S100B as a biomarker of blood-brain barrier disruption after thoracoabdominal aortic aneurysm repair: a secondary analysis from a prospective cohort study.

PURPOSE: The objective of this study was to determine whether the magnitude of the peripheral inflammatory response to cardiovascular surgery is associated with increases in blood-brain barrier (BBB) permeability as reflected by changes in cerebrospinal fluid (CSF)/plasma S100B concentrations. METHODS: We conducted a secondary analysis from a prospective cohort study of 35 patients undergoing elective thoracoabdominal aortic aneurysm repair with (n = 17) or without (n = 18) cardiopulmonary bypass (CPB). Plasma and CSF S100B, interleukin-6 (IL-6), and albumin concentrations were measured at baseline (C0) and serially for up to five days. RESULTS: Following CPB, the median [interquartile range] plasma S100B concentration increased from 58 [32-88] pg·mL-1 at C0 to a maximum concentration (Cmax) of 1,131 [655-1,875] pg·mL-1 over a median time (tmax) of 6.3 [5.9-7.0] hr. In the non-CPB group, the median plasma S100B increased to a lesser extent. There was a delayed increase in CSF S100B to a median Cmax of 436 [406-922] pg·mL-1 in the CPB group at a tmax of 23.7 [18.5-40.2] hr. In the non-CPB group, the CSF concentrations were similar at all time points. In the CPB group, we did not detect significant correlations between plasma and CSF S100B with plasma IL-6 [r = 0.52 (95% confidence interval [CI], -0.061 to 0.84)] and CSF IL-6 [r = 0.53 (95% CI, -0.073 to 0.85)] concentrations, respectively. Correlations of plasma or CSF S100B levels with BBB permeability were not significant. CONCLUSION: The lack of parallel increases in plasma and CSF S100B following CPB indicates that S100B may not be a reliable biomarker for BBB disruption after thoracoabdominal aortic aneurysm repair employing CPB. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00878371); registered 7 April 2009.

RéSUMé: OBJECTIF: L'objectif de cette étude était de déterminer si l'intensité de la réponse inflammatoire périphérique à la chirurgie cardiovasculaire était associée à une augmentation de la perméabilité de la barrière hémato-encéphalique (BHE), telle que reflétée par des changements dans les concentrations de S100B dans le liquide céphalorachidien (LCR) et le plasma. MéTHODE: Nous avons mené une analyse secondaire à partir d'une étude de cohorte prospective portant sur 35 patients bénéficiant d'une réparation élective d'un anévrisme aortique thoraco-abdominal avec (n = 17) ou sans (n = 18) circulation extracorporelle (CEC). Les concentrations plasmatiques et dans le LCR de S100B, d'interleukine-6 (IL-6) et d'albumine ont été mesurées au départ (C0) et en série jusqu'à cinq jours. RéSULTATS: Après la CEC, la concentration médiane [écart interquartile] plasmatique de S100B est passée de 58 [32­88] pg·mL-1 au départ (C0) à une concentration maximale (Cmax) de 1131 [655­1875] pg·mL-1 sur une période médiane (tmax) de 6,3 [5,9­7,0] h. Dans le groupe sans CEC, la concentration plasmatique médiane de S100B a augmenté dans une moindre mesure. Il y a eu une augmentation retardée de S100B dans le LCR à une Cmax médiane de 436 [406­922] pg·mL-1 dans le groupe CEC à une tmax de 23,7 [18,5­40,2] h. Dans le groupe sans CEC, les concentrations dans le LCR étaient similaires à tous les moments. Dans le groupe CEC, nous n'avons pas détecté de corrélations significatives entre la concentration de S100B dans le plasma et le LCR avec les concentrations plasmatiques d'IL-6 [r = 0,52 (intervalle de confiance [IC] à 95 %, -0,061 à 0,84)] et d'IL-6 dans le LCR [r = 0,53 (IC 95 %, -0,073 à 0,85)], respectivement. Les corrélations entre les taux plasmatiques ou dans le LCR de S100B et la perméabilité de la BHE n'étaient pas significatives. CONCLUSION: L'absence d'augmentations parallèles de la concentration de S100B dans le plasma et le LCR après la CEC indique que la S100B pourrait ne pas être un biomarqueur fiable de la perturbation de la BHE après une réparation d'anévrisme aortique thoraco-abdominal sous CEC. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT00878371); enregistrée le 7 avril 2009.

Survey of the Preparation of Cardiovascular Emergency Medications for Adult Cardiovascular Anesthesia.

