Adverse Events in Pediatric Critical Care Nonsurvivors With a Low Predicted Mortality Risk: A Multicenter Case Control Study.

OBJECTIVES: Some patients with a low predicted mortality risk in the PICU die. The contribution of adverse events to mortality in this group is unknown. The aim of this study was to estimate the occurrence of adverse events in low-risk nonsurvivors (LN), compared with low-risk survivors (LS) and high-risk PICU survivors and nonsurvivors, and the contribution of adverse events to mortality. DESIGN: Case control study. Admissions were selected from the national Dutch PICU registry, containing 53,789 PICU admissions between 2006 and 2017, in seven PICUs. PICU admissions were stratified into four groups, based on mortality risk (low/high) and outcome (death/survival). Random samples were selected from the four groups. Cases were "LN." Control groups were as follows: "LS," "high-risk nonsurvivors" (HN), and "high-risk survivors" (HS). Adverse events were identified using the validated trigger tool method. SETTING: Patient chart review study. PATIENTS: Children admitted to the PICU with either a low predicted mortality risk (< 1%) or high predicted mortality risk (≥ 30%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 419 patients were included (102 LN, 107 LS, 104 HN, and 106 HS). LN had more complex chronic conditions (93.1%) than LS (72.9%; p < 0.01), HN (49.0%; p < 0.001), and HS (48.1%; p < 0.001). The occurrence of adverse events in LN (76.5%) was higher than in LS (13.1%) and HN (47.1%) ( p < 0.001). The most frequent adverse events in LN were hospital-acquired infections and drug/fluid-related adverse events. LN suffered from more severe adverse events compared with LS and HS ( p < 0.001). In 30.4% of LN, an adverse event contributed to death. In 8.8%, this adverse event was considered preventable. CONCLUSIONS: Significant and preventable adverse events were found in low-risk PICU nonsurvivors. 76.5% of LN had one or more adverse events. In 30.4% of LN, an adverse event contributed to mortality.

Risk stratification to improve Pediatric Early Warning Systems: it is all about the context.

Early recognition of critically ill patients is of paramount importance to reduce pediatric mortality and morbidity. We created a risk stratification system combining vital parameters and predefined risk factors aimed at reducing the risk of unrecognized clinical deterioration compared with conventional Pediatric Early Warning Systems (PEWS). This single-center retrospective case cohort study included infants (gestational age ≥ 37 weeks) to adolescents (aged <18 years) with unplanned pediatric intensive care unit (PICU) admission between April 01, 2014, and February 28, 2018. The sensitivity in the 24 h prior to endpoint of the Pediatric Risk Evaluation and Stratification System (PRESS) was compared with that of the conventional PEWS and calculated as the proportion of study patients who received a high-risk score. Seventy-four PICU admissions were included. PRESS and PEWS sensitivities at 2 h prior to endpoint were 0.70 (95%CI 0.59 to 0.80) and 0.30 (95%CI 0.20 to 0.42) respectively (p < 0.001). Excluding patients with seizures, PRESS sensitivity increased to 0.75 (95%CI 0.64 to 0.85). Forty-nine patients (66%) scored positive on at least one high-risk factor, and "worried sign" was scored in 31 patients (42%).Conclusion: Risk stratification seems advantageous for a faster detection of clinical deterioration, providing opportunity for earlier intervention. What is Known: • Prompt detection of clinical deterioration is of essential importance to reduce morbidity and mortality. • Conventional Pediatric Early Warning Systems (PEWS) have limited sensitivity and a short window of detection of 1 to 2 h. What is New: • Risk stratification based on context factors allows earlier identification of patients at risk, well before deviation of vital signs. • Risk stratification combined with continuous monitoring of deteriorating trends in vital signs could lead to the development of next-generation warning systems achieving true patient safety.

Retrospective cohort study on factors associated with mortality in high-risk pediatric critical care patients in the Netherlands.

