ABSTRACT & COMMENTARY

Can Occurrence of Delirium Be Predicted by Elevated Proinflammatory Cytokines?

By Linda L. Chlan, RN, PhD, FAAN

Dean’s Distinguished Professor of Symptom Management Research, The Ohio State University, College of Nursing

Dr. Chlan reports that she receives grant/research support from Hospira.

This article originally appeared in the April 2014 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor Emeritus, Pulmonary and Critical Care Medicine, University of Washington, Seattle, and Dr. Thompson is Associate Professor of Medicine, University of Washington, Seattle. Drs. Pierson and Thompson report no financial relationships relevant to this field of study.

SYNOPSIS: This observational study of 224 ICU patients who had serial measurements of C-reactive protein found an association between elevated initial levels and development of delirium. The authors also noted increased delirium incidence in patients whose levels increased on serial measurements.

• SOURCE: Zhang Z, et al. Prediction of delirium in critically ill patients with elevated C-reactive protein. J Crit Care 2014;29:88-92.

Delirium is an unfortunate consequence of the ICU stay for many patients hospitalized for a critical illness or injury, occurring in up to 80% of patients depending on target population and assessment methods. In the past, delirium was viewed by clinicians as "something that just happened to ICU patients." However, findings from studies over the past few years have documented the adverse and detrimental influence of delirium on morbidity and mortality in critically ill patients. Numerous factors — including sepsis, metabolic factors, medications, illness severity, alcohol abuse, older age, and inflammation that occurs with critical illness or infection — contribute to the occurrence of delirium. The study by Zhang and colleagues reviewed here aimed to determine if one proinflammatory cytokine, C-reactive protein (CRP), could be used as a predictor for the development of delirium in a sample of ICU patients in China.

A total of 223 patients (54.1% mechanically ventilated) were enrolled in this prospective, observational study from one 24-bed medical-surgical ICU. Patients had a Glasgow Coma Scale score of ≥ 10, a Richmond Agitation Sedation Scale of -3 or higher, and were expected to remain in the ICU for a minimum of 48 hours. Patients with delirium at ICU admission or those with an acute brain injury (stroke, trauma, hemorrhage, or subdural hematoma) were not enrolled. Participants were predominantly male (63%) with a mean age of 57 years. Obtaining CRP levels is a standard of practice on this ICU; levels were obtained on ICU admission and 24 hours later. Nurses received training in administration of the Confusion Assessment Method-ICU, and performed all delirium assessments at ICU admission and every 8 hours each study day. Clinical variables (demographic data, medical diagnosis, illness severity [APACHE II], drinking and cigarette smoking history, application of physical restraints) were abstracted from the medical record. Analyses included change in CRP levels correlated with the clinical variables of illness severity, age, gender, intubation, history of drinking and smoking, use of physical restraints, and length of hospital stay.

The study participants had median APACHE II scores of 13 (inter-quartile range, 9-17), frequently had physical restraints applied (47.8%), with 26.1% known as heavy alcohol users and cigarette smokers. An overall prevalence of delirium was reported at 24.2%. Not surprisingly, delirium was more common in older, mechanically ventilated patients with higher illness severity scores and longer ICU stays. Higher levels of CRP were associated with delirium, in that for every 10 mg/mL increase in CRP from admission, there was a 7% increase in the risk for delirium. Further, patients with higher levels of CRP at ICU admission were more likely to develop delirium during the ICU stay, particularly in those with higher illness severity scores. The investigators concluded that elevated levels of CRP in patients with higher illness severity scores at ICU admission may be predictive of the occurrence of delirium during the ICU stay.

n Commentary

Delirium is an acute event that can fluctuate over the course of an ICU stay. It is complex and there are many clinical and patient-specific factors that are known contributors to this ICU-acquired syndrome. Likewise, inflammation is a very complex biological process that is confounded by critical illness, infectious processes, and medications. This makes it extremely difficult to single out one marker of inflammation given the complex interrelationships among the numerous pro- and anti-inflammatory biomarkers. Many times, these biomarkers exist in extremely miniscule amounts in the blood, while others may not even be detectable depending on the sensitivity and specificity of the assay. However, CRP is a non-specific biomarker of inflammation that increases 10,000-fold in response to stimuli, making it a strong candidate to investigate in the development of delirium when examining inflammatory processes.

Zhang and colleagues reported that changes in CRP from ICU admission resulting in higher levels of this proinflammatory cytokine during the ICU stay were predictive of the development of delirium, particularly in those patients who had higher illness severity scores. This finding is significant in that other investigators have attempted to link inflammatory biomarkers with the development of delirium — findings from these investigations have been inconsistent across studies. The significant findings by Zhang et al may be due to several factors, including expertise in obtaining and interpreting biomarkers (given CRP is routinely obtained for analysis in their ICU) and the careful selection of participants. Further, the investigators recommend serial measurement of CRP, given that changes toward higher levels of CRP were predictive of delirium development in their sample.

This study is limited in that only one proinflammatory cytokine was examined at two collection points. Given that other biomarkers are known to be associated with delirium, the findings from this study provide only a limited snapshot of the contributions of inflammatory biomarkers to the development of delirium. Further, inflammation can fluctuate over the course of critical illness, which supports the investigators’ recommendation to obtain serial measurements of biomarkers over the course of ICU stay. Perhaps intervention strategies to prevent delirium are needed for all ICU patients, with special attention to those patients deemed to be at higher risk for the development of delirium given its significant impact on morbidity and mortality.