Serum proteomic analysis in esophagectomy patients with postoperative delirium: A case-control study.

BACKGROUND: Postoperative delirium occurs in up to 80% of patients undergoing esophagectomy. We performed an exploratory proteomic analysis to identify protein pathways that may be associated with delirium post-esophagectomy. OBJECTIVES: Identify proteins associated with delirium and delirium severity in a younger and higher-risk surgical population. METHODS: We performed a case-control study using blood samples collected from patients enrolled in a negative, randomized, double-blind clinical trial. English speaking adults aged 18 years or older, undergoing esophagectomy, who had blood samples obtained were included. Cases were defined by a positive delirium screen after surgery while controls were patients with negative delirium assessments. Delirium was assessed using Richmond Agitation Sedation Scale and Confusion Assessment Method for the Intensive Care Unit, and delirium severity was assessed by Delirium Rating Scale-Revised-98. Blood samples were collected pre-operatively and on post-operative day 1, and discovery proteomic analysis was performed. Between-group differences in median abundance ratios were reported using Wilcoxon-Mann-Whitney Odds (WMWodds1) test. RESULTS: 52 (26 cases, 26 controls) patients were included in the study with a mean age of 64 (SD 9.6) years, 1.9% were females and 25% were African American. The median duration of delirium was 1 day (IQR: 1-2), and the median delirium/coma duration was 2.5 days (IQR: 2-4). Two proteins with greater relative abundance ratio in patients with delirium were: Coagulation factor IX (WMWodds: 1.89 95%CI: 1.0-4.2) and mannosyl-oligosaccharide 1,2-alpha-mannosidase (WMWodds: 2.4 95%CI: 1.03-9.9). Protein abundance ratios associated with mean delirium severity at postoperative day 1 were Complement C2 (Spearman rs = -0.31, 95%CI [-0.55, -0.02]) and Mannosyl-oligosaccharide 1,2-alpha-mannosidase (rs = 0.61, 95%CI = [0.29, 0.81]). CONCLUSIONS: We identified changes in proteins associated with coagulation, inflammation, and protein handling; larger, follow-up studies are needed to confirm our hypothesis-generating findings.

Association between Change in the peripheral biomarkers of inflammation, astrocyte activation, and neuroprotection at one week of critical illness and hospital mortality in patients with delirium: A prospective cohort study.

OBJECTIVE: In critically ill adults with delirium, biomarkers of systemic inflammation, astrocyte activation, neuroprotection, and systemic inflammation measured at one week of critical illness may be associated with mortality. DESIGN: Prospective observational study. SETTING: Intensive care unit (ICU). PATIENTS: 178 ICU patients with delirium, alive and remaining in ICU at one week. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood samples collected for a pair of previously published, negative, clinical trials were utilized. Samples were collected at study enrollment/ICU admission (Day 1 sample) and one week later (Day 8 sample), and analyzed for interleukins (IL)-6, 8, 10, Insulin-like Growth Factor (IGF), S100 Binding Protein (S100B), Tumor Necrosis Factor Alpha (TNF-A) and C-Reactive Protein (CRP). Delirium, delirium severity, and coma were assessed twice daily using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), CAM-ICU-7, and Richmond Agitation-Sedation Scale (RASS), respectively. Mortality was assessed until discharge using the electronic medical record. Logistic regression models adjusting for age, sex, severity of illness, comorbidities, sepsis, and randomization status, were used to assess the relationship among biomarkers and mortality. Higher IL-10 quartiles at day 8 were associated with increased odds of hospital mortality (IL-10: OR 2.00 95%CI: 1.1-3.65, p = 0.023). There was a significant interaction between day 1 and day 8 biomarker quartiles only for IL-6. Patients with IL-6 values in the first three quartiles on admission to the ICU that transitioned to higher IL-6 quartiles at day 8 had increased probability of hospital mortality. CONCLUSION: In this hypothesis-generating study, higher IL-6 and IL-10 quartiles at one week, and increase in IL-6 from day 1 to day 8 were associated with increased hospital mortality. Studies with larger sample sizes are needed to confirm the mechanisms for these observations.

Time trends of delirium rates in the intensive care unit.

