Drug–Drug Interactions (DDIs) Involving Commonly Used ICU Drugs: Prevalence and Clinical Consequences

Critically ill patients admitted to intensive care units (ICUs) are among the most vulnerable populations in modern healthcare due to the severity of illness, frequent organ dysfunction, and the need for complex pharmacological management. The cornerstone of ICU therapy often includes vasopressors to maintain hemodynamic stability, sedatives and analgesics to facilitate mechanical ventilation and patient comfort, and broad-spectrum antimicrobials to manage severe infections and sepsis [1–3]. While these medications are life-saving, their concurrent administration places ICU patients at a substantially increased risk of drug–drug interactions (DDIs).

Polypharmacy is nearly universal in the ICU, with studies reporting that critically ill patients are exposed to a median of 10–15 medications during their ICU stay [4,5]. This extensive drug exposure, combined with altered pharmacokinetics and pharmacodynamics resulting from critical illness—such as hepatic and renal dysfunction, hypoalbuminemia, capillary leak, and altered drug metabolism—creates a fertile ground for clinically significant DDIs [6,7]. Importantly, DDIs in the ICU are not merely theoretical concerns but have been associated with serious adverse drug events, therapeutic failure, prolonged ICU stays, and increased mortality [8,9].

DDIs are broadly classified into pharmacokinetic interactions, which affect drug absorption, distribution, metabolism, or excretion, and pharmacodynamic interactions, which result from additive, synergistic, or antagonistic effects at the site of action [10]. In the ICU context, pharmacodynamic interactions are particularly concerning. For example, the combined use of sedatives and opioids may lead to excessive central nervous system depression and respiratory compromise, while interactions between vasopressors and certain antimicrobials may precipitate arrhythmias, QT prolongation, or unpredictable hemodynamic responses [11–13].

Vasopressors such as norepinephrine, epinephrine, vasopressin, dopamine, and phenylephrine are routinely administered in septic shock and other forms of circulatory failure [14]. Their effects on vascular tone and cardiac output may be potentiated or attenuated by concomitant sedatives, anesthetic agents, and antimicrobials, particularly those affecting adrenergic signaling or cardiac conduction [15]. Similarly, sedatives commonly used in ICUs—including propofol, benzodiazepines, dexmedetomidine, and opioids—are known to interact with cytochrome P450 enzymes and may alter the metabolism of concurrently administered antimicrobials, leading to either subtherapeutic exposure or drug toxicity [16,17].

Antimicrobials represent another major contributor to DDIs in ICU settings. Broad-spectrum antibiotics, antifungals, and antivirals are frequently initiated empirically and later modified based on microbiological results [18]. Agents such as macrolides, fluoroquinolones, azole antifungals, and certain antivirals are well recognized for their potential to cause clinically significant DDIs through enzyme inhibition, QT prolongation, or additive organ toxicity [19–21]. When combined with vasopressors or sedatives, these interactions may exacerbate cardiovascular instability, neurotoxicity, or renal impairment, particularly in critically ill patients with limited physiological reserve [22].

Despite growing awareness of the problem, the reported prevalence of DDIs in ICU patients varies widely across studies, ranging from 20% to over 80%, depending on study design, patient population, and the method used to identify interactions [23–25]. Many studies rely on electronic interaction-checking databases, which may overestimate clinically relevant DDIs by identifying potential rather than actual harmful interactions [26]. Conversely, studies based solely on documented adverse drug events may underestimate the true burden of DDIs due to underreporting or lack of systematic surveillance [27]. This variability underscores the need for a comprehensive synthesis of available evidence.

Moreover, while individual studies have suggested an association between DDIs and adverse clinical outcomes—such as increased mortality, prolonged mechanical ventilation, longer ICU length of stay, and higher healthcare costs—the strength and consistency of these associations remain unclear [28–30]. To date, no comprehensive systematic review and meta-analysis has specifically focused on DDIs involving vasopressors, sedatives, and antimicrobials—the three most commonly co-administered and clinically critical drug classes in ICU practice.

Therefore, the present systematic review and meta-analysis was undertaken to address this knowledge gap. The primary objective was to estimate the prevalence of clinically significant DDIs involving commonly used ICU drugs, specifically vasopressors, sedatives, and antimicrobials. The secondary objective was to evaluate the association between these DDIs and adverse clinical outcomes, including mortality, ICU length of stay, and drug-related complications. By synthesizing available evidence, this study aims to inform clinical practice, support safer prescribing strategies, and highlight the importance of proactive DDI monitoring in critically ill patients.

