Drug-Drug Interactions Involving High-Alert Medications that Lead to Interaction-Associated Symptoms in Pediatric Intensive Care Patients: A Retrospective Study.

BACKGROUND: Children treated in a pediatric intensive care unit (PICU) often receive several drugs together, among them drugs defined as high-alert medications (HAMs). Those drugs carry a high risk of causing patient harm, for example, due to a higher potential for interactions. HAMs should therefore be administered with caution, especially in a PICU. OBJECTIVES: The objective of the current study was to identify drug-drug interactions involving HAMs that increase the risk of interaction-associated symptoms in pediatric intensive care. METHODS: In a retrospective study, we analyzed the electronic documentation of patients hospitalized for at least 48 h in a general PICU who received at least two different drugs within a 24-h interval. We assessed potential drug-drug interactions involving HAM on the basis of the two drug information databases UpToDate and drugs.com. Furthermore, we analyzed whether symptoms were observed after the administration of drug pairs that could lead to interaction-associated symptoms. For drug pairs involving HAM administered on at least 2% of patient days, and symptoms observed at least ten times after a respective drug pair, we calculated odds ratios, 95% confidence intervals, and p-values by using a univariate binary logistic regression. RESULTS: Among 315 analyzed patients, 81.3% (256/315) received drugs defined as high-alert medication for pediatric patients. Those high-alert medications were involved in 20,150 potential drug-drug interactions. In 14.0% (2830/20,150) of these, one or more symptoms were observed that could be a possible consequence of the interaction, resulting in 3203 observed symptoms affecting 56.3% (144/256) of patients receiving high-alert medication. The odds ratios for symptoms observed after a drug-drug interaction were increased for eight specific symptoms (each p ≤ 0.05), especially hemodynamic alterations and disturbances of electrolyte and fluid balance. The odds ratio was highest for decreased blood pressure observed after the administration of the drug pair fentanyl and furosemide (OR 5.06; 95% confidence interval 3.5-7.4; p < 0.001). Increased odds ratios for specific symptoms observed after drug-drug interactions resulted from eight combinations composed of eight different drugs: digoxin, fentanyl, midazolam, phenobarbital, potassium salts and vancomycin (high-alert medications), and the diuretics furosemide and hydrochlorothiazide (non-high-alert medications). The resulting drug pairs were: potassium salts-furosemide, fentanyl-furosemide, vancomycin-furosemide, digoxin-furosemide, digoxin-hydrochlorothiazide, fentanyl-phenobarbital, potassium salts-hydrochlorothiazide, and midazolam-hydrochlorothiazide. CONCLUSIONS: In a cohort of PICU patients, this study identified eight specific drug pairs involving high-alert medications that may increase the risk of interaction-associated symptoms, mainly hemodynamic alterations and electrolyte/fluid balance disturbances. If the administration of those drug pairs is unavoidable, patients should be closely monitored.

Intensive care drug therapy and its potential adverse effects on blood pressure and heart rate in critically ill children.

BACKGROUND: Owing to complex treatment, critically ill children may experience alterations in their vital parameters. We investigated whether such hemodynamic alterations were temporally and causally related to drug therapy. METHODS: In a university pediatric intensive care unit, we retrospectively analyzed hemodynamic alterations defined as values exceeding the limits set for heart rate (HR) and blood pressure (BP). For causality assessment, we used the World Health Organization-Uppsala Monitoring Center (WHO-UMC) system, which categorizes the probability of causality as "certain," "probable," "possible," and "unlikely." RESULTS: Of 315 analyzed patients with 43,200 drug prescriptions, 59.7% experienced at least one hemodynamic alteration; 39.0% were affected by increased HR, 19.0% by decreased HR, 18.1% by increased BP, and 16.2% by decreased BP. According to drug information databases, 83.9% of administered drugs potentially lead to hemodynamic alterations. Overall, 88.3% of the observed hemodynamic alterations had a temporal relation to the administration of drugs; in 80.2%, more than one drug was involved. Based on the WHO-UMC system, a drug was rated as a "probable" causing factor for only 1.4% of hemodynamic alterations. For the remaining alterations, the probability ratings were lower because of multiple potential causes, e.g., several drugs. CONCLUSIONS: Critically ill children were frequently affected by hemodynamic alterations. The administration of drugs with potentially adverse effects on hemodynamic parameters is often temporally related to hemodynamic alterations. Hemodynamic alterations are often multifactorial, e.g., due to administering multiple drugs in rapid succession; thus, the influence of individual drugs cannot easily be captured with the WHO-UMC system.

Adverse Drug Reactions at Nonelective Hospital Admission in Children and Adolescents: Comparison of 4 Causality Assessment Methods.

OBJECTIVES: This study aimed to compare assessment methods to determine adverse drug reactions (ADRs) at nonelective hospital admission in pediatric patients, to investigate the interrater reliability of assessment methods in pediatric care, and to analyze symptoms related to ADRs and (suicidal) drug intoxications. METHODS: For 1 year, the medical records of nonelective patients admitted to a university pediatric department were evaluated for potential ADRs using 4 assessments methods by 1 experienced rater. Krippendorff α was calculated from a sample of 14 patients evaluated by 4 experienced raters to determine interrater reliability. RESULTS: In 1831 nonelective hospital admissions, 63.4% (1161 of 1831) of patients had received at least one drug before admission. We found a potential causal relationship between drugs and symptoms documented at admission and thus potential ADRs according to Naranjo in 23.3% (271 of 1161) of those patients, World Health Organization - Uppsala Monitoring Centre (WHO-UMC) in 22.5% (261 of 1161), Koh in 21.7% (252 of 1161), and Begaud in 16.5% (192 of 1161). The probability rating of the potential causal relationships varied considerably between the methods (Naranjo-Begaud, P < 0.01; Naranjo-Koh, P < 0.001; Koh-Begaud, P < 0.01; Begaud-WHO-UMC, P < 0.01). Acceptable interrater reliability (α ≥ 0.667) was only obtained for WHO-UMC (α = 0.7092). The most frequently identified definite ADR was sedation in 1.5% of all nonelective patients with medication before hospital admission. In 1.2% (22 of 1831) of all nonelective admissions, we found drug intoxications with suicidal intent. CONCLUSIONS: The assessment methods showed a high variability in the determination of a potential causal relationship between drug and documented symptom, in the classification of the probability of ADRs, and suboptimal interrater reliability. Thus, their feasibility in pediatric patients is limited.