Cognitive and Cerebrospinal Fluid Alzheimer's Disease-related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls.

BACKGROUND: Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults. METHODS: The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid ß (Aß) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls. RESULTS: The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aß, tau, or p-tau levels, or tau/Aß or p-tau/Aß ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (ß, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up. CONCLUSIONS: During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aß) changes or greater cognitive decline.

Preoperative electroencephalographic alpha-power changes with eyes opening are associated with postoperative attention impairment and inattention-related delirium severity.

BACKGROUND: In the eyes-closed, awake condition, EEG oscillatory power in the alpha band (7-13 Hz) dominates human spectral activity. With eyes open, however, EEG alpha power substantially decreases. Less alpha attenuation with eyes opening has been associated with inattention; thus, we analysed whether reduced preoperative alpha attenuation with eyes opening is associated with postoperative inattention, a delirium-defining feature. METHODS: Preoperative awake 32-channel EEG was recorded with eyes open and eyes closed in 71 non-neurological, noncardiac surgery patients aged ≥ 60 years. Inattention and other delirium features were assessed before surgery and twice daily after surgery until discharge. Eyes-opening EEG alpha-attenuation magnitude was analysed for associations with postoperative inattention, primarily, and with delirium severity, secondarily, using multivariate age- and Mini-Mental Status Examination (MMSE)-adjusted logistic and proportional-odds regression analyses. RESULTS: Preoperative alpha attenuation with eyes opening was inversely associated with postoperative inattention (odds ratio [OR] 0.73, 95% confidence interval [CI]: 0.57, 0.94; P=0.038). Sensitivity analyses showed an inverse relationship between alpha-attenuation magnitude and inattention chronicity, defined as 'never', 'newly', or 'chronically' inattentive (OR 0.76, 95% CI: 0.62, 0.93; P=0.019). In addition, preoperative alpha-attenuation magnitude was inversely associated with postoperative delirium severity (OR 0.79, 95% CI: 0.65, 0.95; P=0.040), predominantly as a result of the inattention feature. CONCLUSIONS: Preoperative awake, resting, EEG alpha attenuation with eyes opening might represent a neural biomarker for risk of postoperative attentional impairment. Further, eyes-opening alpha attenuation could provide insight into the neural mechanisms underlying postoperative inattention risk.

Perioperative changes in neurocognitive and Alzheimer's disease-related cerebrospinal fluid biomarkers in older patients randomised to isoflurane or propofol for anaesthetic maintenance.

BACKGROUND: Animal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans. METHODS: This was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively. RESULTS: There were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aß), tau, or phospho-tau181p levels, or on the tau/Aß or p-tau181p/Aß ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [-0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses. CONCLUSIONS: Intraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults. CLINICAL TRIAL REGISTRATION: NCT01993836.

Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.

OBJECTIVE: Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aß levels after non-cardiac, non-neurologic surgery in older adults. METHODS: Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis. RESULTS: There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aß over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aß42 changes over this interval (p > 0.05 for each). INTERPRETATION: Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aß, tau or p-tau-181p levels or the p-tau-181p/Aß or tau/Aß ratios). TRIAL REGISTRATION: clinicaltrials.gov (NCT01993836).

Relationship Between Depression/Anxiety and Cognitive Function Before and 6 Weeks After Major Non-Cardiac Surgery in Older Adults.

OBJECTIVE: To determine the relationship between affective measures and cognition before and after non-cardiac surgery in older adults. METHODS: Observational prospective cohort study in 103 surgical patients age ≥ 60 years old. All participants underwent cognitive testing, Center for Epidemiologic Studies-Depression, and State Anxiety Inventory screening before and 6 weeks after surgery. Cognitive test scores were combined by factor analysis into 4 cognitive domains, whose mean was defined as the continuous cognitive index (CCI). Postoperative global cognitive change was defined by CCI change from before to after surgery, with negative CCI change indicating worsened postoperative global cognition and vice versa. RESULTS: Lower global cognition before surgery was associated with greater baseline depression severity (Spearman's r = -0.30, p = 0.002) and baseline anxiety severity (Spearman's r = -0.25, p = 0.010), and these associations were similar following surgery (r = -0.36, p < 0.001; r = -0.26, p = 0.008, respectively). Neither baseline depression or anxiety severity, nor postoperative changes in depression or anxiety severity, were associated with pre- to postoperative global cognitive change. CONCLUSIONS: Greater depression and anxiety severity were each associated with poorer cognitive performance both before and after surgery in older adults. Yet, neither baseline depression or anxiety symptoms, nor postoperative change in these symptoms, were associated with postoperative cognitive change.

Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study.

BACKGROUND: Cognitive dysfunction after surgery is a major issue in older adults. Here, we determined the effect of APOE4 on perioperative neurocognitive function in older patients. METHODS: We enrolled 140 English-speaking patients ≥60 yr old scheduled for noncardiac surgery under general anaesthesia in an observational cohort study, of whom 52 underwent neuroimaging. We measured cognition; Aß, tau, p-tau levels in CSF; and resting-state intrinsic functional connectivity in six Alzheimer's disease-risk regions before and 6 weeks after surgery. RESULTS: There were no significant APOE4-related differences in cognition or CSF biomarkers, except APOE4 carriers had lower CSF Aß levels than non-carriers (preoperative median CSF Aß [median absolute deviation], APOE4 305 pg ml-1 [65] vs 378 pg ml-1 [38], respectively; P=0.001). Controlling for age, APOE4 carriers had significantly greater preoperative functional connectivity than non-carriers between several brain regions implicated in Alzheimer's disease, including between the left posterior cingulate cortex and left angular gyrus (ß [95% confidence interval, CI], 0.218 [0.137-0.230]; PFWE=0.016). APOE4 carriers, but not non-carriers, experienced significant connectivity decreases from before to 6 weeks after surgery between several brain regions including between the left posterior cingulate cortex and left angular gyrus (ß [95% CI], -0.196 [-0.256 to -0.136]; PFWE=0.001). Most preoperative and postoperative functional connectivity differences did not change after controlling for preoperative CSF Aß levels. CONCLUSIONS: Postoperative change trajectories for cognition and CSF Aß, tau or p-tau levels did not differ between community dwelling older APOE4 carriers and non-carriers. APOE4 carriers showed greater preoperative functional connectivity and greater postoperative decreases in functional connectivity in key Alzheimer's disease-risk regions, which occur via Aß-independent mechanisms.

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. OBJECTIVE: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. METHODS: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. RESULTS: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13). CONCLUSION: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. OBJECTIVE: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. METHODS: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. CONCLUSION: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

A protocol to reduce self-reported pain scores and adverse events following lumbar punctures in older adults.

OBJECTIVE: Lumbar punctures (LPs) are important for obtaining CSF in neurology studies but are associated with adverse events and feared by many patients. We determined adverse event rates and pain scores in patients prospectively enrolled in two cohort studies who underwent LPs using a standardized protocol and 25 g needle. METHODS: Eight hundred and nine LPs performed in 262 patients age ≥ 60 years in the MADCO-PC and INTUIT studies were analyzed. Medical records were monitored for LP-related adverse events, and patients were queried about subjective complaints. We analyzed adverse event rates, including headaches and pain scores. RESULTS: There were 22 adverse events among 809 LPs performed, a rate of 2.72% (95% CI 1.71-4.09%). Patient hospital stay did not increase due to adverse events. Four patients (0.49%) developed a post-lumbar puncture headache (PLPH). Twelve patients (1.48%) developed nausea, vasovagal responses, or headaches that did not meet PLPH criteria. Six patients (0.74%) reported lower back pain at the LP site not associated with muscular weakness or paresthesia. The median pain score was 1 [0, 3]; the mode was 0 out of 10. CONCLUSIONS: The LP protocol described herein may reduce adverse event rates and improve patient comfort in future studies.

The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.

BACKGROUND/OBJECTIVES: Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN: Observational prospective cohort. SETTING: Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS: Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS: Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION: INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae. J Am Geriatr Soc 67:794-798, 2019.

An Undiagnosed Paraganglioma in a 58-Year-Old Female Who Underwent Tumor Resection.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors that can have high morbidity and mortality if undiagnosed. Here we report a case of an undiagnosed paraganglioma in a 58-year-old female who underwent tumor resection. The patient became severely hypertensive intraoperatively with paroxysmal swings in blood pressure and then later became acutely hypotensive after tumor removal. She was managed in the surgical intensive care unit (SICU) postoperatively and discharged from the hospital without acute complications. We briefly discuss the epidemiology, clinical presentation, perioperative management, and possible complications of these tumors to assist healthcare providers if one were to encounter them.