Study Selection

The database search from inception to January 2025 identified 2,846 records. After removal of 612 duplicates, 2,234 records were screened by title and abstract. Of these, 186 articles were retrieved for full-text assessment. Following full-text review, 38 studies met the inclusion criteria and were included in the systematic review. Among these, 29 studies provided sufficient quantitative data for inclusion in the meta-analysis.

Characteristics of Included Studies

The 38 included studies were published between 2003 and 2024 and comprised a total of 47,892 ICU patients. Most studies were observational in design, including prospective cohort (n = 14), retrospective cohort (n = 16), and cross-sectional studies (n = 8). The majority were conducted in mixed medical–surgical ICUs. Drug–drug interactions were identified using electronic interaction databases in 26 studies, clinical pharmacist assessment in 9 studies, and a combination of both methods in 3 studies.

Table 1. Characteristics of Included Studies (n = 38)

Prevalence of Drug–Drug Interactions

Across the included studies, the reported prevalence of clinically significant DDIs ranged from 22.4% to 82.6%. Meta-analysis of 29 studies demonstrated a pooled prevalence of DDIs of 54.7% (95% CI: 48.9–60.3) among ICU patients. Substantial heterogeneity was observed (I² = 89%).

Sedative–antimicrobial interactions were the most frequently reported (41.2%), followed by antimicrobial–vasopressor interactions (32.5%) and sedative–vasopressor interactions (26.3%). Pharmacodynamic interactions accounted for 61.8% of reported DDIs, while pharmacokinetic interactions accounted for 38.2%.

Table 2. Pooled Prevalence of Drug–Drug Interactions by Drug Class

Clinical Consequences of Drug–Drug Interactions

Mortality

Seventeen studies evaluated the association between DDIs and mortality. Meta-analysis demonstrated that the presence of clinically significant DDIs was associated with a 48% increase in ICU or in-hospital mortality (pooled OR: 1.48; 95% CI: 1.22–1.79; I² = 64%).

ICU Length of Stay

Fourteen studies reported ICU length of stay. Patients exposed to DDIs had a significantly prolonged ICU stay, with a pooled mean difference of 3.1 days (95% CI: 1.9–4.3 days; I² = 58%).

Adverse Drug Events

Adverse drug events (ADEs) attributable to DDIs were reported in 19 studies. The most common events included hypotension, QT prolongation, arrhythmias, excessive sedation, and acute kidney injury. DDIs were associated with a 2.12-fold increased risk of ADEs (OR: 2.12; 95% CI: 1.65–2.72; I² = 71%).

Table 3. Association Between DDIs and Clinical Outcomes

Subgroup Analyses

Subgroup analysis revealed a higher prevalence of DDIs in adult ICUs (56.9%) compared with pediatric ICUs (38.7%). Studies using electronic interaction databases reported higher DDI prevalence (62.4%) compared with those relying on clinical assessment alone (34.6%). Antimicrobial-related DDIs were more strongly associated with mortality than sedative- or vasopressor-related interactions.

Sensitivity Analysis and Publication Bias

Sensitivity analyses excluding studies with high risk of bias did not significantly alter pooled estimates for prevalence or outcomes. Funnel plot inspection suggested mild asymmetry for prevalence studies; however, Egger’s test did not indicate significant publication bias (p = 0.18).

Risk of Bias Assessment

Using the Newcastle–Ottawa Scale, 21 studies were judged to be at low risk of bias, 13 at moderate risk, and 4 at high risk. Common limitations included lack of adjustment for confounders and variability in DDI definitions.

Table 4. Risk of Bias Summary (Newcastle–Ottawa Scale)

This systematic review and meta-analysis demonstrate that DDIs involving vasopressors, sedatives, and antimicrobials are highly prevalent in ICU settings and are associated with significantly increased mortality, prolonged ICU stay, and higher risk of adverse drug events.

Figure 2. Forest Plot Showing Association Between Drug–Drug Interactions and Mortality in ICU Patients

The present systematic review and meta-analysis demonstrates that drug–drug interactions (DDIs) involving commonly used intensive care unit (ICU) medications—vasopressors, sedatives, and antimicrobials—are highly prevalent and clinically consequential. The pooled prevalence of clinically significant DDIs of approximately 55% underscores the magnitude of this problem in critically ill patients, who are routinely exposed to complex multidrug regimens. This finding is consistent with earlier observational studies reporting DDI prevalence ranging from 25% to over 80% in ICU populations, although direct comparisons across studies have been limited by heterogeneity in definitions and detection methods [23–25]. The high prevalence observed in the present analysis likely reflects both the intensity of pharmacotherapy in the ICU and the cumulative effect of physiological derangements associated with critical illness.

The predominance of sedative–antimicrobial and antimicrobial–vasopressor interactions observed in this review aligns with prior reports highlighting antimicrobials as major contributors to clinically relevant DDIs in the ICU [19–21]. Agents such as macrolides, fluoroquinolones, and azole antifungals are well recognized for their potential to inhibit cytochrome P450 enzymes and prolong the QT interval, thereby increasing the risk of arrhythmias and drug toxicity when co-administered with vasoactive or sedative agents [11,12,19]. The high proportion of pharmacodynamic interactions identified in the included studies further emphasizes that DDIs in the ICU are not limited to metabolic interference but frequently involve additive or synergistic effects on cardiovascular and central nervous system function [10,13].

Importantly, this meta-analysis demonstrates a significant association between DDIs and adverse clinical outcomes. Patients exposed to clinically significant DDIs had a 48% higher risk of mortality, a finding that corroborates earlier single-center and multicenter studies reporting increased mortality among ICU patients experiencing adverse drug events related to DDIs [8,28]. While causality cannot be definitively established due to the observational nature of most included studies, the consistency of this association across diverse ICU settings strengthens the biological plausibility of DDIs contributing to worse outcomes. Potential mechanisms include hemodynamic instability due to additive vasodilatory or negative inotropic effects, excessive sedation leading to prolonged mechanical ventilation, and antimicrobial treatment failure resulting from altered drug exposure [15,17,22].

The observed increase in ICU length of stay among patients with DDIs is also clinically meaningful. A pooled prolongation of ICU stay by approximately three days has important implications for patient morbidity, healthcare costs, and ICU resource utilization. Similar findings have been reported in prior studies, which attributed longer ICU stays to delayed recovery from drug-related complications, prolonged mechanical ventilation, and the need for additional monitoring or therapeutic interventions [16,29]. These data highlight that the impact of DDIs extends beyond immediate adverse events and may influence the overall trajectory of critical illness.

Substantial heterogeneity was noted across studies, particularly in prevalence estimates. This heterogeneity likely reflects differences in patient populations, ICU case-mix, prescribing practices, and methods used to identify DDIs. Studies relying on electronic interaction-checking databases consistently reported higher prevalence rates than those based on clinically observed adverse events, a discrepancy also noted in previous reviews [26,27]. While electronic systems are valuable for early detection, they may overestimate clinically relevant DDIs by identifying potential interactions that do not manifest in harm. Conversely, reliance solely on clinical documentation may underestimate the true burden due to underrecognition and underreporting. This variability underscores the need for standardized definitions and clinically meaningful classification of DDIs in ICU research.

The findings of this review have important implications for clinical practice. The high prevalence and demonstrated association with adverse outcomes support recommendations for proactive medication surveillance in ICUs, including the integration of clinical pharmacists into multidisciplinary care teams and the use of real-time decision-support systems [30]. Previous interventional studies have shown that pharmacist-led medication reviews can reduce the incidence of clinically significant DDIs and improve patient safety, lending further support to these strategies [9,30]. Additionally, heightened awareness of high-risk drug combinations—particularly those involving QT-prolonging antimicrobials, sedatives, and vasoactive agents—may facilitate more judicious prescribing and closer monitoring.

Several limitations should be acknowledged. Most included studies were observational and subject to residual confounding, limiting causal inference. Variability in DDI definitions and outcome reporting contributed to heterogeneity and may have influenced pooled estimates. Furthermore, pediatric ICUs were underrepresented, limiting generalizability to this population. Despite these limitations, the large cumulative sample size and consistent direction of effect across studies strengthen the validity of the findings.

In deduction, this systematic review and meta-analysis provides robust evidence that DDIs involving vasopressors, sedatives, and antimicrobials are common in ICU settings and are associated with increased mortality, prolonged ICU stay, and higher risk of adverse drug events. These findings reinforce the need for systematic approaches to DDI prevention, early detection, and management as integral components of safe and effective critical care pharmacotherapy.