OBJECTIVES: To describe current practices and safety concerns regarding cardiac emergency medications in cardiac anesthesia. DESIGN: An anonymous survey with multiple-choice questions. SETTINGS: Online survey using Opinio platform. PARTICIPANTS: Cardiac anesthesiologists from United States and Canada. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Response rate was 12% (n = 320), with 78% of respondents from the United States and 22% from Canada. The majority of the respondents were experienced (66%), academic (60%), and worked in large cardiac institutions (81%). Most cardiac emergency medications were prepared in the operating room (53.4%), followed by the pharmacy (34%) and industry (8.2%). American respondents had more medications prepared by a pharmacy (53%) versus Canadian (10%, p < 0.001). The majority (85%) considered expiration time of cardiac medications prepared in the operating room to be more than 12 hours. Familiarity with the American Society of Anesthesiologists guidelines on labeling was 58%, other medication safety guidelines 25%, and 34% were not familiar with any guidelines. The majority used color-coded labeling (95%), and a minority (11%) used bar-code systems. Most respondents (69%) agreed that lack of availability of preprepared medications could compromise patient safety. Having to prepare medications by themselves was a concern for respondents based on distractions (66%), lack of availability for emergencies (53%), labeling errors (41%), incorrect concentration (36%), sterility (33%), and stability (30%). CONCLUSION: This survey found that cardiac emergency medications commonly are prepared in the operating room. The authors identified gaps in familiarity with parenteral medications safety guidelines. Most safety concerns could be addressed with the application of current medication safety guidelines.

An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid.

PURPOSE: Morphine is administered intravenously for pain management in the perioperative period. The effect of the inflammatory response to surgery on morphine distribution across the blood-brain barrier (BBB) in humans was investigated. We hypothesized that a graded surgically induced, systemic inflammatory response alters cerebrospinal fluid (CSF) levels of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a temporary reduction in BBB drug efflux transporter function. METHODS: We conducted a prospective pharmacokinetic study of the plasma and CSF distribution of the P-glycoprotein (PGP) substrate morphine in 33 patients undergoing open thoracic (n = 18) or endovascular (n = 15) aortic aneurysm repair. Morphine was administered with induction of anesthesia and in the intensive care unit. Plasma and CSF concentrations of interleukin (IL)-6, morphine, M3G, M6G, and albumin were measured prior to surgery (baseline), during surgery, and postoperatively every six hours until removal of the CSF drain. The area under the curve (AUC) was determined for plasma and CSF IL-6, morphine, M3G, and M6G concentrations vs time. The primary endpoint measures were the correlations between the morphine, M6G, and M3G AUC CSF/plasma ratios and systemic inflammation as quantified by the time-normalized IL-6 exposure, which was calculated for each individual by dividing the total exposure (AUC) by time (t). A Bonferroni corrected P < 0.017 indicated a significant correlation. RESULTS: Plasma and CSF IL-6 concentrations increased postoperatively. The median [interquartile range] IL-6 exposures were significantly higher in the open vs endovascular surgical group for plasma (105 [40-256] pg·mL-1 vs 29 [16-70] pg·mL-1, respectively; P = 0.013) and CSF (79 [26-133] pg·mL-1 vs 16 [9-80] pg·mL-1, respectively; P = 0.013). For the primary endpoint, the plasma IL-6 AUC/t did not correlate with the CSF accumulation of morphine (r = -0.009; P = 0.96) or M3G (r = 0.37; P = 0.04) when corrected for surgical procedure, age, and sex. There were insufficient data on CSF concentration to complete the primary analysis for M6G. CONCLUSION: Morphine distribution into the CSF was not significantly altered in patients undergoing thoracic aortic aneurysm repair. This suggests that BBB PGP function may not be affected by the perioperative inflammatory response. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT 00878371. Registered 7 April 2009.

Aspirin in the perioperative period: a review of the recent literature.

PURPOSE OF REVIEW: The indications for aspirin (ASA) for both primary and secondary prevention of thrombotic events continue to evolve. We review some of these indications and the recent literature regarding the perioperative administration of ASA. RECENT FINDINGS: ASA for primary prevention of cardiac ischemia, stroke, cancer, and death remains controversial. When used for primary prevention, ASA may be safely discontinued perioperatively. Patients with coronary or carotid artery stents should continue to receive ASA perioperatively. For patients with ischemic heart disease currently receiving ASA for secondary prevention of cardiac ischemia and stroke undergoing general surgery, orthopedic surgery, ophthalmological surgery, cardiovascular surgery, major vascular surgery, or a urological procedure, continuation of ASA is probably well tolerated, but further study is required. There is no indication to initiate ASA perioperatively in patients with stable ischemic heart disease as the risks outweigh the benefits. Until further data become available, decisions regarding the perioperative continuation of ASA should be made on a case-by-case risk-benefit analysis. SUMMARY: The continuation or discontinuation of ASA perioperatively remains a complicated issue. Further, well designed trials are needed for additional clarification.

The radiological management of pseudoaneurysms complicating pancreatitis.