BACKGROUND: High-risk patients in the pediatric intensive care unit (PICU) contribute substantially to PICU-mortality. Complex chronic conditions (CCCs) are associated with death. However, it is unknown whether CCCs also increase mortality in the high-risk PICU-patient. The objective of this study is to determine if CCCs or other factors are associated with mortality in this group. METHODS: Retrospective cohort study from a national PICU-database (2006-2012, n = 30,778). High-risk PICU-patients, defined as patients < 18 years with a predicted mortality risk > 30% according to either the recalibrated Pediatric Risk of Mortality-II (PRISM) or the Paediatric Index of Mortality 2 (PIM2), were included. Patients with a cardiac arrest before PICU-admission were excluded. RESULTS: In total, 492 high-risk PICU patients with mean predicted risk of 24.8% (SD 22.8%) according to recalibrated PIM2 and 40.0% (SD 23.8%) according to recalibrated PRISM were included of which 39.6% died. No association was found between CCCs and non-survival (odds ratio 0.99; 95% CI 0.62-1.59). Higher Glasgow coma scale at PICU admission was associated with lower mortality (odds ratio 0.91; 95% CI 0.87-0.96). CONCLUSIONS: Complex chronic conditions are not associated with mortality in high-risk PICU patients.

The occurrence of adverse events in low-risk non-survivors in pediatric intensive care patients: an exploratory study.

We studied the occurrence of adverse events (AEs) in low-risk non-survivors (LNs), compared to low-risk survivors (LSs), high-risk non-survivors (HNs), and high-risk survivors (HSs) in two pediatric intensive care units (PICUs). The study was performed as a retrospective patient record review study, using a PICU-trigger tool. A random sample of 48 PICU patients (0-18 years) was chosen, stratified into four subgroups of 12 patients: LNs, LSs, HNs, and HSs. Primary outcome was the occurrence of AEs. The severity, preventability, and nature of the indentified AEs were determined. In total, 45 AEs were found in 20 patients. The occurrence of AEs in the LN group was significantly higher compared to that in the LS group and HN group (AE occurrence: LN 10/12 patients, LS 1/12 patients; HN 2/12 patients; HS 7/12 patients; LN-LS difference, p < 0.001; LN-HN difference, p < 0.01). The AE rate in the LN group was significantly higher compared to that in the LS and HN groups (median [IQR]: LN 0.12 [0.07-0.29], LS 0 [0-0], HN 0 [0-0], and HS 0.03 [0.0-0.17] AE/PICU day; LN-LS difference, p < 0.001; LN-HN difference, p < 0.01). The distribution of the AEs among the four groups was as follows: 25 AEs (LN), 2 AEs (LS), 8 AEs (HN), and 10 AEs (HS). Fifteen of forty-five AEs were preventable. In 2/12 LN patients, death occurred after a preventable AE. CONCLUSION: The occurrence of AEs in LNs was higher compared to that in LSs and HNs. Some AEs were severe and preventable and contributed to mortality. What is Known: • 59-76% of all PICU patients encounter at least one adverse event during their PICU stay. • It is unknown if adverse events play a role in death of low-risk PICU patients. What is New: • In low-risk PICU non-survivors, occurrence of adverse events is higher compared to low-risk PICU survivors and to high-risk PICU non-survivors. • Severe and preventable adverse events occur in low-risk PICU non-survivors, some contributing to mortality.

Factors Associated With Mortality in Low-Risk Pediatric Critical Care Patients in The Netherlands.

OBJECTIVE: To determine differences between survivors and nonsurvivors and factors associated with mortality in pediatric intensive care patients with low risk of mortality. DESIGN: Retrospective cohort study. SETTING: Patients were selected from a national database including all admissions to the PICUs in The Netherlands between 2006 and 2012. PATIENTS: Patients less than 18 years old admitted to the PICU with a predicted mortality risk lower than 1% according to either the recalibrated Pediatric Risk of Mortality or the Pediatric Index of Mortality 2 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 16,874 low-risk admissions were included of which 86 patients (0.5%) died. Nonsurvivors had more unplanned admissions (74.4% vs 38.5%; p < 0.001), had more complex chronic conditions (76.7% vs 58.8%; p = 0.001), were more often mechanically ventilated (88.1% vs 34.9%; p < 0.001), and had a longer length of stay (median, 11 [interquartile range, 5-32] d vs median, 3 [interquartile range, 2-5] d; p < 0.001) when compared with survivors. Factors significantly associated with mortality were complex chronic conditions (odds ratio, 3.29; 95% CI, 1.97-5.50), unplanned admissions (odds ratio, 5.78; 95% CI, 3.40-9.81), and admissions in spring/summer (odds ratio, 1.67; 95% CI, 1.08-2.58). CONCLUSIONS: Nonsurvivors in the PICU with a low predicted mortality risk have recognizable risk factors including complex chronic condition and unplanned admissions.