Intraoperative Frontal Alpha-Band Power Correlates with Preoperative Neurocognitive Function in Older Adults.

Each year over 16 million older Americans undergo general anesthesia for surgery, and up to 40% develop postoperative delirium and/or cognitive dysfunction (POCD). Delirium and POCD are each associated with decreased quality of life, early retirement, increased 1-year mortality, and long-term cognitive decline. Multiple investigators have thus suggested that anesthesia and surgery place severe stress on the aging brain, and that patients with less ability to withstand this stress will be at increased risk for developing postoperative delirium and POCD. Delirium and POCD risk are increased in patients with lower preoperative cognitive function, yet preoperative cognitive function is not routinely assessed, and no intraoperative physiological predictors have been found that correlate with lower preoperative cognitive function. Since general anesthesia causes alpha-band (8-12 Hz) electroencephalogram (EEG) power to decrease occipitally and increase frontally (known as "anteriorization"), and anesthetic-induced frontal alpha power is reduced in older adults, we hypothesized that lower intraoperative frontal alpha power might correlate with lower preoperative cognitive function. Here, we provide evidence that such a correlation exists, suggesting that lower intraoperative frontal alpha power could be used as a physiological marker to identify older adults with lower preoperative cognitive function. Lower intraoperative frontal alpha power could thus be used to target these at-risk patients for possible therapeutic interventions to help prevent postoperative delirium and POCD, or for increased postoperative monitoring and follow-up. More generally, these results suggest that understanding interindividual differences in how the brain responds to anesthetic drugs can be used as a probe of neurocognitive function (and dysfunction), and might be a useful measure of neurocognitive function in older adults.

Toward Designing Information Display to Support Critical Care. A Qualitative Contextual Evaluation and Visioning Effort.

OBJECTIVES: Electronic health information overload makes it difficult for providers to quickly find and interpret information to support care decisions. The purpose of this study was to better understand how clinicians use information in critical care to support the design of improved presentation of electronic health information. METHODS: We conducted a contextual analysis and visioning project. We used an eye-tracker to record 20 clinicians' information use activities in critical care settings. We played video recordings back to clinicians in retrospective cued interviews and queried: 1) context and goals of information use, 2) impacts of current display design on use, and 3) processes related to information use. We analyzed interview transcripts using grounded theory-based content analysis techniques and identified emerging themes. From these, we conducted a visioning activity with a team of subject matter experts and identified key areas for focus of design and research for future display designs. RESULTS: Analyses revealed four unique critical care information use activities including new patient assessment, known patient status review, specific directed information seeking, and review and prioritization of multiple patients. Emerging themes were primarily related to a need for better representation of dynamic data such as vital signs and laboratory results, usability issues associated with reducing cognitive load and supporting efficient interaction, and processes for managing information. Visions for the future included designs that: 1) provide rapid access to new information, 2) organize by systems or problems as well as by current versus historical patient data, and 3) apply intelligence toward detecting and representing change and urgency. CONCLUSIONS: The results from this study can be used to guide the design of future acute care electronic health information display. Additional research and collaboration is needed to refine and implement intelligent graphical user interfaces to improve clinical information organization and prioritization to support care decisions.

The accuracy of a near-infrared spectroscopy cerebral oximetry device and its potential value for estimating jugular venous oxygen saturation.

