primary analyses of the outcome measures involved between-group

comparisons of the PICU cohort and healthy controls. As continuous data

were non-normal, analyses were conducted using bootstrapped t-tests; a form

of robust testing that can withstand violations of normality (28). The data are

presented as means ± bias corrected and accelerated (BCa) 95% confidence

intervals. Effect sizes were calculated using bias corrected standard

deviations (effect size calculator and conversions program, DeFife-Emory

University, 2009). As there were a large number of group comparisons

administered, the false discovery rate procedure was also applied for these

analyses (27).

Secondary analyses were used to explore potential vulnerability and

critical illness risk factors that could contribute to worse outcomes. To reduce

the number of analyses conducted, this analysis focused on the main

outcome variable from each questionnaire (i.e., the total score). We restricted

our risk factors to those with an existing precedence. As research in this area

is in its infancy, consistent vulnerability and critical illness factors have not yet

been identified (7). Thus, we took an exploratory approach to the analysis. All

variables were first evaluated by univariate linear regression to identify those

that were associated with the outcome scores. The following variables were

assessed: 1) vulnerability factors (age, gender, ethnicity, socioeconomic

status, family composition (whether intact or not), pre-existing health

problems) and 2) critical illness factors (length of stay in PICU length of stay in

9

hospital, illness severity, type of admission, and illness type). Any variables

with p <0.1 on the univariate analysis were entered into a multivariate

regression analysis. Hierarchical (blockwise entry) was used, with vulnerability

factors entered in the first block and critical illness factors entered in the

second block. In order to test the assumption of normality of standardised

residuals, histograms and the Kolmogorov-Smirnov test were used. All

residuals were deemed normally distributed.

Results

Of the 175 patient families approached to take part, 88 consented,

representing a recruitment rate of 50% (see Fig 1 for recruitment flow

diagram). Participants and non-participants (i.e., non-responders and

refusals) were similar in age at admission (Mdn=10.00 years; IQR=6.00-13.00

vs. Mdn=10.00 years; IQR =6.00-13.00), number of days spent in PICU

(Mdn=2.00; IQR=1.00-6.25 vs. Mdn=2.00; IQR =1.00-4.00), and gender

(males: 61% vs. 47%) (p≥.05). Although there appeared to be a larger

proportion of White children in the participating group (56% vs. 34%, p=.009),

data on ethnicity were missing for 22% of the non-participant group and thus

this result is not conclusive.

In the healthy control group, participants and non-participants (refusals)

were similar in age (Mdn=11.00; IQR=8.00-13.00 vs. Mdn=10.00; IQR=8.00-

11.00) and gender (males: 47% vs. 57%) (p≥.05). Comparisons regarding

ethnicity were not feasible, as information was not collected from non-

participating healthy controls.

10

Sample Descriptives

PICU and healthy control group characteristics are summarised in

Table 1. Children in the PICU and healthy control groups were similar with

regards to most variables. However, the presence of a chronic medical

condition and ratings of past health problems were more common in the PICU

group (p<.001).

The clinical characteristics of the PICU cohort and three patient

subgroups are summarised in Table 2. Sepsis patients were more likely to

present with shock, spend more days in PICU, had higher PIM2 scores (29),

and suffered more physical complications. The meningo-encephalitis group

demonstrated more neurological complications during their illness (i.e.,

seizures and raised intracranial pressure). Children diagnosed with other

critical illnesses (aside from sepsis and meningo-encephalitis) were more

likely to suffer with a chronic medical condition (e.g., sickle cell disease,

diabetes) and have a history of critical care admissions.

Mental and physical wellbeing following PICU admission

A total of 82/88 families in the PICU group returned questionnaires

(92%). The time between discharge and completion of the questionnaires was

approximately 4.5 months (Mdn=137 days; IQR=112-187). A total of 93/100

(93%) families in the healthy control group returned questionnaires. See Table

3 for the main findings. There is variation in the number of responders for

each questionnaire, which is mainly due to questionnaire age-range criteria

and differential response rates (i.e. missing data).