Short-Term Health-Related Quality of Life of Critically Ill Children Following Daily Sedation Interruption.

OBJECTIVE: Our earlier pediatric daily sedation interruption trial showed that daily sedation interruption in addition to protocolized sedation in critically ill children does not reduce duration of mechanical ventilation, length of stay, or amounts of sedative drugs administered when compared with protocolized sedation only, but undersedation was more frequent in the daily sedation interruption + protocolized sedation group. We now report the preplanned analysis comparing short-term health-related quality of life and posttraumatic stress symptoms between the two groups. DESIGN: Preplanned prospective part of a randomized controlled trial. SETTING: Two tertiary medical-surgical PICUs in the Netherlands. PATIENTS: Critically ill children requiring mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight weeks after a child's discharge from the PICU, health-related quality of life was assessed with the validated Child Health Questionnaire and, only for children above 4 years old, posttraumatic stress was assessed with the Dutch Children's Responses to Trauma Inventory. Additionally, health-related quality of life of all study patients was compared with Dutch normative data. Of the 113 patients from two participating centers in the original study, 96 patients were eligible for follow-up and 64 patients were included (response rate, 67%). No difference was found with respect to health-related quality of life between the two study groups. None of the eight children more than 4 years old showed posttraumatic stress symptoms. CONCLUSIONS: Daily sedation interruption in addition to protocolized sedation for critically ill children did not seem to have an effect on short-term health-related quality of life. Also in view of the earlier found absence of effect on clinical outcome, we cannot recommend the use of daily sedation interruption + protocolized sedation.

Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children.

RATIONALE: Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES: To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children. METHODS: From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MEASUREMENTS AND MAIN RESULTS: In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ. CONCLUSIONS: Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.

A randomized controlled trial of daily sedation interruption in critically ill children.

PURPOSE: To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children. METHODS: In this multicenter randomized controlled trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient's sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the 'open' infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat. RESULTS: From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (n = 66) or PS (n = 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6-25.8) versus PS 24.0 days (IQR 20.6-26.0); median difference 0.02 days (95 % CI -0.91 to 1.09), p = 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2-11.0) versus PS 7.4 days (IQR 5.3-12.8), p = 0.47, and DSI + PS 13.3 days (IQR 8.6-26.7) versus PS 15.7 days (IQR 9.3-33.2), p = 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63, p = 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6-22.6) versus PS 17.0 mg/kg (IQR 8.2-39.8), p = 0.11. CONCLUSION: In critically ill children, daily sedation interruption in addition to protocolized sedation did not improve clinical outcome and was associated with increased mortality compared with protocolized sedation only.

Daily interruption of sedation in critically ill children: study protocol for a randomized controlled trial.

BACKGROUND: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and efficacy of daily sedation interruption in critically ill children. METHODS/DESIGN: Children between 0 and 18 years of age who require mechanical ventilation, with an expected duration of at least 48 h and need for sedative infusion, will be included. After enrollment patients will be randomly assigned to DSI in combination with protocolized sedation (intervention group) or protocolized continuous sedation (control group). A sedation protocol that contains an algorithm for increasing and weaning of sedatives and analgesics will be used. The sedative infusion will be restarted if the patient becomes uncomfortable or agitated according to the sedation protocol. The primary endpoint is the number of ventilator-free days at 28 days. TRIAL REGISTRATION: NTR2030.

Randomized controlled trial of daily interruption of sedatives in critically ill children.

AIM: To study the feasibility of daily interruption of sedatives in critically ill children. METHODS: Prospective randomized controlled open-label trial, performed in a pediatric intensive care unit of a tertiary care teaching and referring hospital. 30 children (0-12 years) receiving mechanically ventilation for >24 h were included. In the intervention group, all sedatives were stopped daily and restarted when COMFORT-behavior score ≥17. The control group received standard care. Primary end points were amounts of sedatives and number of bolus medications in the first 3 days after enrollment and number of (near) incidents. Secondary end points were duration of mechanical ventilation, length of stay in pediatric intensive care, and changes in COMFORT-behavior score. RESULTS: Midazolam and morphine use were lower in the intervention group compared with the control group (P = 0.007 and P = 0.02, respectively), whereas the number of bolus medications did not differ between groups. Two complications were recorded: one patient (intervention group) lost his intravenous line, and one patient (control group) had an unplanned extubation. Duration of mechanical ventilation was significantly shorter in the intervention group compared with the control group (median [interquartile range] of 4 [3-8] and 9 [4-10] days, respectively, P = 0.03). Length of stay in the PICU in the intervention group was significantly shorter than in the control group (median [interquartile range] of 6 [4-9] and 10 [7-15] days, respectively, P = 0.01). CONCLUSIONS: Daily interruption of sedatives in critically ill children is feasible, results in decreased use of sedation, earlier extubation, and shorter length of stay.