BACKGROUND: An intriguing potential clinical use of cerebral oximeter measurements (SctO2) is the ability to noninvasively estimate jugular bulb venous oxygen saturation (SjvO2). Our purpose in this study was to determine the accuracy of the FORE-SIGHT(®) (CAS Medical Systems, Branford, CT), which is calibrated to a weighted average of 70% (SjvO2) and 30% arterial saturation, for Food and Drug Administration pre-market approval 510(k) certification by adapting an industry standard protocol, ISO 9919:2005 (www.ISO.org) (used for pulse oximeters), and to evaluate the use of SctO2 and SpO2 measurements to noninvasively estimate jugular venous oxygen saturation (SnvO2). METHODS: Paired blood gas samples from the radial artery and the jugular venous bulb were collected from 20 healthy volunteers undergoing progressive oxygen desaturation from 100% to 70%. The blood sample pairs were analyzed via co-oximetry and used to calculate the approximate mixed vascular cerebral blood oxygen saturation, or reference SctO2 values (refSctO2), during increasing hypoxia. These reference values were compared to bilateral FORE-SIGHT SctO2 values recorded simultaneously with the blood gas draws to determine its accuracy. Bilateral SctO2 and SpO2 measurements were then used to calculate SnvO2 values which were compared to SjvO2. RESULTS: Two hundred forty-six arterial and 253 venous samples from 18 subjects were used in the analysis. The ipsilateral FORE-SIGHT SctO2 values showed a tolerance interval (TI) of [-10.72 to 10.90] and Lin concordance correlation coefficient (CCC) with standard error (SE) of 0.83 ± 0.073 with the refSctO2 values calculated using arterial and venous blood gases. The ipsilateral data had a CCC of 0.81 + 0.059 with TI of [-9.22 to 9.40] with overall bias of 0.09%, and amplitude of the root mean square of error after it was corrected with random effects analysis was 2.92%. The bias and variability values between the ipsilateral and the contralateral FORE-SIGHT SctO2 measurements varied from person to person. The SnvO2 calculated from the ipsilateral SctO2 and SpO2 data showed a CCC ± SE of 0.79 ± 0.088, TI = [-14.93 to 15.33], slope of 0.98, y-intercept of 1.14% with SjvO2 values with a bias of 0.20% and an Arms of 4.08%. The SnvO2 values calculated independently from contralateral forehead FORE-SIGHT SctO2 values were not as correlated with the SjvO2 values (contralateral side CCC + SE = 0.72 ± 0.118, TI = [-14.86 to 15.20], slope of 0.66, and y-intercept of 20.36%). CONCLUSIONS: The FORE-SIGHT cerebral oximeter was able to estimate oxygen saturation within the tissues of the frontal lobe under conditions of normocapnia and varying degrees of hypoxia (with 95% confidence interval of [-5.60 to 5.78] with ipsilateral blood sample data). These findings from healthy volunteers also suggest that the use of the calculated SnvO2 derived from SctO2 and SpO2 values may be a reasonable noninvasive method of estimating SjvO2 and therefore global cerebral oxygen consumption in the clinical setting. Further laboratory and clinical research is required to define the clinical utility of near-infrared spectroscopy determination of SctO2 and SnvO2 in the operating room setting.

Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis.

The authors aimed to evaluate age-related differences in inflammation biomarkers during the first 72 h of hospitalization for sepsis. This was a secondary analysis of a prospective observational cohort of adult patients (n = 855) from 10 urban academic emergency departments with confirmed infection and two or more systemic inflammatory response syndrome criteria. Six inflammation-related biomarkers were analyzed-chemokine (CC-motif) ligand-23, C-reactive protein, interleukin-1 receptor antagonist, neutrophil gelatinase-associated lipocalin (NGAL), peptidoglycan recognition protein, and tumor necrosis factor receptor-1a (TNFR-1a)-measured at presentation and 3, 6, 12, 24, 48, or 72 h later. The median age was 56 (interquartile range, 43 - 72) years, and sepsis severity was 38% sepsis, 16% severe sepsis without shock, and 46% septic shock; the overall 30-day mortality was 12%. Older age was associated with higher sepsis severity: 41% of subjects aged 18 to 34 years had severe sepsis or septic shock compared with 71% for those aged 65 years or older (P < 0.001). In longitudinal models adjusting for demographics, comorbidities, and infection source, older age was associated with higher baseline values for chemokine (CC-motif) ligand-23, interleukin-1 receptor antagonist, NGAL, and TNFR-1a (all P < 0.05). However, older adults had higher mean values during the entire 72-h period only for NGAL and TNFR-1a and higher final 72-h values only for TNFR-1a. Adjustment or stratification by sepsis severity did not change the age-inflammation associations. Although older adults had higher levels of inflammation at presentation and an increased incidence of severe sepsis and septic shock, these age-related differences in inflammation largely resolved during the first 72 h of hospitalization.

Exploring the impact of augmenting sedation assessment with physiologic monitors.

