No convincing association between post-operative delirium and post-operative cognitive dysfunction: a secondary analysis.

BACKGROUND: Post-operative delirium and post-operative cognitive dysfunction (POCD) are both common but it has not been clarified how closely they are associated. We aimed to assess the possible relationship in a secondary analysis of data from the 'Surgery Depth of anaesthesia and Cognitive outcome'- study. METHODS: We included patients aged ≥ 60 years undergoing non-cardiac surgery planned for longer than 60 min. Delirium was assessed according to the Diagnostic and Statistical Manual of Mental Disorders IV criteria in the post-anaesthesia care unit (PACU) as well as within the first week after surgery. Cognitive function was assessed with a neuropsychological test battery. Multivariable analysis of POCD was performed with consideration of predisposing and precipitating factors. RESULTS: Of 1277 randomized patients, 850 (66.6%) had complete data. Delirium was found in 270 patients (32.9% of 850). We detected POCD in 162 (20.9% of 776) at 1 week and in 52 (9.4% of 553) at 3 months. In multivariable analysis (n = 808), delirium had no overall effect on POCD (P = 0.30). Patients with no delirium in PACU but with postoperative delirium within 7 days had an increased risk of POCD at 3 months (OR = 2.56 (95%-confidence interval: 1.07-6.16), P = 0.035). No significant association was found for the other subgroups. CONCLUSIONS: There is no clear evidence that postoperative delirium is independently associated with POCD up to 3 months.

Enhanced Recovery After Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice.

BACKGROUND: The present interdisciplinary consensus review proposes clinical considerations and recommendations for anaesthetic practice in patients undergoing gastrointestinal surgery with an Enhanced Recovery after Surgery (ERAS) programme. METHODS: Studies were selected with particular attention being paid to meta-analyses, randomized controlled trials and large prospective cohort studies. For each item of the perioperative treatment pathway, available English-language literature was examined and reviewed. The group reached a consensus recommendation after critical appraisal of the literature. RESULTS: This consensus statement demonstrates that anaesthesiologists control several preoperative, intraoperative and postoperative ERAS elements. Further research is needed to verify the strength of these recommendations. CONCLUSIONS: Based on the evidence available for each element of perioperative care pathways, the Enhanced Recovery After Surgery (ERAS®) Society presents a comprehensive consensus review, clinical considerations and recommendations for anaesthesia care in patients undergoing gastrointestinal surgery within an ERAS programme. This unified protocol facilitates involvement of anaesthesiologists in the implementation of the ERAS programmes and allows for comparison between centres and it eventually might facilitate the design of multi-institutional prospective and adequately powered randomized trials.

Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.

BACKGROUND: Postoperative delirium in elderly patients is a frequent complication and associated with poor outcome. The aim of this parallel group study was to determine whether monitoring depth of anaesthesia influences the incidence of postoperative delirium. METHODS: Patients who were planned for surgery in general anaesthesia expected to last at least 60 min and who were older than 60 yr were included between March 2009 and May 2010. A total of 1277 patients of a consecutive sample were randomized (n=638 open, n=639 blinded) and the data of 1155 patients were analysed (n=575 open, n=580 blinded). In one group, the anaesthesiologists were allowed to use the bispectral index (BIS) data to guide anaesthesia, while in the other group, BIS monitoring was blinded. Cognitive function was evaluated at baseline, 1 week, and 3 months after operation. RESULTS: Delirium incidence was lower in patients guided with BIS. Postoperative delirium was detected in 95 patients (16.7%) in the intervention group compared with 124 patients (21.4%) in the control group (P=0.036). In a multivariate analysis, the percentage of episodes of deep anaesthesia (BIS values <20) were independently predictive for postoperative delirium (P=0.006; odds ratio 1.027). BIS monitoring did not alter the incidence of postoperative cognitive dysfunction (7th day P=0.062; 90th day P=0.372). CONCLUSIONS: Intraoperative neuromonitoring is associated with a lower incidence of delirium, possibly by reducing extreme low BIS values. Therefore, in high-risk surgical patients, this may give the anaesthesiologist a possibility to influence one precipitating factor in the complex genesis of delirium. Clinical trial registration ISRCTN Register: 36437985. http://www.controlled-trials.com/ISRCTN36437985/.

Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus.

We have recently reported that Notch 1, a member of the Notch multigene family, is essential for the development of murine T cells. Using a mouse model in which Notch 1 is inactivated in bone marrow (BM) precursors we have shown that B cells instead of T cells are found in the thymus of BM chimeras. However, it is not clear whether these B cells develop by default from a common lymphoid precursor due to the absence of Notch 1 signaling, or whether they arise as a result of perturbed migration of BM-derived B cells and/or altered homeostasis of normal resident thymic B cells. In this report we show that Notch 1-deficient thymic B cells resemble BM B cells in phenotype and turnover kinetics and are located predominantly in the medulla and corticomedullary junction. Peripheral blood lymphocyte analysis shows no evidence of recirculating Notch1(-/)- BM B cells. Furthermore, lack of T cell development is not due to a failure of Notch1(-/)- precursors to home to the thymus, as even after intrathymic reconstitution with BM cells, B cells instead of T cells develop from Notch 1-deficient precursors. Taken together, these results provide evidence for de novo ectopic B cell development in the thymus, and support the hypothesis that in the absence of Notch 1 common lymphoid precursors adopt the default cell fate and develop into B cells instead.

Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells.

Thymic dendritic cells (DCs) form a discrete subset of bone marrow (BM)-derived cells, the function of which is to mediate negative selection of autoreactive thymocytes. The developmental origin of thymic DCs remains controversial. Although cell transfer studies support a model in which T cells and thymic DCs develop from the same intrathymic pluripotential precursor, it remains possible that these two types of cells develop from independent intrathymic precursors. Notch proteins are cell surface receptors involved in the regulation of cell fate specification. We have recently reported that T cell development in inducible Notch1-deficient mice is severely impaired at an early stage, before the expression of T cell lineage markers. To investigate whether development of thymic DCs also depends on Notch1, we have constructed mixed BM chimeric mice. We report here that thymic DC development from Notch1(-/)- BM precursors is absolutely normal (in terms of absolute number and phenotype) in this competitive situation, despite the absence of Notch1(-/)- T cells. Furthermore, we find that peripheral DCs and Langerhans cells are also not affected by Notch1 deficiency. Our results demonstrate that the development of DCs is totally independent of Notch1 function, and strongly suggest a dissociation between intrathymic T cell and DC precursors.

Documentation of post-operative nausea and vomiting in routine clinical practice.

This study investigated the quality of documentation of post-operative nausea and vomiting (PONV) by comparing incidences collected by a research team with those reported routinely by nursing personnel. A total of 560 patients passing through an interdisciplinary recovery room were included in the study. The overall recorded incidence of PONV over 24 h was 30.7%, which was in agreement with the predicted value of 32% calculated using incidences from published randomized controlled trials. Out of the total number of 86 cases of PONV in the recovery room only 36 (42%) were detected by nursing staff. Similarly, out of the total number of 129 cases of PONV on the ward over 24 h, only 37 (29%) were recognized by nursing staff during routine care. In conclusion, PONV in routine clinical care is likely to be under-reported. To use PONV as a valid quality measure, patients need to be actively asked about nausea and vomiting at frequent intervals in a standardized fashion. A considerable proportion of patients experience PONV after discharge from the recovery room, so the assessment of PONV should cover at least 24 h post-operatively.

Remifentanil reduces the incidence of post-operative delirium.

A secondary exploratory analysis of data from an observational study was used to study the influence of the opioid used for intraoperative anaesthesia on the incidence of post-operative delirium. Patients who had been admitted to the recovery room following elective general anaesthesia were divided into those who had received fentanyl or remifentanil. For unbiased patient analysis, matched pairs were built with respect to gender, age, physical status, anaesthetic type and surgery duration. In 752 patients, the overall incidence of delirium was 9.9% in the recovery room and 3.8% on the first post-operative day. Compared with the remifentanil group, the fentanyl group had a significantly higher incidence of delirium in the recovery room (12.2% versus 7.7%) and on the first post-operative day (5.8% versus 1.9%). Delirium in the recovery room and on the first post-operative day were both associated with a significantly prolonged post-operative hospital stay. The choice of intraoperative opioid influences the incidence of post-operative delirium. Remifentanil was associated with a lower incidence of post-operative delirium in the early post-operative period.