11

As the PICU group were all exposed to the stress of critical illness and

PICU admission, we analysed post-traumatic stress responses in this group

only. In the PICU group, 59/82 (72%) children were old enough to complete

the Impact of Events Scale (IES-8) with 53/59 (90%) doing so. Baseline

characteristics (as outlined in Table 1) were compared in IES responders

(n=53) and the rest of the PICU sample (n=29). With the exception of age

(Mdn=2.00; IQR=10.00-15.00 in responders vs. Mdn=6.00; IQR=5.50-7.00 in

the rest of the PICU sample), responders were comparable to the rest of the

PICU sample (p≥.05). The proportion of children scoring at risk of PTSD in the

PICU group was 18/53 (34%).

The Strengths and Difficulties Questionnaire was returned by 79/82

(96%) parents in the PICU group and 93/93 (100%) parents in the healthy

control group. The PICU group scored significantly worse on total difficulties

and on the emotional, hyperactivity, conduct, and pro-social sub-scales

(p≤.01). The most marked differences were seen in emotional symptoms and

hyperactivity, with moderate effect sizes (d) of 0.56 and 0.54 respectively.

Furthermore, 16/79 (20%) children in the PICU group scored in the range at

high risk for a psychiatric disorder in comparison to 8/93 (9%) in the healthy

control group, although this did not meet the adjusted probability when

correcting for multiple comparisons (p=.05).

The Chalder Fatigue Scale was returned by 79/82 (96%) parents in the

PICU group and 89/93 (96%) parents in the healthy control group. The PICU

group scored significantly higher than controls on the total fatigue score and

both sub-scales (p≤.001). The difference in physical fatigue symptoms was

most significant, with a large effect size of 0.95. In the PICU group, 30/79

12

(38%) attained a score indicating high risk for fatigue disorder in comparison

to 1/89 (1%) of the control group (p˂ .001).

Due to the delayed addition of CSHQ, 72 of 82 (88%) of the PICU

group and 93 of 93 (100%) of the healthy control group were sent a copy.

Completed questionnaires were returned by 61 of 72 (85%) parents in the

PICU group and 81 of 93 (87%) parents in the healthy control group. There

were no significant differences in baseline characteristics between

PICU/healthy control responders (n=61 and 81) and the rest of the

PICU/healthy control samples (n=21 and 12) (p≥.05). PICU children suffered

significantly more sleep problems than controls, indexed by a significantly

higher total sleep difficulties score (p=.001). The key sub-scales distinguishing

the two groups were bedtime resistance and night waking’s (p≤.02), with

large-moderate effect sizes of 0.65 and 0.55 respectively. In the PICU group,

44/61 (72%) attained a score indicating high risk for sleep disorder in

comparison to 40/81 (49%) of the control group (p=.009).

Running the above analyses against total questionnaire scores while

adjusting for presence of a chronic medical condition and a history of

poor/intermediate general health (the baseline variables that distinguished the

two groups) did not materially change the findings.

Risk factors associated with worse outcomes in PICU patients

The variables associated with mental and physical wellbeing in the

univariate and multivariate analyses are shown in Table 4.

Post-traumatic symptoms Total score

13

None of the vulnerability factors were associated with post-traumatic

symptoms, as indicated by the univariate analysis (p≥.10). However, two

critical illness factors, sepsis and length of stay in PICU, were associated with

symptoms (p=.001 and p=.07 respectively) and thus these factors were

entered in the multivariate analysis. Being diagnosed with sepsis was the only

significant independent predictor of post-traumatic symptoms (p=.005), with

the model accounting for 20% of the variance in scores (p=.003).

Strengths and Difficulties Total score

The univariate analysis revealed that the vulnerability factors, family

composition (non-intact) and past health problems were associated with total

difficulties (p=.009 and p=.08 respectively). The critical illness factor, length of

stay in PICU, was also significantly associated (p=.04). When included in the

multivariate analysis, they were all shown to be significant independent

predictors of total difficulties (p<.03), with the final model accounting for 19%

of the variance in scores (p=.001).

Fatigue Symptoms Total score

The univariate analysis indicated that the vulnerability factors, age,

ethnicity (White), and family composition (non-intact) were associated with

fatigue (p<.07). In addition, the critical illness factors, length of stay in hospital

and meningo-encephalitis, were associated with fatigue (p<.07). When

included in the multivariate analysis, only ethnicity and family composition

were shown to be significant independent predictors (p<.005), with the final

model accounting for 31% of the variance in scores (p<.001).

