Metabolomics identifies circadian desynchronization and distinct intra-patient variability patterns in critical illness

Abstract

Background: Synchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. ICU patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if circadian rhythms are altered in ICU patients relative to healthy controls by profiling circadian rhythms in vital signs and plasma metabolites. Methods: We monitored circadian rhythms in 5 healthy controls and 5 ICU patients for 24 hours. Heart rate and blood pressure were measured every 30 minutes, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 hours. Bedside sound levels were measured every minute. Circadian rhythms were evaluated in vitals and plasma metabolites individually and in each group using the cosinor method. Results: ICU patient rooms were significantly louder than healthy controls’ rooms and average noise levels were above EPA recommendations. Healthy controls generally had significant circadian rhythms individually and as a group. While a few ICU patients had significant circadian rhythms in isolated variables, no significant rhythms were identified in ICU patients as a group, except in cortisol. This indicates a lack of coherence in circadian phases and amplitudes among ICU patients. Finally, principal component analysis of metabolic profiles showed surprising patterns in plasma sample clustering. Each ICU patient’s samples were clearly discernable in individual clusters, separate from a single cluster of healthy controls. Conclusions: ICU patients’ circadian rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients. Our results show global disordering of metabolism and the circadian system in ICU patients which should be characterized further in order to determine implications for patient care.