Delayed treatment of delirium increases mortality rate in intensive care unit patients.

Delirium in the intensive care unit (ICU) is a serious complication associated with a poor outcome in critically ill patients. In this prospective observational study of the effect of a delay in delirium therapy on mortality rate, 418 ICU patients were regularly assessed using the Delirium Detection Score (DDS). The departmental standard required that if delirium was diagnosed (DDS >7), therapy should be started within 24 h. In total, 204 patients (48.8%) were delirious during their ICU stay. In 184 of the delirious patients (90.2%), therapy was started within 24 h; in 20 patients (9.8%), therapy was delayed. During their ICU stay, patients whose delirium treatment was delayed were more frequently mechanically ventilated, had more nosocomial infections (including pneumonia) and had a higher mortality rate than patients whose treatment was not delayed. Thus, it would appear that a delay in initiating delirium therapy in ICU patients was associated with increased mortality.

[Adherence to treatment guidelines for postoperative nausea and vomiting. How well does knowledge transfer result in improved clinical care?]. / Einhaltung der Behandlungsrichtlinien für postoperative Ubelkeit und Erbrechen. Wie gut gelingt der Wissenstransfer hin zu einer besseren klinischen Versorgung?

BACKGROUND: In order to reduce the incidence of postoperative nausea and vomiting (PONV) a standard operating procedure (SOP) was developed in our department. This consists basically in the administration of one antiemetic intervention for moderate risk (2 risk factors), two interventions for high risk (3-4 risk factors) and no prophylaxis in patients who have no or only one risk factor. The aim of this study was to find out whether PONV prophylaxis according to our SOP was followed and led to a lower incidence of PONV. METHOD AND PATIENTS: A total of 2,729 patients were examined in a prospective observational study with post-ad hoc analysis in our department. Inclusion criteria were age over 14 years after general anesthesia and postoperative care in the recovery room. This group was examined in relation to compliance with the SOP. RESULTS: A total of 725 (26.6%), 1050 (38.5%) and 954 (35.0%) patients were grouped according to risk classification into groups with low, medium and high risks, respectively. An SOP compliant regime occurred in 668 patients (92.1%) of the low risk groups, in 373 patients (35.6%) of the moderate risk group and 177 patients (18.6%) of patients at high risk for PONV. In the high risk group 565 patients (59.2%) received at least one antiemetic medication. Patients with PONV were on average cared for 12 min longer in the recovery room (p=0.048). CONCLUSION: Patients with medium and high risk have a lower incidence of PONV than expected per risk calculation by complying with the SOP. However, the recommended risk-adapted approach was inadequately implemented. Considering this there is room for improvement. Moreover taking into account these implementation issues a general PONV prophylaxis may be beneficial.

Comparison of three scores to screen for delirium in the recovery room.

BACKGROUND: Delirium is often seen in the recovery room and is a predictor for postoperative delirium on the ward. However, monitoring to detect delirium in the recovery room as a basic prerequisite for early intervention is rarely used. The aim of this study was to identify a valid and easy-to-use test for early screening of delirium in the recovery room. METHODS: One hundred and fifty-four adult patients admitted to the recovery room during regular working hours were included. A screening assessment for delirium was performed in the recovery room by a trained research team at the time when the patient was judged to be 'ready for discharge'. Delirium monitoring was performed with the Confusion Assessment Method (CAM), the Delirium Detection Score (DDS), and the Nursing Delirium Screening Scale (Nu-DESC). The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria were used as the gold standard. RESULTS: Delirium in the recovery room was seen in 21 patients (14%) with the DSM-IV criteria, in 11 patients (7%) with the CAM, in four patients (3%) with the DDS, and in 37 patients (24%) with the Nu-DESC. Sensitivity and specificity were 0.43 and 0.98 for the CAM, 0.14 and 0.99 for the DDS, and 0.95 and 0.87 for the Nu-DESC, respectively. CONCLUSIONS: All scores used were very specific, but the CAM and the DDS were less sensitive compared with the gold standard. Overall, the Nu-DESC was the most sensitive test in the recovery room to detect delirium.

