Lethal course of meconium ileus in preterm twins revealing a novel cystic fibrosis mutation (p.Cys524Tyr).

BACKGROUND: In term newborns meconium ileus is frequently associated with cystic fibrosis. Reports on meconium ileus in preterm infants being diagnosed with cystic fibrosis early after birth are very scarce. Associations between genotype and phenotype in cystic fibrosis and its particular comorbidities have been reported. CASE PRESENTATION: Two extremely preterm twin infants (26 weeks of gestation) born from a Malaysian mother and a Caucasian father were presented with typical signs of meconium ileus. Despite immediate surgery both displayed a unique and finally lethal course. Mutation analysis revealed a novel, probably pathogenic cystic fibrosis mutation, p.Cys524Tyr. The novel mutation might explain the severity of disease next to typical sequelae of prematurity. CONCLUSION: Preterm neonates with meconium ileus have to be evaluated for cystic fibrosis beyond ethnical boundaries, but may take devastating clinical courses despite early treatment. The novel, potentially pathogenic CF mutation p.Cys524Tyr might be associated with severe meconium ileus in neonates. Disease-modifying loci are important targets for intestinal comorbidity of cystic fibrosis.

Plasma B-type natriuretic peptide levels in children with heart disease.

AIM: To determine plasma B-type natriuretic peptide (BNP) levels in children with heart diseases before medical or surgical treatment for monitoring therapeutic efficacy in an observational prospective clinical trial at tertiary care centre. METHODS: In 522 paediatric patients at an age of 6.4 ± 5.2 years (mean ± SD; range: 14 days-18 years) with congenital heart disease (CHD), cardiomyopathies (CMP) or pulmonary arterial hypertension (PAH), plasma BNP levels were evaluated before and under treatment. RESULTS: Most types of heart disease are associated with increased mean plasma BNP levels before treatment, with highest values in children with CMP (BNP 6165 pg/mL in dilated CMP vs. 817 pg/mL in hypertrophic, vs. 1236 pg/mL in restrictive CMP, each p < 0.05). Children with PAH showed a significant decrease in BNP levels under medical treatment (mean BNP 981 pg/mL before vs. 26 pg/mL under treatment, p < 0.05). Children with univentricular CHD undergoing surgical staged palliation showed a significant decrease in BNP levels after bidirectional cavopulmonary anastomosis (BDCP) (BNP 109 pg/mL before vs. 70 pg/mL after BDCP, p < 0.05). CONCLUSION: Plasma BNP levels are elevated in children with heart disease before treatment and are a useful laboratory parameter under treatment during long-term follow-up.

Long-term remission after first-line single-agent treatment with arsenic trioxide of relapsed acute promyelocytic leukemia in an 8-year-old boy.

Arsenic trioxide (ATO) has been proven to be highly effective in adults with newly diagnosed or relapsed acute promyelocytic leukemia (APL). Only very limited data are published on the use of ATO as a single agent for first-line therapy of relapsed APL. The authors present a case of a 8-year-old boy with a bone marrow relapse of APL 7 years after first diagnosis, who achieved durable molecular remission with ATO as single agent: induction therapy for 12 weeks, consolidation for 4 weeks, then 6 cycles of 10 days over a period of 6 months. In total, 140 doses of ATO (0.15 mg/kg/day) were given (21 mg/kg). Consecutive promyelocytic leukemia-retinoic acid receptor α (PML-RARα) RT-PCR analyses were negative with a follow-up of 48 months. Acute or late side effects of arsenic were not observed. At present, the boy is in complete remission 4 years after the diagnosis of the relapse.

Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency.

INTRODUCTION: N-Acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder, which may present in the neonatal period with severe hyperammonemia and marked neurological impairment. CASE REPORT: We report on a Turkish family with a patient who died due to hyperammonemia in the neonatal period. Reduced activity of NAGS and carbamyl phosphate synthetase were found at autopsy. A second child who developed hyperammonemia on the second day of life was immediately treated with arginine hydrochloride, sodium benzoate and protein restriction. After NAGS deficiency was suspected by enzyme analysis, sodium benzoate was replaced by N-carbamylglutamate (NCG). A third child who developed slight hyperammonemia on the third day of life was treated with NCG before enzyme analysis confirmed reduced NAGS activity. Neither of the patients developed hyperammonemia in the following years. After the human NAGS gene was identified, mutation analysis revealed that the older sibling on NCG therapy was homozygous for a 971G>A (W324X) mutation. The parents and the younger sibling were heterozygous. Therapy was continued in the older sibling until now without any adverse effects and favourable neurodevelopment outcome. In the younger sibling, therapy was stopped without any deterioration of urea cycle function. CONCLUSION: NAGS deficiency can be successfully treated with NCG and arginine hydrochloride with favourable outcome. Molecular diagnostic rather than enzyme analysis should be used in patients with suspected NAGS deficiency.

Inflammatory response and neurodevelopmental outcome after open-heart surgery in children.

Long-term neurodevelopmental sequelae are commonly detectable in children after open-heart surgery with cardiopulmonary bypass (CPB). The objective of the study was to determine the neurodevelopmental outcome in these children in relation to postoperative inflammatory reaction. This is a prospective, observational study on children with congenital heart defects (n = 32) undergoing elective open-heart surgery in a tertiary pediatric cardiac center. Neurodevelopmental outcome was assessed in the median 6 months after CPB. Neurological examination was done in all children before the operation and, additionally, complete neurodevelopmental status was assessed preoperatively in 14 children. Three hours after the end of CPB, plasma concentrations of interleukin (IL)-6 and IL-8 were strongly elevated (p < 0.001). Moreover, there was a rise of neutrophils and C-reactive protein at 24 h postoperatively (p < 0.001). Intellectual performance after surgery was correlated with preoperative performance, r ( S ) = 0.83, p < 0.001 (mean IQ scores after CPB = 90.4 +/- 18.4 and before CPB = 87.5 +/- 14.5, p = 0.20). Multiple regression analysis demonstrated that preoperative IQ scores accounted for 83.8% of the variance of postoperative IQ scores (p < 0.0001). Inflammatory variables were not significant predictors of postoperative IQ scores. The frequency of neuromotor abnormalities at 6 months after CPB was influenced by the presence of a cyanotic heart defect, duration of CPB and aortic clamp time, and plasma levels of IL-6 shortly after CPB (R (2) = 67.8%, p = 0.002). In conclusion, in the examined population, preexisting neurodevelopmental impairment is frequent and predicts postoperative outcome. The high frequency of postoperative neuromotor disabilities seems to be associated with the type of congenital heart defect but also with the procedure and possible complications of CPB.

Pain relief in ventilated preterms during endotracheal suctioning: a randomized controlled trial.

BACKGROUND: In Switzerland approximately 8% of infants are born prematurely. Some of them undergo mechanical ventilation including endotracheal suctioning (ETS). ETS is one of the most frequently performed interventions and is linked to stress and pain, but its treatment is controversial. In Switzerland there is a lack of standardisation in pain relief for ETS. AIMS: To test the hypothesis that an intermittent dose of morphine reduces pain during ETS and that subsequent multisensorial stimulation (MSS), as a non pharmacological comforting intervention, helps infants to recover from experienced pain. METHOD: A randomized placebo controlled trial in two tertiary neonatal intensive care units (NICU) with a sample of 30 mechanically ventilated preterm infants was conducted. Pain was measured by three pain assessment tools (Bernese Pain Scale for Neonates, Premature Infant Pain Profile and Visual Analogue Scale) RESULTS: Morphine did not lead to any pain relief from ETS as measured by three pain scales. Nor did the comforting intervention of MSS show any effect. Repeated-measure analysis of variance for the within and between groups comparison showed no statistical significance. CONCLUSIONS: The administration of morphine for pain relief in ventilated preterm neonates during ETS remains questionable and the use of MSS as a comforting intervention after painful stimulus cannot be recommended. The validity testing of the instruments for this patient population should undergo a systematic validation trajectory. Future research should focus on options among non pharmacological interventions for relieving pain during ETS.

