High preoperative plasma neopterin predicts delirium after cardiac surgery in older adults.

OBJECTIVES: To examine the association between plasma levels of pterins and amino acids and postoperative delirium. DESIGN: Prospective cohort study. SETTING: Cardiothoracic service in an university hospital in Rotterdam, the Netherlands. PARTICIPANTS: One hundred twenty-five individuals aged 70 and older undergoing elective cardiac surgery. MEASUREMENTS: Plasma pterins and amino acids were measured pre- and postoperatively. Using multiple logistic regression analyses, the associations between pterins and amino acid levels and postoperative delirium were examined in relation to age, sex, comorbidity, cognitive functioning (Mini-Mental State Examination (MMSE) score), and cardiac risk factors. RESULTS: Delirium incidence in the main study group was 31.3%. The preoperative measures associated with delirium were neopterin (odds ratio (OR) = 1.05, P = .009); MMSE score less than 28 (OR = 4.39, P = .001); European System for Cardiac Operative Risk Evaluation score greater than 6 (OR = 2.84, P = .03); and combined coronary artery bypass graft (CABG) and aortic, mitral, or tricuspid valve surgery (OR = 4.32, P = .01). Postoperative measures associated with delirium were neopterin (OR = 3.84, P = .02), homovanillic acid (HVA, OR = 1.01, P = .04), and preoperative MMSE score less than 28 (OR = 3.32, P = .008). CONCLUSION: Preoperatively high neopterin levels predicted delirium after cardiac surgery in older adults, in addition to the well-known risk factors of poor cognitive function, high cardio-surgical risk, and combined CABG and valve surgery. Postoperative neopterin and HVA levels were also found to be associated with delirium, together with preoperative cognitive functioning. Plasma neopterin may be a candidate biomarker for delirium after cardiac surgery in these older adults.

Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-alpha therapy.

Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-alpha (IFN-alpha). Animal studies showed that IFN-alpha administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H(2)O(2) generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-alpha. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-alpha, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-alpha are unlikely to contribute to definite psychiatric disturbance.

Screening methods for delirium: early diagnosis by means of objective quantification of motor activity patterns using wrist-actigraphy.

Delirium after cardiac surgery is a risk factor for adverse outcome and even death. Disturbance of motor activity is a core feature of delirium, but hypoactive delirium often remains unrecognized. We explored wrist-actigraphy as a tool to objectively quantify postoperative recovery of 24-h rest-activity patterns to improve the early recognition of delirium after surgery. Motor activity was recorded by wrist-actigraphy after cardiac surgery in 88 patients over 65 years of age. Patients were assessed daily by using the CAM-ICU. Our final analyses were based on 32 non-delirious patients and 38 patients who were delirious on the first day after surgery. The delirious patients showed lower mean activity levels during the first postoperative night (P<0.05), reduced restlessness during the first day (P<0.05), and a lower mean activity of the 5 h with lowest activity within the first 24 h (P=0.01), as compared to the non-delirious patients. Already at a very early stage after cardiac surgery, a difference in motor activity was observed between patients with and without a delirium. As an unobtrusive method, actigraphy has the potential to be a screening method that may lead to early diagnosis and treatment of delirium.

Disturbed circadian motor activity patterns in postcardiotomy delirium.

AIMS: More than 20% of patients of 65 years or older may develop a delirium after cardiac surgery. Patients with delirium frequently show a disturbed 24-hr motor activity pattern, but objective and quantitative data are scarce. Our aim was to quantify motor activity patterns in elderly patients with or without a postcardiotomy delirium after elective cardiac surgery. METHODS: Wrist-actigraphy was used to quantify 24-hr motor activity patterns for a 5-day period following cardiac surgery in 79 patients of 65 years or older. Clinical state was monitored daily by means of the Confusion Assessment Method-Intensive Care Unit and the Delirium Rating Scale-Revised 98. RESULTS: The activity Amplitude, and the daytime Activity/minute and Restlessness index were significantly higher and the daytime number of Immobility minutes significantly lower for the patients without delirium or with short delirium episodes, as compared to patients with a sustained delirium (>3 days). CONCLUSIONS: Actigraphy proves to be a valuable instrument for evaluating motor activity patterns in relation to clinical state in patients with a postcardiotomy delirium.