T cell fate specification and alphabeta/gammadelta lineage commitment.

The development of T cells from pluripotent stem cells involves a coordinated series of lineage-commitment steps. Common lymphoid precursors in the fetal liver or adult bone marrow must first choose between a T, B or NK cell fate. Committed T cell precursors in the thymus then differentiate into cells committed to the alphabeta or gammadelta lineages. Recent advances have been made in our understanding of the mechanisms underlying T cell fate specification and alphabeta/gammadelta lineage divergence.

To be or not to be a pro-T?

Recent studies have begun to unravel some of the molecular pathways that appear to control the processes of T cell determination in the earliest thymocyte precursors. In addition, the analyses of mouse mutants with an entirely alymphoid thymus have shed light on the developmental relationship of pro-T cells and thymic dendritic cells, revealing that development of thymocytes and thymic dendritic cells can be dissociated.

Incidence and risk factors for cognitive dysfunction in patients with severe systemic disease.

OBJECTIVE: To determine the relevance of surgery and other causative factors to the incidence of postoperative cognitive dysfunction (POCD) in patients with severe systemic disease. METHODS: This observational study included 107 noncardiac surgical patients and 26 nonsurgical control subjects, all of whom had an American Society of Anesthesiologists physical classification status of 3. Cognitive assessment was performed preoperatively and 7 days postoperatively, or with a 7-day interval for the control group. POCD was calculated as a combined Z-score. Mini Mental State Examination (MMSE) was used to exclude patients with pre-existing cognitive deficit (MMSE score ≤ 23). Surgical and other factors including duration of surgery/anaesthesia and length of stay in the intensive care unit (ICU) were recorded. RESULTS: After 7 days, POCD was found in 40/107 (37.4%) surgical patients compared with 4/26 (15.4%) nonsurgical controls. Preoperative MMSE score, duration of surgery/anaesthesia, and length of stay in the ICU and hospital were associated with POCD. Logistic regression analysis revealed that preoperative MMSE score was an independent predictor of POCD. CONCLUSION: Lower baseline MMSE score was the only independent predictor for POCD in patients with severe systemic disease.

RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice.

The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jκ-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/° transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP-Jκ, as it is rescued in mice lacking RBP-Jκ in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jκ. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells.

Documented intraoperative hypotension according to the three most common definitions does not match the application of antihypotensive medication.

This observational study investigated which of the three most common definitions of intraoperative hypotension (IOH), reported in a published systematic literature review, were associated best with anaesthetists' administration of antihypo tensive medication (AHM). IOH and AHM use in anaesthetic procedures in a mixed surgical population (n = 2350) were also reviewed. The definitions were: arterial systolic blood pressure (SBP) < 100 mmHg or a fall in SBP of > 30% of the preoperative SBP baseline; arterial SBP < 80 mmHg; a fall in SBP of > 20% of the preoperative SBP. Accuracy of predicting AHM using these three definitions was 67%, 54% and 65%, respectively. Prediction by a new fourth definition, using an optimal threshold of minimal SBP falling to < 92 mmHg or by > 24% of preoperative baseline, was 68% accurate. In multivariate logistic analysis, age, volatile versus intravenous anaesthetics, medical history of arterial hypertension and all four definitions of IOH were associated with intraoperative AHM, however IOH was not associated with postoperative in-patient stay. The three original definitions correlated poorly with the anaesthetist's judgement about applying AHM. Anaesthetists make complex decisions regarding the relevance of IOH, considering various perioperative factors in addition to SBP. Age, physical status and duration and type of surgery showed better correlations with postoperative in-patient stay than IOH.

Improving the detection of illicit substance use in preoperative anesthesiological assessment.

