Medication Effects on Heart Rate Variability in Critical Illness: The Overlooked Confounder

Abstract

Heart rate variability (HRV) reflects autonomic nervous system function and has emerged as a potential noninvasive biomarker for early detection of physiologic deterioration in critical illness. HRV-based prediction models show promise; however, translation into routine ICU practice has been limited. A major barrier is the insufficient characterization of medication effects on HRV. Pharmacologic agents commonly used in critical care, including vasopressors, steroids, and antiarrhythmics, can directly or indirectly alter autonomic tone, yet existing studies rarely account for these influences. As a result, medication-induced HRV changes may represent meaningful therapeutic response or misleading confounding noise, complicating interpretation. Current studies do not adequately account for medication exposure when evaluating HRV in critical illness. We outline research priorities focused on quantifying medication effects, integrating medication exposure into predictive modeling, evaluating HRV as a marker of treatment response, and determining the utility of HRV as a treatment target.

Keywords: critical care; heart rate variability; medications; sepsis; shock.

Figure 1.

Directed acyclic graph of causal and moderating pathways in a simplified clinical scenario of a patient with septic shock on vasopressor therapy. Sepsis and comorbidities affect the autonomic nervous system (ANS), which, in turn, affects heart rate variability (HRV), which is associated with patient outcomes. Adding vasopressor medications complicates these interactions: vasopressors have their own independent effects on the ANS but may also moderate the effects of the ANS on HRV and the association between HRV and patient outcomes. This simple example highlights one acute problem and one medication class; the causal relationships become more complex with addition of fluid resuscitation, antibiotics, sedatives, corticosteroids, and other medications commonly administered to critically ill patients.