Neurotoxic and neuroprotective metabolites of kynurenine in patients with renal cell carcinoma treated with interferon-alpha: course and relationship with psychiatric status.

AIMS: Immunotherapy with interferon-alpha (IFN-alpha) is associated with psychiatric side-effects, including depression. One of the putative pathways underlying these psychiatric side-effects involves tryptophan (TRP) metabolism. Cytokines including IFN-alpha induce the enzyme indoleamine 2,3-dioxygenase (IDO), which converts TRP to kynurenine (KYN), leading to a shortage of serotonin (5-HT). In addition, the production of neurotoxic metabolites of KYN such as 3-hydroxykynurenine and quinolinic acid (QA) might increase and contribute to IFN-alpha-induced psychopathology. In contrast, other catabolites of KYN, such as kynurenic acid (KA), are thought to have neuroprotective properties. METHODS: In a group of 24 patients treated with standard IFN-alpha for metastatic renal cell carcinoma (RCC), combined psychiatric and laboratory assessments were performed at baseline, 4 and 8 weeks, and at 6 months. RESULTS: No psychopathology was observed, despite an increase in neurotoxic challenge as reflected in indices for the balance between neurotoxic and neuroprotective metabolites of KYN. CONCLUSIONS: The present hypothesis that a shift in the balance between neurotoxic and neuroprotective metabolites of KYN underlies the neuropsychiatric side-effects of IFN-alpha-based immunotherapy, is neither supported nor rejected.

Interferon-alpha in oncology patients: fewer psychiatric side effects than anticipated.

Interferon-alpha (IFN-alpha) treatment in both oncological and hepatological settings is associated with depression. If IFN-alpha treatment induces depression in high numbers, it could serve as a model for studying the pathophysiology of depression, in general. The authors therefore studied 43 oncology patients treated with standard or pegylated IFN-alpha with baseline psychiatric assessment and at regular time-points in the first 6 months of treatment. Apart from a severe depression because of brain metastases, authors observed only two clinically relevant depressive states. Contrary to findings in most of the literature, most depressive episodes in this study were self-limiting and short-lasting and were associated with either episodes of flu-like symptoms common at the start of the treatment or with concurrent psychosocial events. In the group as a whole, scores on both observer-based and self-report rating scales did not show clinically relevant changes. The results of this study indicate that IFN-alpha treatment is not suitable as a study model for depression in general.

Interferon-alpha influences tryptophan metabolism without inducing psychiatric side effects.

BACKGROUND: Interferon-alpha (IFN-alpha) treatment is often associated with psychiatric side effects and has been found to lower the amount of tryptophan (TRP) available to the brain. The alterations in tryptophan metabolism might underlie the psychiatric side effects during treatment with IFN-alpha. METHODS: In this study, 43 oncology patients treated with IFN-alpha were included. In order to study de novo depressions, depressed patients at baseline were excluded. Psychiatric evaluation comprising clinical judgment combined with a structured psychiatric interview and observer-based and self-report rating scales was performed at baseline and at 4 weeks, 8 weeks and 6 months after the start of treatment with IFN-alpha, and in the case of emerging psychopathology. Blood samples were drawn at the same evaluation times and assessed for concentrations of TRP, large neutral amino acids, kynurenine, 5-hydroxyindole acetic acid, neopterin and biopterin. RESULTS: During treatment with IFN-alpha, several alterations in laboratory parameters occurred that were consistent with an increased degradation of peripheral TRP. Psychometric ratings revealed hardly any psychiatric changes. No consistent associations were found between changes in the laboratory assessments determined and the diverse psychiatric measures. CONCLUSION: In this study, IFN-alpha was found to alter TRP metabolism without inducing psychiatric side effects. Therefore, a possible relationship between TRP metabolism and depression was not substantiated by this study.