BACKGROUND: Effects of clinical practice changes on ICU delirium are not well understood. OBJECTIVES: Determine ICU delirium rates over time. METHODS: Data from a previously described screening cohort of the Pharmacological Management of Delirium trial was analyzed. Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the ICU (CAM-ICU) were assessed twice daily. We defined: Any delirium (positive CAM-ICU at any time during ICU stay) and ICU-acquired delirium (1st CAM-ICU negative with a subsequent positive CAM-ICU). Mixed-effects logistic regression models were used to test for differences. RESULTS: 2742 patient admissions were included. Delirium occurred in 16.5%, any delirium decreased [22.7% to 10.2% (p < 0.01)], and ICU-acquired delirium decreased [8.4% to 4.4% (p = 0.01)]. Coma decreased from 24% to 17.4% (p = 0.04). Later ICU years and higher mean RASS scores were associated with lower odds of delirium. CONCLUSIONS: Delirium rates were not explained by the measured variables and further prospective research is needed.

Effect of Delirium on Physical Function in Noncardiac Thoracic Surgery Patients.

BACKGROUND: The effect of delirium on physical function in patients undergoing noncardiac thoracic surgery has not been well described and may differ from that in other surgical populations. OBJECTIVE: To determine the effects of delirium on muscle strength and functional independence. The primary end point was change in Medical Research Council sum score (MRC-SS) by delirium status. METHODS: A secondary analysis of data from a clinical trial involving English-speaking adults aged 18 years or older who were undergoing major noncardiac thoracic surgery. Exclusion criteria were history of schizophrenia, Parkinson disease, dementia, alcohol abuse, or neuroleptic malignant syndrome; haloperidol allergy; being pregnant or nursing; QT prolongation; and taking levodopa or cholinesterase inhibitors. Delirium was assessed twice daily using the Confusion Assessment Method for the Intensive Care Unit. Preoperatively and postoperatively, muscle strength was assessed using the modified MRC-SS and functional independence was assessed using the Katz scale of activities of daily living. Changes in MRC-SS and Katz score by delirium status were analyzed using the Fisher exact test. RESULTS: Seventy-three patients were included in the analysis. Median (interquartile range) MRC-SS and Katz score before surgery did not differ significantly between patients without and with delirium (MRC-SS: 30 [30-30] vs 30 [30-30], P > .99; Katz score: 6 [6-6] vs 6 [6-6], P = .63). The percentage of patients with a change in MRC-SS was similar in patients without and with delirium (17% vs 13%, respectively; P > .99). More patients in the delirium group had a change in Katz score (13% vs 0%, P = .04). CONCLUSIONS: Postoperative delirium was not associated with change in muscle strength. Follow-up studies using other muscle measures may be needed.

Biomarkers of Delirium Duration and Delirium Severity in the ICU.

OBJECTIVES: Both delirium duration and delirium severity are associated with adverse patient outcomes. Serum biomarkers associated with delirium duration and delirium severity in ICU patients have not been reliably identified. We conducted our study to identify peripheral biomarkers representing systemic inflammation, impaired neuroprotection, and astrocyte activation associated with delirium duration, delirium severity, and in-hospital mortality. DESIGN: Observational study. SETTING: Three Indianapolis hospitals. PATIENTS: Three-hundred twenty-one critically ill delirious patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed the associations between biomarkers collected at delirium onset and delirium-/coma-free days assessed through Richmond Agitation-Sedation Scale/Confusion Assessment Method for the ICU, delirium severity assessed through Confusion Assessment Method for the ICU-7, and in-hospital mortality. After adjusting for age, gender, Acute Physiology and Chronic Health Evaluation II score, Charlson comorbidity score, sepsis diagnosis and study intervention group, interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100ß levels in quartile 4 were negatively associated with delirium-/coma-free days by 1 week and 30 days post enrollment. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium-/coma-free days at both time points. Interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100ß levels in quartile 4 were also associated with delirium severity by 1 week. At hospital discharge, interleukin-6, -8, and -10 retained the association but tumor necrosis factor-α, C-reactive protein, and S-100ß lost their associations with delirium severity. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium severity at both time points. Interleukin-8 and S-100ß levels in quartile 4 were also associated with higher in-hospital mortality. Interleukin-6 and -10, tumor necrosis factor-α, and insulin-like growth factor-1 were not found to be associated with in-hospital mortality. CONCLUSIONS: Biomarkers of systemic inflammation and those for astrocyte and glial activation were associated with longer delirium duration, higher delirium severity, and in-hospital mortality. Utility of these biomarkers early in delirium onset to identify patients at a higher risk of severe and prolonged delirium, and delirium related complications during hospitalization needs to be explored in future studies.