14

Sleep Disturbance Total Score

Of note, age and length of stay in PICU were linked to sleep

disturbance in the univariate analysis, but neither were shown to

independently predict sleep disturbance in the multivariate analysis and thus

the final model was not significant (p≥.05).

Discussion

This study documents worse mental and physical wellbeing in school-

aged children following discharge from PICU in comparison to healthy

controls. Approximately five months following discharge from PICU, 34% of

children scored at risk of PTSD, 20% at risk of a general psychiatric disorder,

38% at risk of fatigue disorder, and 80% at risk of a sleep disorder.

Our findings support prior research in documenting an increased risk

for general psychiatric problems and PTSD in a significant minority of PICU

survivors (7, 8).

A third of PICU admitted children in our sample were at risk for PTSD.

This compares with 3-month prevalence rates of PTSD symptoms in the

general paediatric population of 2% (25% in those reporting two stressful

events) and is in line with rates of probable PTSD or sub-clinical

symptomatology following PICU admission (35-62%) (8, 31). The wide range

in these studies may be related to differences in inclusion criteria, length of

follow-up, measures and cut-offs used and to the representation of different

illness types in the PICU cohort.

15

Septic illness was found to be the single independent predictor of post-

traumatic stress symptoms in the multivariate analysis. The sepsis group in

our study was noted to be the most severely ill, as measured by both

biological illness severity scores and length of PICU admission, however,

although PICU length of stay was included in the regression model, it did not

independently predict outcome. This suggests that the systemic septic

process may be of more relevance to later PTSD symptomatology than other

types of illness or critical illness factors. Sepsis involves an inflammatory

response that affects coagulation, immune, hormonal and metabolic

pathways. It is possible that the toxic cerebral effects of systemic inflammation

in sepsis could be responsible - in part at least - for sequelae (32).

Psychosocial factors may add to these effects. Perceived life threat in severe

sepsis can be especially dramatic and stressful and may contribute to the

development of PTSD symptoms in parents, which in turn may impact

symptoms in the children (2, 4, 12, 33, 34).

Our observed rates for general psychiatric problems, as measured by

total difficulties on the SDQ, are in line with a systematic review of PICU

admitted children (7). Children in the PICU group had significantly higher total

SDQ symptom scores than healthy controls, with marked differences in

scores on the hyperactivity and emotional sub-scales. Previous work following

critical illness such as meningococcal disease in children has similarly found a

subsequent increase in psychological problems in these domains. In the

previous study, the hyperactivity symptoms decreased over time, but the

emotional symptoms persisted and if anything became more impairing at one-

year follow up (9). This points to the importance of attending to and monitoring

16

emotional symptoms during follow-up surveillance of children with a history of

critical illness.

In contrast with PTSD, more general psychopathology was not

associated with type of illness, but it was linked to length of PICU admission,

pre-morbid health problems in the child, and coming from a non-intact family.

Both broken families and health problems are risk factors for childhood

psychiatric disorder in general populations (35, 36). Our findings suggest that

the length of the PICU experience, a proxy for illness severity, has an additive

risk for mental health problems in these children.

As far as we are aware, fatigue and sleep quality following discharge

from PICU have not been assessed previously. Thus, our study provides

important new information, and shows that critical illness may lead to

impairing levels of fatigue and sleep disturbance in children. Fatigue and

sleep problems were common and affected the group of PICU children as a

whole, independent of type of illness. Fatigue levels were predicted by

vulnerability factors (White Ethnicity and non-intact homes) but critical illness

factors (such as hospital length of stay and meningo-encephalitis), which were

included in the regression model failed to contribute significantly on

multivariate regression analysis. Similar to other fatigue states (15), this

points to the relevance of psychosocial factors for fatigue following critical

illness. Nevertheless, the high overall clinical rates of fatigue (present in a

third of the PICU sample), and particularly the high physical fatigue scores,

highlight this as an area requiring on-going monitoring.

Although sleep problems were also common in the healthy control

sample, they were significantly more frequent in PICU survivors, being

17

present in the majority. The most discriminating features were indicative of

both resistance about sleep and disrupted sleep, in part possibly as a direct

consequence of the sleep disruption characteristic of PICU admission (18-20).

In our sample sleep disturbance was however not predicted by vulnerability or

critical illness factors suggesting a global critical illness effect.

The limitations of this study include reduced take-up rates, but these

are common to postal recruitment studies, for example see the study by Viner

et al (14). Non-participants were comparable to participants in terms of age,

number of days in PICU, gender, but not ethnicity. However, the

demographics of our final PICU cohort were consistent with those reported by

the most recent UK national audit of PICU admissions (1), indicating children

in this sample are broadly representative. We did not examine the possible

effects of delirium as there was a lack of consensus on appropriate

assessment tools at the time of study (37), but we acknowledge the impact of

delirium should be investigated in future studies. Given the exploratory nature

of the regression analyses, the final models yielded are not guaranteed to be

optimal, and therefore, replication in a larger sample is clearly called for. It

should be noted that we excluded from the study children with pre-morbid

psychiatric and neurodevelopmental problems, which have been linked to

worse outcomes and we did not study the influence of parental mental

function on child outcomes (7). These remain important areas for further

investigation.

The strengths of this study include a comprehensive assessment of

mental and physical wellbeing. Through exclusion of children with previous or

concurrently diagnosed neurological, developmental, or psychiatric

18

diagnoses, our results strongly support that these symptoms are likely to be

associated with critical illness. In addition, the comparison of different illness

groups has allowed clarification of their potential effects on outcome.

Conclusions

School-aged children admitted to PICU show an increased risk for

reduced mental and physical wellbeing. Risk for post-traumatic stress disorder

was particularly linked to septic illness, suggesting that the systemic

inflammatory process is of more relevance than acute brain infection or critical

illness per se. Our findings support the importance of short-term follow-up

and, if appropriate, intervention. Indeed, what may initially present as subtle

changes in psychological function, if left untreated, may lead to persisting, and

thus, more impairing effects (33).

Acknowledgements

We are extremely grateful to the volunteering children and families;

medical and nursing staff at participating PICUs; Seray Vezir and Sau-Ming

Hau for their invaluable research assistance; Emma Dean for help with data

analyses; Sarah Elison contributed to the study design; Julia Gledhill provided

research advice; and Jared Smith provided statistical review. Preliminary data

analyses were presented in abstract form (38).

19

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Figure legends

Figure 1. Recruitment flow diagram.

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Table 1. Baseline characteristics of paediatric intensive care unit cohort and healthy control group.

Baseline characteristicsPICU cohort(n = 82)

Healthy controls(n = 93)

Age, yr 10.00 (7.00, 13.25) 11.00 (8.00, 13.00)Gender (%) Male 32 (39) 49 (53) Female 50 (61) 44 (47)Socio-economic statusa (%) Level I 30 (40) 47 (52) Level II 17 (23) 21 (23) Level III 19 (25) 17 (19) Not assigned 9 (12) 6 (6)Ethnicity (%) White 46 (56) 55 (59) Other 36 (44) 38 (41)Complications during pregnancy (%) 23 (28) 20 (22)Neonatal special care (%) 13 (16) 6 (6)Family compositionb (%) Intact home 55 (68) 74 (80)Chronic medical conditionc*** (%) 44 (54) 22 (24)Past general healthb*** (%) Intermediate/Poor 21 (26) 4 (4)Prior emotional/behavioural difficulties (%)

6 (7) 9 (10)

a Data available for n = 75 PICU and n = 91 healthy controls. Occupation was provided by the primary earner. The “not assigned” category included parents that were unemployed, students, or retired.b Data available for n = 81 PICU; c Data available for n = 92 healthy controls. d p<.001Data are median (inter-quartile range) or frequency (percent).

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Table 2. Medical history and clinical characteristics of paediatric intensive care unit cohort and patient sub-groups.

Clinical characteristicsPICU cohort (n = 82)

Meningo-encephalitis (n = 19)

Sepsis(n = 22)

Other critical illnesses(n = 41)

p(df = 2)

Age at illness, yr 10.00 (6.00,13.00) 10.00 (6.00, 14.00) 9.50 (6.75, 14.00) 9.00 (6.00, 13.00) .49 a

Previous critical care b (%)Chronic medical condition (%)

14 (18)44 (54)

4 (22)6 (32)

0 (0)5 (23)

10 (26)33 (81)

.02 c

<.001e

Paediatric Index of Mortality 2 d

Total days in PICU0.05 (0.01, 0.12)2.00 (1.00, 5.25)

0.05 (0.04, 0.06)3.00 (1.00, 5.00)

0.13 (0.03, 0.25)6.00 (2.00, 8.25)

0.04 (0.01, 0.07)1.00 (0.00, 2.50)

.008 a

<.001a

Total days in hospital 10.00 (6.00,16.50) 10.00 (6.00, 13.00) 14.50 (8.50, 27.25) 9.00 (4.00, 16.00) .10 a

Shock (%) 29 (35) 3 (16) 19 (86) 7 (17) <.001e

Raised Intra-Cranial Pressure (%) 7 (9) 6 (32) 0 (0) 1 (2) .001c

Seizures (%) 8 (10) 7 (37) 0 (0) 1 (2) <.001c

Intubated (%) 63 (77) 18 (95) 18 (82) 27 (66) .04 e, f

Steroids administered (%) 35 (43) 10 (53) 12 (55) 13 (32) .14 e

Hypoglycaemia (%) 2 (2) 0 (0) 2 (9) 0 (0) .12 c

Physical complications g (%) 13 (16) 1 (5) 8 (36) 4 (10) .13 c

Drug withdrawal symptoms (%) 10 (12) 1 (5) 5 (23) 4 (10) .24 c

a Kruskal-Wallis test.b Data available for 78 patients.c Fisher’s exact test.d Data available for 81 patients.e Chi Square test. f The observed (Obs.) probability was ≤ 0.05, but this failed to meet the adjusted probability (Prob.) when correcting for multiple comparisons using the false discovery rate controlling procedure (27).g Physical complications included pressure sores, scarring, skin loss (none of the children needed amputations).All data presented are median (inter-quartile range) or frequency (percent).

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Table 3. Mental and physical wellbeing in children admitted to paediatric intensive care and healthy controls.

Questionnaires n PICU cohort n Healthy controlsp

(df = 1)Effect size(d) a

Child-rated measures:Impact of Events Scale b

Post-traumatic symptoms total score 53 12.00 (8.98, 15.34) - - - - Intrusions sub-scale 53 6.08 (4.49, 7.83) - - - - Avoidance sub-scale 53 5.92 (4.26, 7.77) - - - - Caseness (%) 53 18 (34) - - - -Parent-rated measures:Strength and Difficulties Questionnaire Total difficulties total score c 79 11.41 (10.06, 12.85) 9

37.69 (6.62, 8.85) .001 0.63

Emotional sub-scale 79 3.11 (2.56, 3.66) 93

1.88 (1.50, 2.28) .002 0.56

Conduct sub-scale 79 2.19 (1.82, 2.58) 93

1.46 (1.14, 1.79) .008 0.41

Hyperactivity sub-scale 79 4.52 (3.93, 5.13) 93

3.15 (2.66, 3.65) .003 0.54

Peer problems sub-scale 79 1.58 (1.23, 1.94) 93

1.19 (0.90, 1.51) .11 0.25

Pro-social sub-scale 79 7.61 (7.07, 8.15) 93

8.40 (7.97, 8.78) .01 0.38

Impact sub-scale 79 0.90 (0.52, 1.38) 93

0.31 (0.15, 0.51) .03 d 0.40

Caseness (%) 79 16 (20) 93

8 (9) .05 d 0.34

Chalder Fatigue Scale Fatigue symptoms total score 79 14.08 (12.81, 15.39) 8

910.19 (9.70, 10.65) .001 0.90

Physical sub-scale 79 9.47 (8.54, 10.47) 89

6.48 (6.13, 6.79) .001 0.95

Mental sub-scale 79 4.61 (4.15, 5.10) 8 3.71 (3.48, 3.91) .001 0.5628

9 Caseness (bimodal scoring) (%) 79 30 (38) 8

91 (1) ˂.001 1.08

Child Sleep Habits Questionnaire Sleep disturbance total score 61 46.64 (44.79, 48.81) 8

