Early weight measures and long-term neuropsychological outcome of critically ill neonates and infants: a secondary analysis of the PEPaNIC trial.

Neonates and infants surviving critical illness show impaired growth during critical illness and are at risk for later neuropsychological impairments. Early identification of individuals most at risk is needed to provide tailored long-term follow-up and care. The research question is whether early growth during hospitalization is associated with growth and neuropsychological outcomes in neonates and infants after pediatric intensive care unit admission (PICU). This is a secondary analysis of the PEPaNIC trial. Weight measurements upon PICU admission, at PICU discharge, at hospital discharge, at 2- and 4-year follow-up, and of different subgroups were compared using (paired) t-tests. Multiple linear regression analyses were performed to investigate the association between early growth in weight measures and neuropsychological outcomes at 4-year follow-up. One hundred twenty-one infants were included, and median age upon admission was 21 days. Growth in weight per week was less than the age-appropriate norm, resulting in a decrease in weight-for-age Z-score during hospitalization. Weight is normalized at 2- and 4-year follow-up. Weight gain in kilograms per week and change in weight Z-score were not associated with neurodevelopmental outcome measures at 4-year follow-up. Lower weight-for-age Z-score at PICU admission and at hospital discharge was associated only with lower weight and height Z-scores at 4-year follow-up. CONCLUSION: Growth in weight during hospital stay of young survivors of critical illness is impaired. Worse early growth in weight is associated with lower weight and height but not with neuropsychological outcomes at 4-year follow-up. WHAT IS KNOWN: • Critically ill neonates and infants show impaired early growth during admission and are at risk for later neuropsychological impairments. • Unraveling the association between early growth and later neuropsychological impairments is crucial since the first year of life is critical for brain development. WHAT IS NEW: • Critically ill neonates and infants had age appropriate weight measures at 4-year follow-up. • Poor growth in weight during hospital stay was not associated with poorer cognitive, emotional, or behavioral functioning four years after critical illness.

Early hypophosphatemia in critically ill children and the effect of parenteral nutrition: A secondary analysis of the PEPaNIC RCT.

BACKGROUND & AIMS: Hypophosphatemia during critical illness has been associated with adverse outcome. The reintroduction of enteral or parenteral nutrition, leading to refeeding hypophosphatemia (RFH), has been presented as potential risk factor. We investigated the occurrence of early RFH, its association with clinical outcome, and the impact of early parenteral nutrition (PN) on the development of early RFH in pediatric critical illness. METHODS: This is a secondary analysis of the PEPaNIC randomized controlled trial (N = 1440), which showed that withholding supplemental parenteral nutrition (PN) for 1 week (late-PN) in the pediatric intensive care unit (PICU) accelerated recovery and reduced new infections compared to early-PN (<24 h). Patients with renal replacement therapy or unavailable phosphate concentrations were excluded from this analysis. Early RFH was defined as serum/plasma phosphate <0.65 mmol/L and a drop of >0.16 mmol/L within 3 days of admission to the PICU. The association between baseline characteristics and early RFH, and the association of early RFH with clinical outcome were investigated using logistic and linear regression models, both uncorrected and corrected for possible confounders. To examine the impact of nutritional intake on phosphate concentrations, structural nested mean models with propensity score and censoring models were used. RESULTS: A total of 1247 patients were eligible (618 early-PN, 629 late-PN). Early RFH occurred in 40 patients (3%) in total, significantly more in the early-PN group (n = 31, within-group occurrence 5%) than in the late-PN-group (n = 9, within-group occurrence 1%, p < 0.001). Patients who were older (OR 1.14 (95% CI 1.08; 1.21) per year added, p < 0.001) and who had a higher Pediatric Risk of Mortality (PIM3) score had a higher risk of developing early RFH (OR 1.36 (95% CI 1.15; 1.59) per unit added, p < 0.001), whereas patients in the late-PN group had a lower risk of early RFH (OR 0.24 (95% CI 0.10; 0.49), p < 0.001). Early RFH was significantly associated with a 56% longer PICU stay (p = 0.003) and 42% longer hospital stay (p = 0.007), but not with new infections (OR 2.01 (95% CI 0.90; 4.30), p = 0.08) or length of mechanical ventilatory support (OR 1.05 (95% CI -3.92; 6.03), p = 0.68), when adjusted for possible confounders. Increase of parenteral nutrition intake (in % kcal of predicted resting energy expenditure) decreased phosphate concentrations (c = -0.002 (95% CI -0.002; -0.001). CONCLUSIONS: Early RFH occurred in 3% of critically ill children. Patients randomized to late-PN had a lower chance of developing early RFH, which may be explained by the more gradual build-up of nutrition. As early RFH might impact recovery, it is important to closely monitor phosphate concentrations in patients, especially of those at risk for early RFH.

Impact of supplemental parenteral nutrition early during critical illness on invasive fungal infections: a secondary analysis of the EPaNIC randomized controlled trial.

