Potentially Life-Threatening Interaction between Opioids and Intrathecal Baclofen in Individuals with a Childhood-Onset Neurological Disorder: A Case Series and Review of the Literature.

BACKGROUND: Spasticity and dystonia are movement impairments that can occur in childhood-onset neurological disorders. Severely affected individuals can be treated with intrathecal baclofen (ITB). Concomitant use of ITB and opioids has been associated with central nervous system (CNS) depression. This study aims to describe the clinical management of this interaction, based on a case series and review of literature. METHODS: Four individuals with childhood-onset CNS disorders (age 8-24) and CNS-depressant overdose symptoms after the concomitant use of ITB and opioids are described. The Drug Interaction Probability Scale (DIPS) was calculated to assess the cause-relationship (doubtful <2, possible 2-4, probable 5-8, and highly probable >8) of the potential drug-drug interaction. A literature review of similar previously reported cases and the possible pharmacological mechanisms of opioid-baclofen interaction is provided. RESULTS: After ITB and opioid co-administration, three out of four patients had decreased consciousness, and three developed respiratory depression. DIPS scores indicated a possible cause-relationship in one patient (DIPS: 4) and a probable cause-relationship in the others (DIPS: 6, 6, and 8). Discontinuation or adjusting ITB or opioid dosages resulted in clinical recovery. All patients recovered completely. In the literature, two articles describing nine unique cases were found. CONCLUSION: Although the opioid-ITB interaction is incompletely understood, concomitant use may enhance the risk of symptoms of CNS-depressant overdose, which are potentially life-threatening. If concomitant use is desirable, we strongly recommend to closely monitor these patients to detect interaction symptoms early. Awareness and monitoring of the potential opioid-ITB interaction is essential to reduce the risk of severe complications.

Neurocognitive, Psychosocial, and Quality of Life Outcomes After Multisystem Inflammatory Syndrome in Children Admitted to the PICU.

OBJECTIVES: To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission. DESIGN: National prospective cohort study March 2020 to November 2021. SETTING: Seven PICUs in the Netherlands. PATIENTS: Children with MIS-C (0-17 yr) admitted to a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g ) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found. CONCLUSIONS: Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated.

Health-related quality of life 6 months after pediatric intensive care unit admission for bronchiolitis: a prospective single-center cohort study.

Health-Related Quality of Life (HRQoL) after Pediatric Intensive Care Unit (PICU) admission is considered a valuable outcome measure. Yet, data on HRQoL after PICU admission are scarce and often collected in heterogeneous patient groups. The current study aimed to evaluate HRQoL in children with bronchiolitis 6 months after PICU admission, which represents a homogenous patient group. This study was conducted at the Radboud University Medical Centre in the Netherlands. Children admitted to the PICU between November 2019 and April 2020 were eligible. HRQoL was assessed with the "TNO-AZL Preschool children Quality of Life" (TAPQOL) questionnaire and compared to Dutch normative data. Lower scores represent worse HRQoL. HRQoL was assessed in 34 children (response rate 81%), mean age at assessment was 7.6 months (SD 2.5 months), and median length of stay was 5 days (range 1-17). Parents reported significant lower scores on stomach problems (p < 0.001; d = 0.8) and lung problems (p < 0.001; d = 1.2) and significant higher scores on appetite (p < 0.001; d = 0.6) and problem behavior (p < 0.001; d = 0.5) compared to normative data. Effect sizes were moderate to large. CONCLUSION: Significant differences in several HRQoL domains were found after PICU admission for bronchiolitis compared to normative data. Whereas the domains lung and stomach problems showed significantly impaired scores, most domains revealed HRQoL levels comparable with healthy peers. This study may contribute to the optimization of HRQoL PICU outcomes by highlighting specific HRQoL domains to focus on at admission and during follow-up. WHAT IS KNOWN: • With the decline in PICU mortality, HRQoL became an important outcome measure. Yet, the currently limited number of studies on HRQoL outcomes often involve heterogeneous patient groups. • Bronchiolitis is one of the most frequent reasons for PICU admission, and although a significant part of children admitted for bronchiolitis has a medical history, compared with other reasons for PICU admission, this patient group is relatively homogeneous in terms of age, disease course, and treatment. WHAT IS NEW: • In the present study, six months after PICU admission for bronchiolitis, children scored differently on multiple HRQoL domains compared to healthy peers. • Significantly impaired HRQoL scores were reported on lung and stomach problems in comparison to normative data.

Efficacy of a loading dose of IV salbutamol in children with severe acute asthma admitted to a PICU: a randomized controlled trial.

The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, ß-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 µg/L (IQR 5-24) in the intervention group and 4 µg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups. CONCLUSION: We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered. WHAT IS KNOWN: • Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled ß2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction. WHAT IS NEW: • This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.

Effects of glucocorticoids on serum amino acid levels during cardiac surgery in children.

BACKGROUND AND AIMS: Children undergoing cardiac surgery with cardio pulmonary bypass often receive glucocorticoids to reduce the systemic inflammatory response. Glucocorticoids stimulate protein breakdown and increase amino acid availability. We studied whether glucocorticoid treatment influences the availability of amino acids, specifically those involved in the nitric oxide pathway. METHODS: We prospectively studied 49 children with congenital heart disease undergoing cardiac surgery. Serum cortisol and amino acid levels were measured in arterial blood sampled before surgery (t = -5 min), directly after surgery (t = 0 h) and at t = 12 h and t = 24 h after surgery. Serum cortisol and amino acid levels were compared between children who had received glucocorticoids (G+) and children who had not (G-). RESULTS: Of 49 patients included ((49% male, age 1.7 (0.5-8.7) y)), 33 (67%) received glucocorticoids. Baseline characteristics were not different between groups, except a higher weighted inotropic score in the G+ group. At t = 0 h, serum cortisol levels in the G+ group were significantly higher than in the G- group (7218 vs. 660 nmol/L; (p < 0.05)), but not different at the other time points. The levels of plasma amino acids had dropped after surgery. Compared to the G- group, in the G+ group the total amount of amino acids was significantly higher at t = 12 and t = 24; citrulline levels were higher at t = 12 and t = 24; and glutamine and arginine levels were higher at t = 12. CONCLUSIONS: Glucocorticoid treatment during cardiac surgery in children preserves serum amino acid levels post-surgery. The preservation of glutamine, citrulline and arginine levels might have a beneficial effect on the related NO metabolism.

Effect of non-human neutral and acidic oligosaccharides on allergic and infectious diseases in preterm infants.

UNLABELLED: Short-term supplementation of non-human neutral and acidic oligosaccharides during the first postnatal weeks may enhance the maturation of the immune response in preterm infants and may lead to less allergic and infectious diseases during the first year of life. In a randomized controlled trial, 113 preterm infants (gestational age <32 weeks and/or birth weight <1500 g) were allocated to receive enteral neutral and acidic oligosaccharide supplementation or placebo between days 3 and 30 of life. The median age at follow-up was not different in both groups: 12 months corrected age (interquartile range [IQR], 11-15) in the prebiotic mixture group and 12 months corrected age in the placebo group (IQR, 10-19), respectively. In addition, baseline patient, maternal, and environmental characteristics were not different between the prebiotic mixture (n = 48) and placebo (n = 46) group. Incidence of allergic and infectious diseases was assessed by validated questionnaires. In total, 94/98 (96 %) of the eligible, surviving infants participated in this follow-up study. The incidence of atopic dermatitis (odds ratio [OR], 0.80; 95 % confidence interval [CI], 0.24-2.67), bronchial hyper-reactivity (OR, 1.04; 95 % CI, 0.38-2.87) and infections of the upper respiratory (OR, 0.95; 95 % CI, 0.37-2.44), lower respiratory (OR, 1.03; 95 % CI, 0.37-2.88), and gastrointestinal (OR, 1.77; 95 % CI, 0.55-5.73) tract was not different between the groups. Adjustment for potential confounding factors did not change the results of the primary analysis. CONCLUSION: Short-term enteral supplementation of non-human neutral and acidic oligosaccharides during the neonatal period in preterm infants does not decrease the incidence of allergic and infectious diseases during the first year of life.

Effects of neonatal enteral glutamine supplementation on cognitive, motor and behavioural outcomes in very preterm and/or very low birth weight children at school age.

In very preterm ( < 32 weeks of gestation) and/or very low birth weight (VLBW, < 1500 g birth weight) children, serious neonatal infections are among the main causes of poor developmental outcomes later in childhood. The amino acid glutamine has been shown to reduce the incidence of serious neonatal infections in very preterm and/or VLBW children, while developmental effects beyond 24 months are unknown. We determined the cognitive, motor and behavioural outcomes at school age of a cohort of sixty-four very preterm and/or VLBW children (aged 7·5 (sd 0·4) years) who participated in a randomised placebo-controlled trial using enteral glutamine between day 3 and day 30 of life. Cognitive and motor outcomes were studied using the Wechsler Intelligence Scale for Children-III, the Movement Assessment Battery for Children (MABC), the Attention Network Test and a visual working memory task. Behavioural outcomes were evaluated using parent- and teacher-rated questionnaires. Intelligence quotient, processing speed, attentional functioning, working memory and parent- and teacher-rated behavioural outcomes were not different between children treated with glutamine or placebo; only visuomotor abilities as measured by the Ball Skills scale of the MABC (P = 0·002; d = 0·67) were poorer in the glutamine group. This effect persisted after taking into account the beneficial effects of lower serious neonatal infections rates in children treated with glutamine (P = 0·005). In conclusion, glutamine supplementation between day 3 and day 30 of life had neither beneficial nor detrimental effects on long-term cognitive, motor and behavioural outcomes of very preterm and/or VLBW children at school age, although visuomotor abilities were poorer in children that received glutamine.

[An infant with meningitis caused by resistant pneumococcus: infection despite vaccination]. / Zuigeling met meningitis door resistente pneumokok: ondanks vaccinatie toch besmetting.

BACKGROUND: Following the introduction of a heptavalent pneumococcal conjugate vaccine (PCV7) in the Netherlands in 2006, the incidence of invasive pneumococcal disease (IPD) declined significantly. Since then a shift towards non-vaccine serotype IPD has been noted. CASE DESCRIPTION: We present the case of multidrug resistant non-vaccine serotype 19A pneumococcal meningitis in a 5-month-old boy. He was admitted to our Paediatric Intensive Care Unit (PICU) with seizures and septic shock. A barbiturate-induced coma was eventually required to control the seizures; shock was combated with intravenous fluids and inotropes. He received a 6-week course of ceftriaxone and vancomycin. At follow-up, one year after discharge, he had unilateral deafness and minor developmental delay. CONCLUSION: Worldwide, pneumococcal serotype 19A is now the most common cause of IPD in children, with an increasing incidence of multidrug resistant strains. This trend has not yet been observed in the Netherlands. This case demonstrates that even following the introduction of PCV7 pneumococcal meningitis can still occur. Prompt recognition of the symptoms is still essential.

Long-term effects of neonatal glutamine-enriched nutrition in very-low-birth-weight infants.

Several studies in very-low-birth-weight (VLBW) infants have investigated the effect of parenteral or enteral glutamine supplementation on morbidity, mortality, and outcome in the neonatal period. No evidence of toxicity of glutamine supplementation was found in these clinical trials, but the results for efficacy on a limited number of outcomes have been mixed. The use of glutamine supplementation in VLBW infants has not become routine. Some authors suggest that further study in this area is no longer warranted. In this review, more recent research in the area of glutamine supplementation is described, which suggests additional studies are warranted.

Clinical features of a Dutch cohort of critically ill children due to the 2009 new influenza A H1N1 pandemic.

OBJECTIVE: This study describes the clinical course, treatment, and outcome of 13 critically ill children due to infection with new influenza A H1N1, admitted to 2 pediatric intensive care units (PICUs) in the northwestern part of the Netherlands. METHODS: Retrospective case series, conducted in 2 PICUs in Amsterdam, the Netherlands. RESULTS: A total of 13 children with a new influenza A H1N1 infection were admitted at 2 Dutch PICUs. The majority of these children were 12 to 16 years old and had an underlying disease. All children required mechanical ventilatory support. Shock was present in 7 of 13 (54%) children. Two children were transferred to a supraregional PICU with facilities for extracorporeal membrane oxygenation. CONCLUSIONS: In a Dutch cohort of 13 critically ill children due to infection with new influenza (H1N1), respiratory (100%) and circulatory (54%) failure characterized the course of this infection in most of these children. All children survived.

Glutamine-enriched enteral nutrition in very low birthweight infants and allergic and infectious diseases at 6 years of age.

In a previous randomised controlled trial, we found that glutamine-enriched enteral nutrition in 102 very low birthweight (VLBW) infants decreased both the incidence of serious infections in the neonatal period and the risk of atopic dermatitis during the first year of life. We hypothesised that glutamine-enriched enteral nutrition in VLBW infants in the neonatal period influences the risk of allergic and infectious disease at 6 years of age. Eighty-eight of the 102 infants were eligible for the follow-up study (13 died, 1 chromosomal abnormality). Doctor-diagnosed allergic and infectious diseases were assessed by means of validated questionnaires. The association between glutamine-enriched enteral nutrition in the neonatal period and allergic and infectious diseases at 6 years of age was based on univariable and multivariable logistic regression analyses. Seventy-six of the 89 (85%) infants participated, 38 in the original glutamine-supplemented group and 38 in the control group. After adjustment, we found a decreased risk of atopic dermatitis in the glutamine-supplemented group: adjusted odds ratio (aOR) 0.23 [95% CI 0.06, 0.95]. No association between glutamine supplementation and hay fever, recurrent wheeze and asthma was found. A decreased risk of gastrointestinal tract infections was found in the glutamine-supplemented group (aOR) 0.10 [95% CI 0.01, 0.93], but there was no association with upper respiratory, lower respiratory or urinary tract infections. We concluded that glutamine-enriched enteral nutrition in the neonatal period in VLBW infants decreased the risk of atopic dermatitis and gastrointestinal tract infections at 6 years of age.

Cytokine profiles in 1-yr-old very low-birth-weight infants after enteral glutamine supplementation in the neonatal period.

In a previous study, we found that glutamine-enriched enteral nutrition in 102 very low-birth-weight (VLBW) infants decreased both the incidence of serious neonatal infections and atopic dermatitis during the first year of life. The aims of this follow-up study were to determine whether these beneficial effects are attended by changes in Th(1) and Th(2) cytokine profiles at age 1 yr. Furthermore, we studied changes in cytokine profiles during the first year of life in these VLBW infants. In total, 89 infants were eligible for the follow-up study (12 died, 1 exclusion due to a chromosomal abnormality). Th(1) (IFN-gamma, TNF- alpha and IL-2) and Th(2) cytokine (IL-10, IL-5, and IL-4) profiles following in vitro whole blood stimulation were measured at 1 yr. Cytokine profiles were measured in 59/89 (66%) infants. Glutamine-enriched enteral nutrition in neonatal period did not influence cytokine profiles at 1 yr. Cytokine profiles were not different in infants with and without allergic or infectious diseases. The beneficial effect of glutamine-enriched enteral nutrition on the incidence of serious neonatal infections and atopic dermatitis during the first year of life is not related to changes in the Th(1) and Th(2) cytokine profiles. Both Th(1) and Th(2) cytokine profiles increased during the first year of life in this cohort of VLBW infants.

Cytokine responses in very low birth weight infants receiving glutamine-enriched enteral nutrition.