AIM: Illicit substance use (ISU) is a worldwide burden, and its prevalence in surgical patients has not been well investigated. Co-consumption of legal substances, such as alcohol and tobacco, complicates the perioperative management and is frequently underestimated during routine preoperative assessment. The aim of this study was to compare the anesthesiologists' detection rate of ISU during routine preoperative assessment with a computerized self-assessment questionnaire. METHODS: In total, 2,938 patients were included in this study. Prior to preoperative assessment, patients were asked to complete a computer-based questionnaire that addressed ISU, alcohol use disorder (AUDIT), nicotine use (Fagerström) and socio-economic variables (education, income, employment, partnership and size of household). Medical records were reviewed, and the anesthesiologists' detection of ISU was compared to the patients' self-reported ISU. RESULTS: Seven point five percent of patients reported ISU within the previous twelve months. ISU was highest in the age group between 18 and 30 years (26.4%; P<0.01). Patients reporting ISU were more often men than women (P<0.01), smokers (P<0.01) and tested positive for alcohol use disorder (P<0.01). Anesthesiologists detected ISU in one in 43 patients, whereas the computerized self-assessment reported it in one in 13 patients. The detection was best in the subgroup self-reporting frequent ISU (P<0.01). CONCLUSIONS: Anesthesiologists underestimate the prevalence of ISU. Computer-based self-assessment increases the detection of ISU in preoperative assessment and may decrease perioperative risk. More strategies to improve the detection of ISU as well as brief interventions for ISU are required in preoperative assessment clinics.

Risk factors for inadequate emergence after anesthesia: emergence delirium and hypoactive emergence.

AIM: Inadequate emergence after anesthesia in the adult patient may be distinguished by the patients' activity level into two subtypes: emergence delirium and hypoactive emergence. The aim of this study was to determine the incidence of inadequate emergence in its different forms, to identify causative factors and to examine the possible influence on postoperative length of stay in the recovery room and in the hospital. METHODS: In this prospective observational study, 1868 non-intubated adult patients who had been admitted to the recovery room were analyzed. Inadequate emergence was classified in its different forms according to the Richmond agitation and sedation scale (RASS) 10 minutes after admission to the recovery room. Emergence delirium was defined as a RASS score >or=+1, and hypoactive emergence was defined as a RASS score

Cytotoxicity, mutagenicity, and tumorigenicity of mainstream smoke from three reference cigarettes machine-smoked to the same yields of total particulate matter per cigarette.

The particle phase of mainstream smoke from three types of cigarettes was investigated in vitro in the Neutral Red cytotoxicity assay and the Salmonella typhimurium Reverse Mutation Assay (Ames Assay) and in vivo in the two-stage dermal tumorigenicity assay (Skin Painting Assay) in SENCAR mice. The cigarettes used were the Reference Cigarettes 1R5F, 2R4F, and 2R1F from the University of Kentucky, USA, which, when smoked according to the smoking regimen defined by the International Standards Organization (ISO), produce a yield of approximately 2, 12, and 26 mg total particulate matter (TPM)/cigarette, respectively. All cigarettes were machine smoked according to ISO and then again in such a way that the TPM yields per cigarette equaled the ISO TPM yields of the other two cigarette types. The TPM from cigarettes with inherently different smoke yields showed similar in vitro toxicity and in vivo toxicity when, with different smoking regimens, these cigarettes were smoked to the same TPM yield. More intensive smoking conditions were associated with lower in vitro and in vivo activity per gram of TPM. The strongest decrease, and the tightest correlation, in this regard was observed for dermal tumorigenicity (tumor incidence).

Notch and cancer: a double-edged sword.

The highly conserved Notch signaling pathway plays pleiotropic roles during embryonic development and is important for the regulation of self-renewing tissues. The physiological functions of this signaling cascade range from stem cell maintenance and influencing cell fate decisions of barely differentiated progenitor cells, to the induction of terminal differentiation processes, all of which have been found to be recapitulated in different forms of cancers. Although Notch signaling has mostly been associated with oncogenic and growth-promoting roles, depending on the tissue type it can also function as a tumor suppressor. Here we describe recent findings on Notch signaling in cancer and tumor angiogenesis, and highlight some of the therapeutic approaches that are currently being developed to interfere with tumor growth and progression.