The efficacy of non-pharmacological interventions in the management of procedural pain in preterm and term neonates. A systematic literature review.

BACKGROUND: Neonates in a neonatal intensive care unit are exposed to a high number of painful procedures. Since repeated and sustained pain can have consequences for the neurological and behaviour-oriented development of the newborn, the greatest attention needs to be paid to systematic pain management in neonatology. Non-pharmacological treatment methods are being increasingly discussed with regard to pain prevention and relief either alone or in combination with pharmacological treatment. AIMS: To identify effective non-pharmacological interventions with regard to procedural pain in neonates. METHODS: A literature search was conducted via the MedLine, CINAHL, Cochrane Library databases and complemented by a handsearch. The literature search covered the period from 1984 to 2004. Data were extracted according to pre-defined criteria by two independent reviewers and methodological quality was assessed. RESULTS: 13 randomised controlled studies and two meta-analyses were taken into consideration with regard to the question of current nursing practice of non-pharmacological pain management methods. The selected interventions were "non-nutritive sucking", "music", "swaddling", "positioning", "olfactory and multisensorial stimulation", "kangaroo care" and "maternal touch". There is evidence that the methods of "non-nutritive sucking", "swaddling" and "facilitated tucking" do have a pain-alleviating effect on neonates. CONCLUSIONS: Some of the non-pharmacological interventions have an evident favourable effect on pulse rate, respiration and oxygen saturation, on the reduction of motor activity, and on the excitation states after invasive measures. However, unambiguous evidence of this still remains to be presented. Further research should emphasise the use of validated pain assessment instruments for the evaluation of the pain-alleviating effect of non-pharmacological interventions.

Prognostic value of plasma N-terminal pro-brain natriuretic peptide in children with congenital heart defects and open-heart surgery.

OBJECTIVE: To assess whether preoperative and postoperative plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) predict postoperative outcome of open-heart surgery in children. STUDY DESIGN: A prospective observational study was conducted with 40 children with congenital heart defects who were undergoing elective open-heart surgery. Plasma levels of NT-proBNP, troponin T, lactate, C-reactive protein, and total neutrophil cell counts were measured before, during, and 1 and 3 hours after the end of cardiopulmonary bypass grafting (CPB). Outcomes were assessed by means of the kind, dosage, and duration of inotropic drug use during the postoperative period, lactate concentrations, and the duration of mechanical ventilation. RESULTS: Preoperative levels of NT-proBNP were significantly increased irrespective of the type of congenital heart defect and the age of the patient. Preoperative NT-proBNP levels were higher in patients receiving prolonged postoperative inotropic drug therapy (r = 0.56, P = .0003). By means of multivariate analysis with the duration of inotropic therapy as the dependent variable, a significant impact of preoperative NT-proBNP levels, the presence of a cyanotic heart defect, the risk adjustment for congenital heart surgery score, duration of CPB time, and postoperative lactate levels were demonstrated (R squared = 76.8%, P <.0001). CONCLUSION: Preoperative NT-proBNP levels were associated with complicated postoperative outcome in children who underwent low-risk open-heart surgery. This marker may therefore be a useful tool in risk stratification of patients with congenital heart defects.

Electroencephalographic changes after pediatric cardiac surgery with cardiopulmonary bypass: is slow wave activity unfavorable?