OBJECTIVE: Very low birth weight (VLBW) infants receiving glutamine-enriched enteral nutrition may present with a lower infection rate, which may result from enhanced antimicrobial innate or Th1 cytokine responses. We investigated whether glutamine-enriched enteral nutrition in VLBW infants increased these cytokine responses following in vitro stimulation of whole blood cells. METHODS: In a double-blind, placebo-controlled, randomized controlled trial, VLBW infants (gestational age <32 weeks and/or birth weight <1500 g) received enteral glutamine supplementation (0.3 g x kg(-1) x day(-1)) or isonitrogenous placebo supplementation (alanine) between days 3 and 30 of life. Cytokine responses following in vitro whole blood cell stimulation with anti-(alpha)CD3/alphaCD28 or lipopolysaccharide were analyzed by cytometric bead array at 3 time points: before the start of the study, at day 7 of life, and at day 14 of life. RESULTS: Baseline patient and nutritional characteristics were not different between groups. At least 2 blood samples were analyzed in 25 of 52 (48%) and 38 of 50 (76%) infants in the glutamine-supplemented and control groups, respectively. Glutamine-enriched enteral nutrition was not associated with significant alterations in cytokine responses (interferon-gamma, tumor necrosis factor-alpha, interleukin [IL]-2, IL-4, IL-5, and IL-10) of peripheral blood cells upon stimulation with either anti-alphaCD3/alphaCD28 or lipopolysaccharide. CONCLUSIONS: We hypothesize that glutamine-enriched enteral nutrition decreases the infection rate in VLBW infants by influencing the mucosal and not the systemic immune system.

Neurodevelopmental outcomes of very low-birth-weight infants after enteral glutamine supplementation in the neonatal period.

AIM: To determine the effect of neonatal glutamine-enriched enteral nutrition in very low birth weight (VLBW) infants on neurodevelopmental outcome at 2 years of age. METHODS: Eighty-eight out of one hundred two infants participating in the initial study were eligible for the follow-up study (13 died, one exclusion due to a chromosomal abnormality). Neurodevelopmental outcome (neurologic status, vision, hearing and Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development II) was evaluated at the corrected age of 2 years. To adjust for potential confounders, data were analyzed by multiple linear or logistic regression (for continuous and dichotomous variables, respectively) RESULTS: Seventy-two out of eighty-eight (82%) infants participated in the follow-up study: 40 and 32 infants in glutamine-supplemented and control groups, respectively. The incidence of neither an MDI nor a PDI

Glutamine-enriched enteral nutrition in very low-birth-weight infants: effect on the incidence of allergic and infectious diseases in the first year of life.

OBJECTIVE: To determine the effect of glutamine-enriched enteral nutrition in very low-birth-weight infants on the incidence of allergic and infectious diseases during the first year of life. DESIGN: Follow-up study. SETTING: Tertiary care hospital. PARTICIPANTS: All surviving infants who participated in a trial of glutamine-enriched enteral nutrition in very low-birth-weight infants. INTERVENTION: Enteral glutamine supplementation (l-glutamine, 0.3 g/kg per day) from 3 through 30 days of life. MAIN OUTCOME MEASURES: The incidence of allergic and infectious diseases during the first year of life, as assessed by means of validated questionnaires. RESULTS: Seventy-seven of 90 infants (86%) participated in the follow-up study. Baseline patient, maternal, and environmental characteristics did not differ between the glutamine-supplemented (n = 37) and control (n = 40) groups, except for the incidence of serious neonatal infections and child care attendance. After adjustment for confounding factors, the risk for atopic dermatitis was lower in the glutamine-supplemented group (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.02-0.97). However, the incidence of bronchial hyperreactivity (OR, 0.34; 95% CI, 0.10-1.21) and infections of the upper respiratory (OR, 0.99; 95% CI, 0.35-2.79), lower respiratory (OR, 0.39; 95% CI, 0.13-1.24), and gastrointestinal (OR 1.25, 95% CI 0.23-6.86) tracts was not different between the treatment groups. CONCLUSIONS: Glutamine-enriched enteral nutrition in very low-birth-weight infants decreased the incidence of atopic dermatitis during the first year of life but had no effect on the incidence of bronchial hyperreactivity and infectious diseases during the first year of life.