BACKGROUND: Pharmacological sedation is a necessary tool in the management of critically ill, mechanically ventilated patients. The intensive care unit (ICU) sedation strategy is to use the least amount of medication to meet safety and comfort goals. Titration of pharmacological agents is currently guided by clinical assessment tools. The purpose of this study was to determine whether the addition of a neurophysiological monitor, bispectral index (BIS), aided the ICU nurse in reducing the amount of drug used, compared to a clinical tool alone, in a general critical care population. METHODS: In this prospective clinical trial, mechanically ventilated adults (N=300) were randomised to sedation assessment using only the observational assessment tool (RASS) or a combination of observational and physiologic measures (RASS+BIS). Subjects were enrolled from a medical ICU (N=154), a trauma ICU (N=72) and a general mixed-use ICU (N=74). RESULTS: BIS-augmented sedation was only associated with the reduction of drug use when patients were sedated with propofol or narcotic agents (propofol [1.61 mg/kg/h vs. 1.77 mg/kg/h; p<0.0001], fentanyl [54.73 mcg/h vs. 66.81 mcg/h; p<0.0001], and hydromorphone [0.97 mg/h vs. 4.00 mg/h: p<0.0001] compared to RASS alone. In contrast, patients sedated with dexmedetomidine or benzodiazepines were given higher doses under the BIS-augmented dexmedetomidine [0.46 mcg/kg/h vs. 0.33 mcg/kg/h; p<0.0001], lorazepam [4.13 mg/h vs. 3.29 mg/h p<0.0001], and midazolam [3.73 mg/h vs 2.86 mg/h; p<0.0001]) protocol compared to clinical assessment alone. CONCLUSION: The clinical evaluation of depth of sedation remains the most reliable method for the titration of pharmacological sedation in the critical care unit. However, BIS-augmented assessment is helpful in reducing the amount of propofol and narcotic medication used and may be considered an adjunct when these agents are utilised.

Relationship between B-type natriuretic peptide and adverse outcome in patients with clinical evidence of sepsis presenting to the emergency department.

OBJECTIVES: Myocardial dysfunction is an important aspect of sepsis pathophysiology. B-type natriuretic peptide (BNP) is a neurohormone released from the ventricles in response to myocardial stretch and volume overload. The authors hypothesized that an elevated BNP in patients presenting to the emergency department (ED) with suspected sepsis are at increased risk for development of adverse events. METHODS: This was a prospective, observational, multicenter cohort study in 10 EDs. Patients were eligible if they were older than 18 years, had two or more systemic inflammatory response syndrome (SIRS) criteria, and had suspected infection or a serum lactate level > 2.5 mmol/L. Patients were excluded if they were pregnant, had do-not-attempt-resuscitation status, sustained a cardiac arrest prior to hospital arrival, had known chronic renal insufficiency, or were on dialysis. BNP levels were obtained at arrival. The primary outcome was a composite of severe sepsis, septic shock within 72 hours, or in-hospital mortality. RESULTS: There were 825 patients enrolled (mean ± standard deviation [SD] age = 53.5 ± 19.6 years; 51% were female and 37% were African American). The area under the curve (AUC) for BNP to predict the triple composite outcome was 0.69, and the optimal cut-point of BNP was 49 pg/mL. Patients with a BNP > 49 pg/mL had a greater mortality rate (11.6% vs. 2.1%; p = 0.0001), a greater risk of development of severe sepsis (67.7% vs. 36.8%; p = 0.0001) and septic shock (51.7% vs. 26.4%; p = 0.0001), and a higher rate of the triple composite outcome (69% vs. 37%; unadjusted odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.6 to 2.1; p < 0.001). The sensitivity was 63% (95% CI = 58% to 67%), specificity was 69% (95% CI = 65% to 73%), negative predictive value (NPV) was 63% (95% CI = 58% to 67%), and positive predictive value (PPV) was 69% (95% CI = 65% to 74%). In multivariate modeling, after adjusting for age, sex, heart rate, white blood cell count, and creatinine, an elevated BNP was associated with increased odds of having the composite outcome. The outcome was similar in the subset of patients who did not have severe sepsis or septic shock upon arrival. CONCLUSIONS: In patients who present to the ED with SIRS criteria and suspected infection, an elevated BNP is associated with a worse prognosis but has limited diagnostic utility.

The diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin in the prediction of acute kidney injury in emergency department patients with suspected sepsis.

STUDY OBJECTIVE: We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. METHODS: We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. RESULTS: There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). CONCLUSION: In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted.