According to the ISMP, HAMs carry a higher risk of patient harm compared with ordinary drugs [7]. Even when used as prescribed, they significantly increase the risk of drug-related problems [11]. In our study, 81% of critically ill children received at least one drug defined as HAM for pediatric patients by Schilling et al. [6]. Potassium salts, midazolam, and vancomycin were the HAMs most frequently administered. This is in line with a previous study in a pediatric emergency setting reporting that 91% of patients were prescribed at least one HAM, with potassium salts being the most frequently administered [12].

It is widely known that pDDIs are highly prevalent in PICUs. They are associated with various factors, such as a high number of administered drugs, a complex chronic condition, or an increased length of hospitalization [4, 13, 14]. Although previous studies determined pDDI as a cause of drug-related problems with HAM for pediatric patients, there is only limited knowledge about the frequency of pDDIs in pediatric intensive care [6, 8, 10]. In our study, we found more than 20,000 pDDIs involving HAM in 256 pediatric patients over the 1-year study period. A previous Brazilian study of adult intensive care patients reported 846 HAM-related pDDIs in 60 patients [15]. Compared with our research, the Brazilian study reported a considerably lower rate of HAM-related pDDIs per patient (79 versus 14). Part of this difference may be explained by the fact that pediatric patients requiring intensive care are more susceptible to drug–drug interactions [16]. However, it may also be related to the fact that the Brazilian study was performed on the basis of the database Micromedex 2.0 only [15]. Several studies recommended using at least two databases to determine pDDIs in daily routine [17,18,19]. Thus, we used the two databases, UpToDate and drugs.com, to avoid underestimating any potential risks. However, since the concordance between different databases is limited, comparing various studies can be challenging [20, 21].

For 2830 pDDIs, we observed 3203 symptoms occurring after the administration of the potentially interacting drug pairs. More than one in four detected symptoms were eventually associated with a DDI. Those interaction-associated symptoms comprised eight specific symptoms, mainly hemodynamic alterations or electrolyte and fluid balance disturbances. These symptoms were frequently reported in previous pediatric intensive care studies [3, 22,23,24]. The study presented here shows that DDI involving HAM should be considered a likely trigger for symptoms in addition to other factors, such as the underlying disease or non-drug treatments, such as surgeries. It can also be assumed that various factors contribute to the occurrence of a symptom. When identifying DDIs and following interaction-associated symptoms, we did not distinguish between different severity grades of DDI or symptoms, as the main aim of our study was to identify drug pairs that are frequently associated with symptoms that are considered clinically relevant by the responsible physicians and nurses. Physicians usually receive a considerable number of alerts when using a database-related interaction checker. This may quickly lead to over-alerting. Therefore, we aimed to provide physicians with a concise overview of clinically relevant DDIs that occur frequently in a PICU. Our findings could be implemented in commonly used database-related interaction checkers to draw physicians’ attention to drug pairs involving HAM that are potentially associated with an increased risk of adverse events.

We identified eight specific drug pairs composed of eight different drugs that may lead to an increased risk of interaction-associated symptoms. By calculating the OR for a DDI and a respective symptom, we took into account how often a symptom was observed on patient days when the interacting drug pair was administered compared with days when the respective drug pair was not administered. In particular, this should minimize the risk that certain combinations of DDI and symptoms are over- or underestimated. For the interaction of fentanyl and furosemide, we found the highest OR for the symptom of decreased blood pressure. Both drugs have been shown to belong to the top ten of the most frequently administered drugs and to be among the drugs most commonly involved in pDDIs in the pediatric intensive care setting [4]. In our study, DDI was associated with a potential fivefold increased risk of decreased blood pressure. The second highest OR, indicating a potential fourfold increased risk, was found for the interaction of digoxin with hydrochlorothiazide and the observed symptom of hypokalemia. Consequently, when the administration of drug pairs associated with a potentially increased risk of interaction-associated symptoms is unavoidable, patients should be closely monitored for potential symptoms.