Pediatric cardiac surgery with cardiopulmonary bypass (CPB) is frequently associated with neurologic deficits. We describe the postoperative EEG changes, assess their possible causes, and evaluate their relevance to neurologic outcome. Thirty-one children and five neonates with congenital heart disease were included. EEG recording started after intubation and continued until 22-96 h after CPB. In addition to conventional analysis, spectral analysis was performed for occipital and frontal electrodes, and differences between pre- and postoperative delta power (delta-deltaP) were calculated. Maximum values of occipital delta-deltaP that occurred within 48 h after CPB were correlated with clinical variables and with perioperative markers of oxidative stress and inflammation. Occipital delta-deltaP correlated with frontal delta-deltaP, and maximum delta-deltaP correlated with conventional rating. Distinct rise of deltaP was detected in 18 of 21 children without any acute or long-term neurologic deficits but only in five of 10 children with temporary or permanent neurologic deficits. Furthermore, maximally registered delta-deltaP was inversely associated with duration of CPB and postoperative ventilation. Maximal delta-deltaP was also inversely associated with the loss of plasma ascorbate (as an index of oxidative stress) and plasma levels of IL-6 and IL-8. Slow wave activity frequently occurs within 48 h after CPB. However, our data do not support the notion that EEG slowing is associated with adverse neurologic outcome. This is supported by the fact that EEG slowing was associated with less oxido-inflammatory stress.

Monocyte function-associated antigen expression during and after pediatric cardiac surgery.

OBJECTIVE: Systemic inflammatory response syndrome and infectious complications are major causes of morbidity and mortality after cardiopulmonary bypass. Recent work in adult patients suggests that the balance between proinflammatory and anti-inflammatory mediators is important. We hypothesized that the expression of different function-related receptors on circulating monocytes might reflect the net response of the inflammatory reaction. METHODS: We performed a prospective and observational study in a tertiary pediatric cardiac center in a population of children (n = 40) undergoing elective cardiac surgery. Expression of receptors on the surface of monocytes was assessed before, during, and after surgical intervention. RESULTS: Early monocyte activation was demonstrated by changes of the expression of the chemokine receptor CCR2, which was inversely correlated with plasma levels of monocyte chemotactic protein 1 (rho = -0.54, P = .002). High levels of monocyte chemotactic protein 1 were found in children with high expression of the adhesion receptor CD11b/CD18 on circulating monocytes. The intensity of human leukocyte antigen DR expression rapidly decreased in all children after the onset of cardiopulmonary bypass ( P < .001). Low human leukocyte antigen DR expression was correlated with increased plasma levels of interleukin 10 postoperatively. Children who had signs of bacterial pneumonia postoperatively had lower levels of human leukocyte antigen DR expression before surgical intervention (relative risk, 13.3; P = .007). CONCLUSIONS: The expression of monocyte function-related receptors is altered after cardiac surgery. Early activation of monocytes by monocyte chemotactic protein 1 possibly released from the heart is followed by an anti-inflammatory response with suppression of monocyte human leukocyte antigen DR expression. The increased risk of bacterial infection after pediatric cardiac surgery can be anticipated by surveillance of monocyte function before surgical intervention.

Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation.

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.

CXC-chemokine stimulation of neutrophils correlates with plasma levels of myeloperoxidase and lactoferrin and contributes to clinical outcome after pediatric cardiac surgery.

Several CXC-chemokines, of which interleukin (IL)-8 is the prototype, are potent neutrophil chemotactic and activating cytokines, inducing the secretion of granule proteins and the generation of reactive oxygen intermediates that may cause tissue damage and amplify inflammatory responses. Here, we investigated whether chemokines play a key role in the inflammatory process following cardiac surgery with cardiopulmonary bypass (CPB) in children. We performed an observational prospective clinical study of 40 pediatric patients before, during, and after open heart surgery with CPB. Plasma levels of chemokines, myeloperoxidase (MPO), and lactoferrin were measured by immunoassays. Cell surface receptors were detected by flow cytometry. Plasma levels of IL-8 were increased after CPB, correlating strongly with a reduction of expression of the CXC-chemokine receptors (CXCR) 1 and 2 on neutrophils indicating in vivo activation of neutrophils by IL-8. Other CXC-chemokines with Glu-Leu-Arg motif showed no correlation with CXCR1 or CXCR2 expression. Two components of neutrophilic granules, MPO and lactoferrin, were strongly elevated postoperatively, and the levels of both were correlated with IL-8. Levels of monocyte chemoattractant protein (MCP)-1 were increased postoperatively, correlating with a reduction of CCR2 expression and an increase of CD11b expression on monocytes, suggesting monocyte activation by MCP-1. The early postoperative course was complicated in patients with an increase of these inflammatory parameters. Impaired cardiovascular function correlated with increased levels of IL-8 and activation of neutrophils and was most prominent in patients with a long time on CPB and in those with cyanotic heart lesions. In conclusion, MCP-1 is involved in the regulation of chemotaxis and function of monocytes during and early after the end of CPB. Activation of neutrophils and down-regulation of CXCR1 and CXCR2 were predominantly caused by IL-8. This activation implies release of components of neutrophilic granules and correlates with the need for inotropic support.