Hospital outcomes in non-surgical patients identified at risk for OSA.

BACKGROUND: In-hospital respiratory outcomes of non-surgical patients with undiagnosed obstructive sleep apnea (OSA), particularly those with significant comorbidities are not well defined. Undiagnosed and untreated OSA may be associated with increased cardiopulmonary morbidity. STUDY OBJECTIVES: Evaluate respiratory failure outcomes in patients identified as at-risk for OSA by the Berlin Questionnaire (BQ). METHODS: This was a retrospective study conducted using electronic health records at a large health system. The BQ was administered at admission to screen for OSA to medical-service patients under the age of 80 years old meeting the following health system criteria: (1) BMI greater than 30; (2) any of the following comorbid diagnoses: hypertension, heart failure, acute coronary syndrome, pulmonary hypertension, arrhythmia, cerebrovascular event/stroke, or diabetes. Patients with known OSA or undergoing surgery were excluded. Patients were classified as high-risk or low-risk for OSA based on the BQ score as follows: low-risk (0 or 1 category with a positive score on the BQ); high-risk (2 or more categories with a positive score on BQ). The primary outcome was respiratory failure during index hospital stay defined by any of the following: orders for conventional ventilation or intubation; at least two instances of oxygen saturation less than 88% by pulse oximetry; at least two instances of respiratory rate over 30 breaths per minute; and any orders placed for non-invasive mechanical ventilation without a previous diagnosis of sleep apnea. Propensity scores were used to control for patient characteristics. RESULTS: Records of 15,253 patients were assessed. There were no significant differences in the composite outcome of respiratory failure by risk of OSA (high risk: 11%, low risk: 10%, p = 0.55). When respiratory failure was defined as need for ventilation, more patients in the low-risk group experienced invasive mechanical ventilation (high-risk: 1.8% vs. low-risk: 2.3%, p = 0.041). Mortality was decreased in patients at high-risk for OSA (0.86%) vs. low risk for OSA (1.53%, p < 0.001). CONCLUSIONS: Further prospective studies are needed to understand the contribution of undiagnosed OSA to in-hospital respiratory outcomes.

Perioperative Risk Factors for Postoperative Delirium in Patients Undergoing Esophagectomy.

BACKGROUND: Postoperative delirium affects up to 50% of patients undergoing esophagectomy and is associated with negative outcomes. The perioperative risk factors for delirium in this population are not well understood. We conducted this study to assess perioperative risk factors for postoperative delirium among esophagectomy patients. METHODS: We performed a secondary data analysis of patients enrolled in a randomized controlled trial evaluating the efficacy of haloperidol prophylaxis postoperatively in reducing delirium among esophagectomy patients. Postoperative delirium was assessed twice daily using the Confusion Assessment Method for the ICU. Univariate and logistic regression analyses were performed to examine the association between perioperative variables and development of postoperative delirium. RESULTS: Of 84 consecutive esophagectomy patients, postoperative delirium developed in 27 (32%). These patients had higher Acute Physiology and Chronic Health Evaluation II scores (22.1 [SD, 6.5] vs 17.4 [SD, 6.8]; p = 0.003), longer mechanical ventilation days (1.7 [SD, 1.4] days vs 1.0 [SD, 1.1] days; p = 0.001), and longer intensive care unit (ICU) days (5.1 [SD, 2.6] days vs 2.6 [SD, 1.6] days; p < 0.001). In a logistic regression model, only ICU length of stay had a significant association with postoperative delirium (odds ratio, 1.65; 95% confidence interval, 1.21 to 2.25). CONCLUSIONS: ICU length of stay was significantly associated with postoperative delirium. Other perioperative factors, including duration of procedure, blood loss, and hemoglobin levels, were not significantly associated with postoperative delirium.