Until now, few studies have dealt with interaction-associated symptoms in the pediatric intensive care setting [14, 25, 26]. One of those studies only focused on cytochrome P450-mediated drug–drug interactions [25]. Two other studies concentrated on symptoms on the basis of clinical monitoring and laboratory results, as we did in our research. Both studies also identified hemodynamic alterations and electrolyte and fluid balance disturbances as symptoms following DDIs. However, neither of those studies noted specific interactions that increased the risk of the detected symptoms [14, 26]. Our study went one step further by revealing eight interacting drug pairs that may increase the risk of the identified interaction-associated symptoms in clinical practice. We found symptoms that are widely known to follow the respective DDI, such as the association of hyponatremia with the DDI of potassium salts and furosemide, or the increased risk for hypokalemia associated with the DDI of digoxin and furosemide. However, we also observed symptoms after a DDI that we did not expect. For example, we unexpectedly found that the DDI of fentanyl and furosemide was associated with a potential risk increase for urinary retention, or that the DDI of vancomycin and furosemide was associated with edema. Especially for symptoms that unexpectedly are observed after a specific DDI, other factors, such as the state of illness or a surgery that could also lead to the symptom, should be critically evaluated.

Some limitations have to be considered when interpreting our study results. First of all, the relevance of some drugs administered in our study can vary in different PICUs around the world. However, the 15 drugs defined as HAM that were in the focus of our study are used in many PICUs worldwide [4, 27,28,29,30,31].

As recommended by previous studies [17,18,19], we used two databases to prevent failure to detect interactions that could lead to interaction-associated symptoms. However, we could not identify a database specializing in DDI for pediatrics. Previous studies did not find an age-related trend in the magnitude of DDIs, although it should be noted that there are insufficient data for children under 2 years of age [32, 33]. In addition, extrapolating data from adults to children may over- or underestimate the severity of DDIs [34]. Additionally, as most databases are limited to the information on the interactions of two drugs, potential synergistic or antagonistic effects of combinations consisting of three or more drugs might be overlooked.

Furthermore, the allowed maximum time interval of 24 h between the administration of two drugs may be too long for an interaction for some drug pairs. According to a previous review by Bakker et al., the optimal time interval would consider the half-lives of interacting drugs [21]. However, due to the developmental variability of pharmacokinetics and pharmacodynamics in children, it is very challenging to determine standardized drug half-lives in the pediatric population [35]. In addition, the individual patients’ conditions, such as renal function, can also have significant influence on drugs’ half-lives [36]. In addition, a constant plasma concentration is aimed for with many drugs, which is why a longer-lasting interaction potential can be assumed, although the half-lives of the individual drugs are varying. To ensure a standardized approach for evaluating DDI, we established a 24-h time interval as described in the review by Bakker et al. if consideration of drug half-lives is not feasible [21]. This methodological approach might potentially increase the risk of overestimation.

The retrospective design is another limitation of this study, as using nurses’ and physicians’ daily documentation entails the risk of missing data. That could lead to information bias, as the documentation was not primarily compiled to answer research questions. Consequently, using the patient documentation as data basis may have an impact on the identification of symptoms themselves, and on the observed associations between interacting drugs pairs and subsequent symptoms. Furthermore, due to the retrospective design, we could not assess whether the physicians accepted certain expectable symptoms as an inevitable consequence of the chosen drug therapy because the patient’s state of health required the administration.

In addition, it should be kept in mind that the administration of a HAM alone and the underlying disease may also increase the risk of adverse events. However, we focused on acknowledged DDIs and interaction-associated symptoms reported in established databases. We endeavored to identify symptoms prone to being associated with a DDI by calculating ORs, as those interactions potentially contribute to evoking symptoms, or to prolonging or exacerbating existing symptoms. These drug combinations should therefore be given special consideration in the routine care of critically ill pediatric patients who are already at risk.