142.06 (40.69, 43.43) .001 0.64

Bedtime resistance sub-scale 61 8.07 (7.42, 8.69) 81

6.77 (6.47, 7.07) .003 0.65

Sleep onset delay sub-scale 61 1.71 (1.50, 1.93) 81

1.50 (1.37, 1.63) .12 0.29

Sleep duration sub-scale 61 4.31 (3.88, 4.75) 81

3.88 (3.61, 4.16) .09 0.30

Sleep anxiety sub-scale 61 5.38 (4.95, 5.88) 81

4.69 (4.43, 4.97) .02 0.44

Night wakings sub-scale 61 4.08 (3.78, 4.40) 81

3.49 (3.31, 3.71) .004 0.55

Parasomnias sub-scale 61 8.84 (8.37. 9.36) 81

8.43 (8.08, 8.80) .19 0.22

Sleep disordered breathing sub-scale 61 3.64 (3.40, 3.91) 81

3.35 (3.18, 3.52) .09 0.31

Daytime sleepiness sub-scale 61 13.28 (12.32, 14.25) 81

12.19 (11.53, 12.84) .07 0.32

Caseness (%) 61 44 (72) 81

40 (49) .009 0.47

a An effect size (d) between 0.2 and 0.5 was considered a small effect, 0.5 and 0.8 a moderate effect, and 0.8 and above a large effect (30). b The IES was completed in relation to the PICU admission and therefore data are not presented for healthy controls. c The total difficulties score is calculated based on the scores from four of the sub-scales (excluding the prosocial sub-scale).d The observed (Obs.) probability was ≤ 0.05, but this failed to meet the adjusted probability (Prob.) when correcting for multiple comparisons using the false discovery rate controlling procedure (27).Data are presented as means (BCa 95% Confidence Interval) or frequency (percent). Aside from the Pro-social sub-scale, higher scores indicate worse outcomes.

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Table 4. Predictors of mental and physical sequelae in paediatric intensive care patientsUnivariate Analysis

Multivariate AnalysisModel

R2Model

pR2 p B 95% CI B β p

Impact of Events Scale Total scoreModel 1 0.20 .003Constant 8.27 4.57, 11.96PICU length of stay (days) 0.06 .07 0.24 -0.32, 0.79 0.12 .40Sepsis 0.19 .001 9.98 3.20, 16.76 0.40 .005

Strength and Difficulties Questionnaire Total scoreModel 1 0.14 .004Constant 14.64 8.58, 20.70Family composition a 0.09 .009 -4.29 -7.18, -1.41 -0.32 .004Past health problems b 0.04 .078 3.21 0.13, 6.29 0.23 .04Model 2 0.19 .001Constant 12.81 6.66, 18.96Family composition a -4.03 -6.85, -1.20 -0.30 .006Past health problems b 3.50 0.48, 6.52 0.25 .02PICU length of stay (days) 0.06 .036 0.21 0.02, 0.41 0.23 .03

Chalder Fatigue Scale Total scoreModel 1 0.27 <.001Constant 20.18 14.40, 25.95Age (yr) 0.04 .07 0.26 -0.07, 0.59 0.16 .12Ethnicity c 0.13 .001 -4.63 -7.00, -2.26 -0.39 <.001Family composition a 0.08 .01 -3.97 -6.46, -1.48 -0.32 .002Model 2 0.31 <.001Constant 17.60 11.37, 23.83Age (yr) 0.30 -0.04, 0.64 0.18 .08Ethnicity c -4.17 -6.57, -1.76 -0.35 .001Family composition a -3.63 -6.10, -1.15 -0.29 .005Hospital length of stay (days) 0.04 .07 0.07 -0.01, 0.14 0.18 .08Meningo-encephalitis 0.04 .07 1.30 -1.57, 4.17 0.09 .09

Child Sleep Habits Questionnaire Total scoreModel 1 0.05 .07Constant 51.45 45.81, 57.09Age (yr) 0.05 .07 -0.51 -1.06, 0.05 0.28 .07Model 2 0.08 .09Constant 49.63 43.31, 55.95Age (yr) -0.41 -0.98, 0.17 -0.19 .16PICU length of stay (days) 0.05 .09 0.20 -0.12, 0.51 0.16 .22

B, unstandardized coefficient; β (beta), standardised coefficient.a Non-intact family versus intact family: a negative regression coefficient means worse outcome for those from a non-intact family; b Good health versus intermediate/poor health in the six months prior to PICU

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admission: a positive regression coefficient means worse outcome for those with past health problems; c

White versus all other categories: a negative regression coefficient means worse outcome for those of a white ethnicity.

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