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. Intensive care unit (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 24-h rhythms are altered in ICU patients relative to healthy controls by profiling 24-h rhythms in vital signs and plasma metabolites.Methods: We monitored daily rhythms in 5 healthy controls and 5 ICU patients for 24 h. Heart rate and blood pressure were measured every 30 min, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 h. Bedside sound levels were measured every minute. Twenty-four hours rhythms were evaluated in vitals and putatively identified 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 24-h rhythms individually and as a group. While a few ICU patients had significant 24-h 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 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: In this pilot study, ICU patients' 24-h rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients' clinical courses longitudinally. 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.
Highlights
Circadian rhythms span multiple levels of hierarchical organization in biological systems, through molecular processes to whole-body rhythms such as core body temperature [1]
Features with ANOVA q < 0.05 were retained. This reduced the data set from 25,000 identified features to 15,000 features. Since this is still a very large dataset, we explored it with Ingenuity Pathway Analysis (IPA)
Restricting the untargeted metabolomics data from 25,000 features to those that differ between intensive care unit (ICU) patients and healthy controls at the level of q < 0.05 only reduced the data set to 15,000 features. These results indicate that ICU patients have highly disordered metabolism relative to healthy controls
Summary
Circadian rhythms span multiple levels of hierarchical organization in biological systems, through molecular processes (peripheral oscillators) to whole-body rhythms such as core body temperature [1]. It may be beneficial to support circadian rhythms in intensive care unit (ICU) patients [8, 9]. While there is evidence that circadian rhythms are disrupted in the critically ill, the etiology is complex and multifaceted [10]. Intensive care unit (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 24-h rhythms are altered in ICU patients relative to healthy controls by profiling 24-h rhythms in vital signs and plasma metabolites
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