Mortality prediction models for pediatric intensive care: comparison of overall and subgroup specific performance.

AIM: To validate paediatric index of mortality (PIM) and pediatric risk of mortality (PRISM) models within the overall population as well as in specific subgroups in pediatric intensive care units (PICUs). METHODS: Variants of PIM and PRISM prediction models were compared with respect to calibration (agreement between predicted risks and observed mortality) and discrimination (area under the receiver operating characteristic curve, AUC). We considered performance in the overall study population and in subgroups, defined by diagnoses, age and urgency at admission, and length of stay (LoS) at the PICU. We analyzed data from consecutive patients younger than 16 years admitted to the eight PICUs in the Netherlands between February 2006 and October 2009. Patients referred to another ICU or deceased within 2 h after admission were excluded. RESULTS: A total of 12,040 admissions were included, with 412 deaths. Variants of PIM2 were best calibrated. All models discriminated well, also in patients <28 days of age (neonates), with overall higher AUC for PRISM variants (PIM = 0.83, PIM2 = 0.85, PIM2-ANZ06 = 0.86, PIM2-ANZ08 = 0.85, PRISM = 0.88, PRISM3-24 = 0.90). Best discrimination for PRISM3-24 was confirmed in 13 out of 14 subgroup categories. After recalibration PRISM3-24 predicted accurately in most (12 out of 14) categories. Discrimination was poorer for all models (AUC < 0.73) after LoS of >6 days at the PICU. CONCLUSION: All models discriminated well, also in most subgroups including neonates, but had difficulties predicting mortality for patients >6 days at the PICU. In a western European setting both the PIM2(-ANZ06) or a recalibrated version of PRISM3-24 are suited for overall individualized risk prediction.

Construction and psychometric testing of the EMPATHIC questionnaire measuring parent satisfaction in the pediatric intensive care unit.

PURPOSE: To construct and test the reliability and validity of the EMpowerment of PArents in THe Intensive Care (EMPATHIC) questionnaire measuring parent satisfaction in the pediatric intensive care unit (PICU). METHODS: Structured development and psychometric testing of a parent satisfaction-with-care instrument with the results of two cohorts of parents (n = 2,046) from eight PICUs in the Netherlands. RESULTS: In the first cohort, 667/1,055 (63%) parents participated followed by 551/991 (56%) parents in the second cohort. The empirical structure of the instrument was established by confirmatory factor analysis with the first sample of parents confirming 65 statements within five theoretically conceptualized domains: information, care and cure, organization, parental participation, and professional attitude. The standardized factor loadings were greater than 0.40 in 63 statements. Cronbach's α, a measure of reliability, per domain ranged from 0.73 to 0.93 in both cohorts with no significant difference documenting the reliability over time. Beside rigorous content and face validity, the congruent validity of the instrument showed adequate correlation with four gold standard questions measuring overall satisfaction. The non-differential validity was confirmed with no significant differences between the population characteristics and the domains, except that parents with a child for a surgical admission were more satisfied on information issues. CONCLUSIONS: The final EMPATHIC questionnaire incorporates 65 statements. The empirical structure of the satisfaction statements and domains was satisfactory. The reliability and validity proved to be adequate. The EMPATHIC questionnaire is a valid quality performance indicator to measure quality of care as perceived by parents.

A qualitative study exploring the experiences of parents of children admitted to seven Dutch pediatric intensive care units.