Age of transfused red blood cells and health outcomes in two surgical cohorts.

RATIONALE: Red blood cells (RBC) undergo morphologic and biochemical changes during storage which may lead to adverse health risks upon transfusion. In prior studies, the effect of RBC age on health outcomes has been conflicting. We designed the study to assess the effects of RBC units' storage duration on health outcomes specifically for hospitalized patients undergoing hip fracture surgery or coronary artery bypass grafting (CABG) surgery. METHODS: Using International Classification of Diseases (ICD) 9 codes, hip fracture surgery and CABG surgery patients, who received RBC transfusions between 2008 and 2013, were retrospectively identified from the electronic medical records system. Hip fracture surgery and CABG cohorts were sub-divided into 3 blood age groups based upon RBC unit age at the time of transfusion: young blood (RBC units stored less than or equal to 14 days), old blood (RBC units were stored for greater than or equal to 28 days), or mixed blood for the remaining patients. Outcome variables were 30-day, 90-day, and inpatient mortality as well as hospital length of stay. RESULTS: A total of 3,182 patients were identified: 1,121 with hip fractures and 2,061 with CABG. Transfusion of old blood was associated with higher inpatient mortality in the hip fracture surgery cohort (OR 166.8, 95% CI 1.067-26064.7, p = 0.04) and a higher 30-day mortality in the CABG cohort (OR 4.55, 95% CI 1.01-20.49, p = 0.03). CONCLUSIONS: Transfusing RBC units stored for greater than or equal to 28 days may be associated with a higher mortality for patients undergoing hip fracture or CABG.

Preventing Postoperative Delirium After Major Noncardiac Thoracic Surgery-A Randomized Clinical Trial.

OBJECTIVES: To assess the efficacy of haloperidol in reducing postoperative delirium in individuals undergoing thoracic surgery. DESIGN: Randomized double-blind placebo-controlled trial. SETTING: Surgical intensive care unit (ICU) of tertiary care center. PARTICIPANTS: Individuals undergoing thoracic surgery (N=135). INTERVENTION: Low-dose intravenous haloperidol (0.5 mg three times daily for a total of 11 doses) administered postoperatively. MEASUREMENTS: The primary outcome was delirium incidence during hospitalization. Secondary outcomes were time to delirium, delirium duration, delirium severity, and ICU and hospital length of stay. Delirium was assessed using the Confusion Assessment Method for the ICU and delirium severity using the Delirium Rating Scale-Revised. RESULTS: Sixty-eight participants were randomized to receive haloperidol and 67 placebo. No significant differences were observed between those receiving haloperidol and those receiving placebo in incident delirium (n=15 (22.1%) vs n=19 (28.4%); p = .43), time to delirium (p = .43), delirium duration (median 1 day, interquartile range (IQR) 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, ICU length of stay (median 2.2 days, IQR 1-3.3 days vs median 2.3 days, IQR 1-4 days; p = .29), or hospital length of stay (median 10 days, IQR 8-11.5 days vs median 10 days, IQR 8-12 days; p = .41). In the esophagectomy subgroup (n = 84), the haloperidol group was less likely to experience incident delirium (n=10 (23.8%) vs n=17 (40.5%); p = .16). There were no differences in time to delirium (p = .14), delirium duration (median 1 day, IQR 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, or hospital length of stay (median 11 days, IQR 10-12 days vs median days 11, IQR 10-15 days; p = .26). ICU length of stay was significantly shorter in the haloperidol group (median 2.8 days, IQR 1.1-3.8 days vs median 3.1 days, IQR 2.1-5.1 days; p = .03). Safety events were comparable between the groups. CONCLUSION: Low-dose postoperative haloperidol did not reduce delirium in individuals undergoing thoracic surgery but may be efficacious in those undergoing esophagectomy. J Am Geriatr Soc 66:2289-2297, 2018.

Characterization of hepatic enzyme activity in older adults with dementia: potential impact on personalizing pharmacotherapy.

