Cholinesterases and Anticholinergic Medications in Postoperative Pediatric Delirium.

OBJECTIVES: To describe the relationships between anticholinergic drug exposure, cholinesterase enzyme activity, inflammation, and the development of postoperative delirium in children. DESIGN: Single-center prospective cohort study. SETTING: Twenty-two bed PICU in a tertiary-care academic medical center in Germany. PATIENTS: A consecutive cohort of children admitted after major elective surgery. INTERVENTIONS: Children were screened for delirium bid over 5 consecutive postoperative days. Acetylcholinesterase and butyrylcholinesterase plasma activity levels were measured prior to surgery and once daily during the 5 day study period. Number of anticholinergic drugs and Anticholinergic Drug Scale score were calculated for each patient. MEASUREMENTS AND MAIN RESULTS: Ninety-three children (age range, 0-17 yr) were included. The number of anticholinergic drugs as well as the Anticholinergic Drug Scale score were significantly correlated with development of postoperative delirium, independently of disease severity. Baseline cholinesterase enzyme levels did not differ between patients who did and did not develop postoperative delirium. Butyrylcholinesterase levels, but not acetylcholinesterase levels, dropped by 33% postoperatively, independent of the presence of postoperative delirium. Postoperative butyrylcholinesterase levels were inversely related to number of anticholinergic drugs, Anticholinergic Drug Scale score, and C-reactive protein levels. CONCLUSIONS: Anticholinergic drug exposure was related to development of postoperative delirium in this cohort, with demonstration of a dose-response relationship. As there are alternative options available for many of these medications, it may be reasonable to avoid anticholinergic exposure in the PICU whenever possible.

Risk Factors for the Development of Postoperative Delirium in Pediatric Intensive Care Patients.

OBJECTIVES: To determine and quantify risk factors for postoperative pediatric delirium. DESIGN: Single-center prospective cohort study. SETTING: Twenty-two bed PICU in a tertiary care academic medical center in Germany. PATIENTS: All children admitted after major elective surgery (n = 93; 0-17 yr). INTERVENTIONS: After awakening, children were screened for delirium using the Cornell Assessment of Pediatric Delirium bid over a period of 5 days. Demographic and clinical data were collected from the initiation of general anesthesia. MEASUREMENTS AND MAIN RESULTS: A total of 61 patients (66%) were delirious. Younger children developed delirium more frequently, and the symptoms were more pronounced. The number of preceding operations did not influence the risk of delirium. Total IV anesthesia had a lower risk than inhalational anesthesia (p < 0.05). Duration of anesthesia was similar in all groups. Patients with delirium had a longer duration of mechanical ventilation in the PICU (p < 0.001). Significant differences in cumulative doses of various medications (e.g., sedatives, analgesics, and anticholinergics) were noted between groups; these differences were independent of disease severity. Invasive catheters and respiratory devices (p < 0.01) as well as infections (p < 0.001) increased risk of delirium. CONCLUSIONS: A high prevalence of delirium was noted in the PICU, and several perioperative risk factors were identified. Our data may be a base for development of strategies to prevent and treat postoperative delirium in children.

Patterns of Postoperative Delirium in Children.

OBJECTIVE: Intensive care delirium is a substantial problem in adults. Intensive care delirium is increasingly recognized in pediatrics in parallel with the development of specific scoring systems for children. However, little is known about the fluctuating course of intensive care delirium in children after surgery and possible implications on diagnostic and therapeutic strategies. DESIGN: Patients that needed treatment in the PICU following elective surgery were screened for intensive care delirium with the Cornell Assessment of Pediatric Delirium. When the patients were awake (Richmond Agitation and Sedation Score > -3), two trained investigators conducted the Cornell Assessment of Pediatric Delirium twice daily for five consecutive days. PATIENTS: Ninety-three patients aged 0 to 17 years. INTERVENTIONS: Eight hundred forty-five assessments completed. MEASUREMENTS AND MAIN RESULTS: Of the 845 scores, 230 were consistent with delirium (27.2%). Sixty-one patients (65.5%) were diagnosed with intensive care delirium. Half of these patients (n = 30; 32.2%) had a short-lasting delirium that resolved within 24 hours, and half (n = 31; 33.3%) had delirium of longer duration. Delirium could be clearly distinguished from sedation by analysis of individual test items of the Cornell Assessment of Pediatric Delirium. Time spent delirious had a measurable effect on outcome variables, including hospital length of stay. CONCLUSION: Most postoperative PICU patients develop intensive care delirium. Some have a short-lasting course, which underlines the need for early screening. Our findings support the view of delirium as a continuum of acute neurocognitive disorder. Further research is needed to investigate prophylactic and treatment approaches for intensive care delirium.