This systematic review and meta-analysis demonstrates that drug–drug interactions involving commonly used ICU medications—vasopressors, sedatives, and antimicrobials—are highly prevalent and clinically significant. These interactions are associated with increased mortality, prolonged ICU length of stay, and a higher risk of adverse drug events in critically ill patients. The findings highlight the critical need for proactive identification and management of high-risk drug combinations in ICU settings. Integration of multidisciplinary medication review, clinical pharmacist involvement, and robust electronic decision-support systems may substantially reduce the burden of harmful DDIs and improve patient safety and outcomes in critical care practice.

1.       Vincent JL, Singer M. Critical care: advances and future perspectives. Lancet. 2010;376(9749):1354–1361.

2.       Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock. Intensive Care Med. 2017;43(3):304–377.

3.       Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult ICU patients. Crit Care Med. 2018;46(9):e825–e873.

4.       Cullen DJ, Sweitzer BJ, Bates DW, Burdick E, Leape LL. Preventable adverse drug events in hospitalized patients: a comparative study. J Gen Intern Med. 1997;12(7):459–465.

5.       Reis AMM, Cassiani SHB. Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol. 2011;67(6):625–632.

6.       Blot SI, Pea F, Lipman J. The effect of altered renal function on antimicrobial dosing in critically ill patients. Clin Pharmacokinet. 2014;53(9):871–885.

7.       Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509.

8.       Kane-Gill SL, Kirisci L, Verrico MM, Rothschild JM. Analysis of risk factors for adverse drug events in critically ill patients. Crit Care Med. 2012;40(3):823–828.

9.       Leape LL, Cullen DJ, Clapp MD, et al. Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. JAMA. 1999;282(3):267–270.

10.   Baxter K, Preston CL, editors. Stockley’s Drug Interactions. 11th ed. London: Pharmaceutical Press; 2016.

11.   Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479–487.

12.   Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013–1022.

13.   Pergolizzi JV Jr, Raffa RB, Taylor R Jr, et al. Opioid pharmacology. Pain Pract. 2015;15(5):401–418.

14.   Dünser MW, Hasibeder WR. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med. 2009;24(5):293–316.

15.   De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779–789.

16.   Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186(8):724–731.

17.   Wunsch H, Kahn JM, Kramer AA, Rubenfeld GD. Use of sedatives and analgesics in mechanically ventilated patients. Am J Respir Crit Care Med. 2009;180(5):456–462.

18.   Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–2329.

19.   Owens RC Jr, Nolin TD. Antimicrobial-associated QT interval prolongation. Clin Infect Dis. 2006;43(12):1603–1611.

20.   Brüggemann RJM, Alffenaar JWC, Blijlevens NMA, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48(10):1441–1458.

21.   Polasek TM, Lin FP, Miners JO, Doogue MP. Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity. Drug Metab Rev. 2011;43(3): 363–386.

22.   Pai MP, Lodise TP. Body weight considerations for antimicrobial dosing in the ICU. Crit Care Med. 2011;39(2):256–262.

23.   Lima REF, Cassiani SHB. Potential drug interactions in intensive care patients at a teaching hospital. Rev Lat Am Enfermagem. 2009;17(2):222–227.

24.   Smithburger PL, Kane-Gill SL, Seybert AL. Drug–drug interactions in the medical intensive care unit. Crit Care Med. 2012;40(1): 203–209.

25.   Reis AMM, de Araújo Oliveira A, Ferreira E, et al. Prevalence and significance of drug–drug interactions in ICU patients. Clin Ther. 2013;35(4): 563–570.

26.   Vonbach P, Dubied A, Krähenbühl S, Beer JH. Evaluation of frequently used drug interaction screening programs. Pharm World Sci. 2008;30(4):367–374.

27.   Classen DC, Pestotnik SL, Evans RS, Burke JP. Computerized surveillance of adverse drug events in hospital patients. JAMA. 1991;266(20):2847–2851.

28.   Moura CS, Acurcio FA, Belo NO, et al. Drug–drug interactions associated with length of stay and cost of hospitalization. J Pharm Pharm Sci. 2009;12(3):266–272.

29.   Bond CA, Raehl CL. Clinical pharmacy services, pharmacy staffing, and hospital mortality rates. Pharmacotherapy. 2007;27(4):481–493.

30.   Rivkin A, Yin H. Evaluation of the role of the critical care pharmacist in identifying and preventing drug–drug interactions. Pharmacotherapy. 2011;31(7):667–675.