PURPOSE: To explore parents' experiences during the admission of their children to a pediatric intensive care unit (PICU). METHOD: Qualitative method using in-depth interviews. Thematic analysis was applied to capture parents' experiences. Thirty-nine mothers and 25 fathers of 41 children admitted to seven of the eight PICUs in university medical centers in The Netherlands were interviewed. RESULTS: Parents were interviewed within 1 month after their child's discharge from a PICU. Thematic analysis identified 1,514 quotations that were coded into 63 subthemes. The subthemes were categorized into six major themes: attitude of the professionals; coordination of care; emotional intensity; information management; environmental factors; parent participation. Most themes had an overarching relationship representing the array of experiences encountered by parents when their child was staying in a PICU. The theme of emotional intensity was in particular associated with all the other themes. CONCLUSIONS: The findings provided a range of themes and subthemes describing the complexity of the parental experiences of a PICU admission. The subthemes present a systematic and thematic basis for the development of a quantitative instrument to measure parental experiences and satisfaction with care. The findings of this study have important clinical implications related to the deeper understanding of parental experiences and improving family-centered care.

Differences in the perceptions of parents and healthcare professionals on pediatric intensive care practices.

OBJECTIVE: To explore similarities and differences in perceptions on pediatric intensive care practices between parents and staff by using data from two studies. DESIGN: A two-round Delphi method among nurses and physicians followed by an empiric survey among parents. SETTINGS: Pediatric intensive care units at eight university medical centers. SUBJECTS: Parents whose child has been admitted to a pediatric intensive care unit, nurses, and physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcome measures were 74 satisfaction-with-care items divided into five domains: 1) information; 2) care and cure; 3) organization; 4) parental participation; and 5) professional attitude. The Delphi study was completed by 218 nurses and 46 physicians and the survey by 559 of 1042 (54%) parents. Parents rated 31 items more important than the professionals based on the standardized mean difference (Cohen's d, 0.21-1.18, p < .003). Ten of these were related to information provision. Information on the effects of medication had the largest effect size (Cohen's d 1.18, p = .001). Correct medication administration by professionals was also rated significantly more important by parents (Cohen's d 0.64, p = .001). The professionals rated 12 items more important than the parents (Cohen's d -0.23 to -0.73, p < .005), including three about multicultural care. Significant differences remained on two of the three multicultural care items when the Dutch (n = 483) and non-Dutch parents (n = 76) were separately compared with professionals. On the domain level, parents rated the domains information and parental participation more important than the professionals (Cohen's d 0.36 and 0.26, p = .001). CONCLUSIONS: Compared with the parents' perceptions, nurses and physicians undervalued a substantial number of pediatric intensive care unit care items. This finding may reflect a gap in the understanding of parental experiences as well as incongruity in recognizing the needs of parents.

[Death of an infant following 'craniosacral' manipulation of the neck and spine]. / Overleden zuigeling na 'craniosacrale' manipulatie van hals en wervelkolom.

A healthy 3-month-old girl died after manipulation of the cervical and thoracolumbar spine by a so-called craniosacral therapist. During persistent forced deep flexion of the neck and spine, the infant developed faecal incontinence, atonia and apnoea followed by an asystole. A physical examination, additional MRI studies and an autopsy indicated that the infant probably died as a consequence of local neurovascular lesions of the cervical spine or a mechanically-induced respiratory problem. This is the second reported case of an infant dying after forced manipulations of the neck. Until there is scientific evidence for the effectiveness and safety of forced manipulations of the vertebral column, we advise against this treatment in neonates and infants.

Perceptions of parents on satisfaction with care in the pediatric intensive care unit: the EMPATHIC study.

PURPOSE: To identify parental perceptions on pediatric intensive care-related satisfaction items within the framework of developing a Dutch pediatric intensive care unit (PICU) satisfaction instrument. METHODS: Prospective cohort study in tertiary PICUs at seven university medical centers in The Netherlands. PARTICIPANTS: Parents of 1,042 children discharged from a PICU. RESULTS: A 78-item questionnaire was sent to 1,042 parents and completed by 559 (54%). Seventeen satisfaction items were rated with mean scores <8.0 (1, completely unimportant, to 10, very important) with standard deviations > or =1.65, and thus considered of limited value. The empirical structure of the items was in agreement with the theoretically formulated domains: Information, Care and Cure, Organization, Parental Participation, and Professional Attitude. The Cronbach's alpha of the domains ranged between 0.87 and 0.94. CONCLUSIONS: Parental perceptions on satisfaction with care measures were identified and prioritized. Reliabilities of the items and domains were of high level.