Liver cell transplantation in severe infantile oxalosis--a potential bridging procedure to orthotopic liver transplantation?

BACKGROUND: The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. METHODS: We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. RESULTS: Pox decreased from 104.3±8.4 prior to 70.0±15.0 µmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P<0.001) comparing mean levels prior to (103.8 µmol/L) and after Day 14 of LCT until LKTx (77.3 µmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patient's clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. CONCLUSIONS: With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects.

Despite advances in pharmacological therapy of urea cycle disorders (UCDs), the overall long-term prognosis is poor, especially for neonatal manifestations. Transplantation of liver tissue or isolated cells appears suitable for transfer of the missing enzyme. Liver transplantation (LT) for UCDs has an excellent 5-year survival rate of approximately 90% and is the only way to completely cure the disease. However, major neurological damage can only be prevented if the operation is performed during the first months of life. Unfortunately, such early LTs have a substantial risk for peri- and postoperative complications, mostly caused by a relatively large liver graft. Liver cell transplantation (LCT) is less invasive than LT, but has still to be regarded as an experimental therapy with about 100 patients treated since its first use in 1993. UCDs are a model disease for LCT, because of the poor prognosis, mainly hepatic enzyme defects, and excellent outcome after LT. So far, 10 children underwent LCT for UCDs with very few technical complications and encouraging clinical results. A first prospective study on its use in severe neonatal UCDs has recently started. However, availability of hepatocytes is limited by the scarcity of donor livers; therefore the use of stem cells is under investigation. Several different cell types may be regarded as liver stem cells, and in vivo transformation into hepatocyte-like cells has been shown in animal studies. However, a clear proof of principle in animal models of human metabolic disease is still missing, which is the prerequisite for clinical application in humans.

Adenovirus infection and treatment with cidofovir in children after liver transplantation.

In a retrospective study, serum samples from 21 pediatric liver transplant recipients were analysed by quantitative real-time PCR for ADV infection up to 24 wk after Tx. ADV DNA was detected in serum of eight children after Tx, one of whom developed life-threatening fulminant hepatitis and sepsis. None of these children were symptomatic at the time of first detection of ADV DNA in serum after Tx. Seven children with positive ADV PCR had low adenoviral loads, showed no increase in viral load and remained clinically asymptomatic in the follow-up period of 24 wk. After 10 wk under immunosuppression one child presented clinically with adenoviral sepsis and severe necrotizing hepatitis. This patient revealed a dramatic increase of ADV from baseline titers up to 1.3 x 10(9 )copies/mL serum within 10 wk after Tx. ADV was also detected in a liver biopsy of this child at 1.2 x 10(4) copies/cell and typed by sequence analysis as human ADV species C, type 6, a rarely detected ADV type and first described in a liver transplant patient. Immunosuppression was reduced in this patient immediately and the antiviral drug cidofovir administered intravenously followed by viral suppression and clinical improvement of the child.

Liver transplantation for inborn errors of metabolism.

Liver transplantation (LT) has become an accepted treatment for various hepatic-based metabolic disorders. For diseases with hepatic origin but mainly extrahepatic manifestations, it can be regarded as a means of gene therapy. Depending on the underlying disease, optimal dietary and medicamentous treatment cannot reliably prevent periods of metabolic decompensation resulting in severe organ damage. In severe neonatal forms of urea cycle disorders, liver transplantation should be considered in early infancy. The same applies to propionic acidemia, although severe perioperative complications have been described. In methylmalonic aciduria, there is no consensus whether LT alone is prior to combined liver and kidney transplantation (LKT). Moreover, late neurologic complications can occur in some patients with propionic and methylmalonic acidemias. LT as well as LKT is discussed in primary hyperoxaluria. For patients with cystic fibrosis and biliary cirrhosis, LT has become an established treatment that may even improve pulmonary function. Careful individual decisions must be made in patients with mitochondrial disorders because of possible progressive neuromuscular involvement. In most hepatic-based metabolic disorders, restoration of only about 10% of the original enzyme activity is sufficient to warrant sufficient metabolic control.