OBJECTIVE: To determine the frequency of pharmacogenomic variants and concurrent medications that may alter the efficacy and tolerability of acetylcholinesterase inhibitors (AChEIs). MATERIALS AND METHODS: A multisite cross-sectional study was carried out across four memory care practices in the greater Indianapolis area. Participants were adults aged 65 years and older with a diagnosis of probable or possible Alzheimer's disease (AD) (n=105). Blood samples and self-reported medication data were collected. Since two of the three AChEIs are metabolized by cytochrome P450 (CYP)-2D6, we determined the frequency of functional genetic variants in the CYP2D6 gene and calculated their predicted CYP2D6-activity scores. Concurrent medication data were collected from self-reported medication surveys, and their predicted effect on the pharmacokinetics of AChEIs was determined based on their known effects on CYP2D6 and CYP3A4/5 enzyme activities. RESULTS: Among the 105 subjects enrolled, 72% were female and 36% were African American. Subjects had a mean age of 79.6 years. The population used a mean of eight medications per day (prescription and nonprescription). The CYP2D6 activity score frequencies were 0 (3.8%), 0.5 (4.8%), 1.0 (36.2%), 1.5-2.0 (51.4%), and >2.0 (3.8%). Nineteen subjects (18.1%) used a medication considered a strong or moderate inhibitor of CYP2D6, and eight subjects (7.6%) used a medication considered a strong or moderate inhibitor of CYP3A4/5. In total, 28.6% of the study population was predicted to have reduced activity of the CYP2D6 or CYP3A4/5 enzymes due to either genetic variants or concomitant medications. CONCLUSION: Both pharmacogenetic variants and concurrent drug therapies that are predicted to alter the pharmacokinetics of AChEIs should be evaluated in older adults with AD. Pharmacogenetic and drug-interaction data may help personalize AD therapy and increase adherence by improving tolerability.

Cardiac compression secondary to a massively dilated substernal colon conduit.

With the growing success of surgical repairs of congenital defects previously incompatible with life, it is expected of these patients to live longer and experience the complications of these corrective procedures. Esophageal atresia is a congenital defect that occurs in 1 out of 4000 births and is oftentimes a surgical emergency in which colonic conduits are routinely used for esophageal reconstruction. Colonic conduit redundancy and dilatation are well-recognized late complications of colon conduit surgeries for esophageal reconstructions. We report a rare case of symptomatic cardiac compression secondary to a massively dilated substernal colon conduit occurring 44 years after the initial childhood surgery in 1964 with rapid reversal of hemodynamic compromise after conduit removal.

Comparison and agreement between the Richmond Agitation-Sedation Scale and the Riker Sedation-Agitation Scale in evaluating patients' eligibility for delirium assessment in the ICU.

BACKGROUND: Delirium evaluation in patients in the ICU requires the use of an arousal/sedation assessment tool prior to assessing consciousness. The Richmond Agitation-Sedation Scale (RASS) and the Riker Sedation-Agitation Scale (SAS) are well-validated arousal/sedation tools. We sought to assess the concordance of RASS and SAS assessments in determining eligibility of patients in the ICU for delirium screening using the confusion assessment method for the ICU (CAM-ICU). METHODS: We performed a prospective cohort study in the adult medical, surgical, and progressive (step-down) ICUs of a tertiary care, university-affiliated, urban hospital in Indianapolis, Indiana. The cohort included 975 admissions to the ICU between January and October 2009. RESULTS: The outcome measures of interest were the correlation and agreement between RASS and SAS measurements. In 2,469 RASS and SAS paired screens, the rank correlation using the Spearman correlation coefficient was 0.91, and the agreement between the two screening tools for assessing CAM-ICU eligibility as estimated by the κ coefficient was 0.93. Analysis showed that 70.1% of screens were eligible for CAM-ICU assessment using RASS (7.1% sedated [RASS −3 to −1]; 62.6% calm [0]; and 0.4% restless, agitated [+1 to +3]), compared with 72.1% using SAS (5% sedated [SAS 3]; 66.5% calm [4]; and 0.6% anxious, agitated [5, 6]). In the mechanically ventilated subgroup, RASS identified 19.1% CAM-ICU eligible patients compared with 24.6% by SAS. The correlation coefficient in this subgroup was 0.70 and the agreement was 0.81. CONCLUSION: Both SAS and RASS led to similar rates of delirium assessment using the CAM-ICU.