OBJECTIVE: In the EPaNIC RCT (N=4640), postponing the administration of parenteral nutrition (PN) to beyond 1 week in the intensive care unit (ICU) (late-PN) reduced the number of ICU-acquired infections and the costs for antimicrobial drugs compared with initiation of PN within 24-48 hours of admission (early-PN). In a secondary analysis, we hypothesize that late-PN reduces the odds to acquire an invasive fungal infection (IFI) in the ICU. METHODS: The impact of late-PN (N=2328) versus early-PN (N=2312) on acquired IFI and on the likelihood to acquire an IFI over time was assessed in univariable and multivariable analyses. Subsequently, we performed multivariable analyses to assess the effect of the mean total daily administered calories from admission until day 3, day 5, and day 7 on the likelihood over time of acquiring an IFI. RESULTS: Fewer late-PN patients acquired an IFI compared with early-PN patients (77/2328 versus 112/2312) (p 0.008). After adjusting for risk factors, the odds to acquire an IFI and the likelihood of acquiring an IFI at any time were lower in late-PN (adjusted odds ratio 0.66, 95% CI 0.48-0.90, p 0.009; adjusted hazard ratio (HRadj) 0.70, 95% CI 0.52-0.93, p 0.02). Larger caloric amounts from admission until day 7 were associated with a higher likelihood to acquire an IFI over time (HRadj 1.09, 95% CI 1.02-1.16, p 0.009). CONCLUSION: Postponing PN to beyond 1 week and smaller caloric amounts until day 7 in the ICU reduced ICU-acquired IFIs and the likelihood to develop an IFI over time.

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.

BACKGROUND: Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRalpha, of which two splice variants involving the hormone-binding domain exist, GRbeta and GR-P. OBJECTIVE: To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. DESIGN AND METHODS: We assessed mRNA expression of the GRalpha, GRbeta and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. RESULTS: GRalpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GRbeta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3.9 +/- 0.4%, beta = 0.010 +/- 0.002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0.001 for all). Serum cortisol levels were negatively associated with liver GRalpha and muscle GR-P expression (P < 0.05). mRNA expression of both liver GRalpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0.01). CONCLUSION: We demonstrate the presence of GRalpha and GR-P mRNA in liver and of GRalpha, GRbeta and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.

Insulin therapy protects the central and peripheral nervous system of intensive care patients.

OBJECTIVE: To investigate the effectiveness of maintaining blood glucose levels below 6.1 mmol/L with insulin as prevention of secondary injury to the central and peripheral nervous systems of intensive care patients. METHODS: The authors studied the effect of intensive insulin therapy on critical illness polyneuropathy (CIPNP), assessed by weekly EMG screening, and its impact on mechanical ventilation dependency, as a prospectively planned subanalysis of a large randomized, controlled trial of 1,548 intensive care patients. In the 63 patients admitted with isolated brain injury, the authors studied the impact of insulin therapy on intracranial pressure, diabetes insipidus, seizures, and long-term rehabilitation at 6 and 12 months follow-up. RESULTS: Intensive insulin therapy reduced ventilation dependency (p = 0.0007; Mantel-Cox log rank test) and the risk of CIPNP (p < 0.0001). The risk of CIPNP among the 405 long-stay (> or =7 days in intensive care unit) patients was lowered by 49% (p < 0.0001). Of all metabolic and clinical effects of insulin therapy, and corrected for known risk factors, the level of glycemic control independently explained this benefit (OR for CIPNP 1.26 [1.09 to 1.46] per mmol blood glucose, p = 0.002). In turn, prevention of CIPNP explained the ability of intensive insulin therapy to reduce the risk of prolonged mechanical ventilation (OR 3.75 [1.49 to 9.39], p = 0.005). In isolated brain injury patients, intensive insulin therapy reduced mean (p = 0.003) and maximal (p < 0.0001) intracranial pressure while identical cerebral perfusion pressures were obtained with eightfold less vasopressors (p = 0.01). Seizures (p < 0.0001) and diabetes insipidus (p = 0.06) occurred less frequently. At 12 months follow-up, more brain-injured survivors in the intensive insulin group were able to care for most of their own needs (p = 0.05). CONCLUSIONS: Preventing even moderate hyperglycemia with insulin during intensive care protected the central and peripheral nervous systems, with clinical consequences such as shortening of intensive care dependency and possibly better long-term rehabilitation.

Correlations between phototoxicity of some 7-chloro-1,4-benzodiazepines and their (photo)chemical properties.

In relation to the phototoxicity of 7-chloro-I,4-benzodiazepine-N-oxides the photostability of some of these N-oxides and the thermostability of their photoproducts, the oxaziridines, were studied. Rather than a consequence of a direct phototoxic effect by the N-oxides the ultimate toxic effect in the test system Salmonella typhimurium appeared to be caused by products formed during and after the irradiation. For chlordiazepoxide (CDZ) and its main metabolites in man desmethylchlordiazepoxide (DES) and demoxepam (DEM) the formation of an oxaziridine is indeed a crucial factor for the onset of the toxic effect. However, DEM oxaziridine (DEM OX.) being very thermolabile in protic medium forms non-toxic conjugates with the solvent. CDZ OX. and DES OX. are thermally converted into their N-oxide, although DES OX. partly decomposes into 6-chloro-4-phenylquinazoline-2-carboxaldehyde as well. This compound proved to be an important factor in the toxic action of DES after irradiation.