Pain assessment in the neonate using the Bernese Pain Scale for Neonates.

BACKGROUND: Neonates who require treatment in the neonatal intensive care unit (NICU) are subjected to many invasive painful procedures. AIMS: Assessment of pain in preterm and term neonates with or without ventilation on continuous positive airway pressure using the Bernese Pain-Scale for Neonates (BPSN). The validity and the reliability of the BPSN was established. STUDY DESIGN AND SUBJECTS: Pain assessments (n=288) were performed by 6 health care workers in different situations of term and preterm neonates. Each neonate (n=12) was observed in four given situations (after feeding, while a foot was being warmed, while a routine capillary blood sample was taken and 15 min after the blood sample was taken). Pain assessments were made by two nurses at the bedside using the BPSN, the Visual-Analogue Scale (VAS) and the Premature Infant Pain Profile (PIPP). At the same time, a video sequence was made which was shown later to four different nurses to assess pain using the BPSN, the PIPP, and the VAS. RESULTS: The construct validity of the BPSN was very good (F=41.3, p<0.0001). Moreover, concurrent and convergent validity of the BPSN compared to VAS and PIPP was r=0.86, and r=0.91, p<0.0001, respectively. Finally, the study demonstrated high coefficients for interrater (r=0.86-0.97) and intrarater reliability (r=0.98-0.99). CONCLUSION: The BPSN was shown to be a valid and reliable tool for assessing pain in term and preterm neonates with and without ventilation.

Cytomegalovirus-associated necrotizing enterocolitis in a preterm twin after breastfeeding.

Cytomegalovirus (CMV) in breast milk is transmitted to infants and may be associated with disease especially in preterm infants. We present a preterm twin with postnatally acquired CMV infection and evidence of CMV-associated necrotizing enterocolitis.

Plasma levels of interleukin-8 and expression of interleukin-8 receptors on circulating neutrophils and monocytes after cardiopulmonary bypass in children.

OBJECTIVE: Cardiopulmonary bypass induces a systemic inflammatory response that causes substantial clinical morbidity. This study sought to determine cellular and humoral variables of inflammation. We hypothesized that chemokines are a major source of stimulation of neutrophils and monocytes in pediatric cardiac surgery. METHODS: We performed an observational prospective clinical study of 20 pediatric patients before and after cardiopulmonary bypass. Plasma levels of interleukin-6, interleukin-8, myeloperoxidase, and nitric oxide were measured by immunoassays. Expression of interleukin-8 receptors (CXCR1, CXCR2) and CD14 of circulating neutrophils and monocytes was assessed by flow cytometry. Clinical evaluations included length of inotropic support and mechanical ventilation as well as oxygenation. RESULTS: Two hours after cardiopulmonary bypass, plasma levels of interleukin-6 and interleukin-8 were strongly increased (P =.0001 and P =.0032, respectively). Interleukin-6 and interleukin-8 concentrations correlated with the length of inotropic support, as well as with the length of mechanical ventilation (r >.70, P .62, P

Age-related low expression of HLA-DR molecules on monocytes of term and preterm newborns with and without signs of infection.

OBJECTIVES: Presentation of human leucocyte antigen (HLA) molecules is an important part of an efficient immune response. Since bacterial infections are more common in newborns, we hypothesized that the level of HLA-DR expression may influence the host defense system. STUDY DESIGN: HLA-DR expression on monocytes was examined by flow cytometry during the first week of life of term and preterm neonates with and without signs of infection and of adults. RESULTS: HLA-DR expression of term and preterm newborns with or without signs of infection was lower compared with adults during the first day of life (p<0.0001). Prematurity correlates with lower expression in neonates with gestational age less than 32 weeks (p=0.0008). HLA-DR expression in neonates with signs of infection was decreased compared to healthy neonates (p=0.0196). Maternal conditions such as preeclampsia, prenatal treatment with steroids and mode of delivery had no influence on the expression of HLA-DR. In contrast, newborns with respiratory distress syndrome but without signs of infection showed reduced HLA-DR expression (p=0.0370). CONCLUSION: Low HLA-DR expression on monocytes contributes to impaired neonatal host defense, especially in preterm neonates.

Increased respiratory burst and increased expression of complement receptor-3 (CD11b/CD18) and of IL-8 receptor-A in neutrophil granulocytes from newborns after vaginal delivery.

To study neutrophil activation in cord blood as a function of the mode of delivery, we performed analysis of the function of neutrophil granulocytes by assessing their ability to produce reactive oxygen products (ROP) as well as neutrophil cell surface expression of CD11b/CD18 and interleukin (IL)-8 receptors quantified with flow cytometry. Plasma levels of granulocyte colony-stimulating factor (G-CSF) were measured using an immunoassay. Neutrophil granulocytes were derived from cord blood of term newborns delivered vaginally (n = 20) and by cesarean section (n = 10), and, for comparison, from adult peripheral blood (n = 15). Blood neutrophil counts and the capacity of neutrophil granulocytes to produce ROP in response to stimulation with Escherichia coli was increased in newborns after vaginal delivery as compared to newborns delivered by cesarean section. The level of expression of the adhesion molecule/complement receptor CD11b/CD18 and the chemokine receptor IL-8 RA was also higher after vaginal delivery. Plasma concentrations of G-CSF in cord blood of newborns were higher than those of adults with no difference detectable between vaginal delivery and cesarean section. The data demonstrate a higher functional responsiveness and a higher expression level of functionally important receptors in neutrophils after vaginal delivery possibly due to activation of neutrophil granulocytes during labor.

Does critical incident reporting contribute to medication error prevention?

UNLABELLED: Medication-related critical incidents (CIs) comprise harmful and potentially harmful events. The aim of CI monitoring is quality improvement through system changes. In a prospective survey, we analysed our drug-related CIs of the year 2001 with an emphasis on how they contributed to system changes. A voluntary, anonymous, non-punitive CI reporting was used. The study was performed in a multidisciplinary, 23-bed, neonatal-paediatric intensive care unit (ICU). CI severity was graded: minor (no interventions required), moderate (requiring routine therapy, available outside the ICU), major (need for therapeutic interventions specific to the ICU). There were 284 drug-related CIs, 76% (95% confidence interval 71%-81%) of minor, 19% of moderate and 5% of major severity. A total of 24 CIs were potentially life threatening (if not detected). Some 27% of CIs were intercepted, 17% before preparation and 10% before administration of the drug to the patient. There was a negative correlation between median delay (from CI to detection) and mean severity of the different drug classes involved (P = 0.027). As to the impact on quality, 46 CIs were followed by system changes and 63% (95% confidence interval 49%-77%) of these CIs were of minor severity. Examples of system changes are: double checking for potentially harmful drugs, standardised prescription form and contact to the national drug control agency regarding misleading drug labels. CONCLUSION: most of the system changes were based on minor critical incidents which were often detected only after a longer period of time. This shows the value of our "low-threshold" critical incident monitoring. Repeated checks along the drug delivery process (prescription, preparation, administration) are an important means to reduce adverse drug events.