CONTEXT: Pseudoaneurysms associated with pancreatitis are rare, and bleeding pseudoaneurysms are associated with a high mortality. OBJECTIVE: The aim of this study was to report the outcomes of endovascular and percutaneous therapy in the management of pseudoaneurysms secondary to pancreatitis. PATIENTS: Patients who underwent angiography for pseudoaneurysms associated with pancreatitis from 2005 to 2011 were identified from the angiography database. MAIN OUTCOME MEASURES: Patient demographics, clinical presentation, radiological findings, treatment, and outcomes were retrospectively reviewed. RESULTS: Nineteen pseudoaneurysms associated with pancreatitis in 13 patients were identified. The diagnosis of a pseudoaneurysm was made by computerised tomography angiography in seven patients, followed by portal venous phase contrast enhanced CT (n=4), duplex ultrasound (n=1) and angiography (n=1). At angiography, coil embolisation was attempted in 11 patients with an initial success rate of 82% (n=9). One patient underwent successful embolisation with percutaneous thrombin injection. The recurrence rate following initial successful embolisation was 11% (n=1). There were no episodes of re-bleeding following embolisation but re-bleeding following thrombin injection was observed in one case. The morbidity and mortality rate in the 12 patients that were successfully treated was 25% (n=3) and 8% (n=1), respectively. All 12 patients that were successfully treated demonstrated radiological resolution of their pseudoaneurysms, with a median follow-up of 20 months. CONCLUSION: Endovascular embolisation is a suitable first-line management strategy associated with low recurrence rates. The role of percutaneous thrombin injection is yet to be defined.

Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials.

OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury. DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles. STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury. DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results. DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure. CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.

Lymph node ratio versus number of affected lymph nodes as predictors of survival for resected pancreatic adenocarcinoma.

BACKGROUND: The objective of this study was to compare the prognostic significance of the lymph node ratio (LNR) with the absolute number of affected lymph nodes for resected pancreatic ductal adenocarcinoma. METHODS: Data were collected from 84 patients who had undergone pancreatoduodenectomy for pancreatic ductal adenocarcinoma over a 10-year period. Patients were categorized into four groups according to the absolute LNR (0, 0-0.199, 0.2-0.299, > or =0.3). Kaplan-Meier and Cox proportional hazard models were used to evaluate the prognostic effect. RESULTS: An LNR of > or =0.2 (median survival 8.1 vs. 35.7 months with LNR < 0.2; p < 0.001) and > or =0.3 (median survival 5.9 vs. 29.6 months with LNR < 0.3; p < 0.001), tumor size (p < 0.017), positive resection margin (p < 0.001), and nodal involvement (p < 0.001) were found to be significant prognostic markers following univariate analysis. Following multivariate analysis, only LNR at both levels [> or =0.2 (p = 0.05; HR 1.8) and LNR of > or =0.3 (p = 0.01; HR 2.7)] were independent predictors of a poor outcome. The number of lymph nodes examined had no effect on overall survival in either node-positive patients (p = 0.339) or node-negative patients (p = 0.473). CONCLUSIONS: The LNR represents a stronger independent prognostic indicator than the absolute number of affected lymph nodes in patients with resected pancreatic ductal adenocarcinoma.

Should ancillary brain blood flow analyses play a larger role in the neurological determination of death?

PURPOSE: We present two patients who regained spontaneous respiration following clinical neurological determination of death (NDD) while ancillary radiological imaging demonstrated brain blood flow. CLINICAL FEATURES: A 26-yr-old male with chronic otitis media presented with a Glasgow Coma Scale (GCS) score of 3 and fixed 7-mm pupils. Computed tomography demonstrated right-sided mastoiditis and a temporal lobe abscess associated with uncal herniation. The patient was diagnosed brain dead seven-hr later when motor responses and brainstem reflexes were absent and his apnea test was positive. Approximately 28-hr after NDD, during post-declaration organ resuscitation, the patient regained spontaneous respiration and magnetic resonance imaging revealed brain blood flow. Spontaneous respirations persisted for five-days before cardiovascular collapse occurred. In the second case, a 50-yr-old female presented with a GCS score of 3 and fixed 6-mm pupils following a traumatic brain injury and a five-minute cardiac arrest. The patient was deemed clinically brain dead six-hr later when physical examination revealed absent motor responses and brainstem reflexes and her apnea test was positive. As confirmation of brain death, a cerebral radionuclide angiogram was performed, which surprisingly revealed intracranial arterial flow. During organ resuscitation, 11-hr after NDD, the patient regained spontaneous respiration. She expired hours after family decision to withdraw treatment. CONCLUSION: For both patients, several unrecognized confounding factors for NDD were present. These cases illustrate the difficulties encountered by experienced clinicians in determining brain death using clinical criteria alone, and they suggest that more routine use of ancillary brain blood flow analyses should be recommended.

Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain.

OBJECTIVE: In animals, central nervous system inflammation increases drug accumulation in the brain partly due to a loss of central nervous system drug efflux transporter function at the blood-brain barrier. To determine whether a similar loss of active drug efflux occurs in humans after acute inflammatory brain injury. DESIGN: Observational human pharmacokinetic study. SETTING: Medical-surgical-neurosurgical intensive care unit at a university-affiliated, Canadian tertiary care center. PATIENTS: Patients with acute inflammatory brain injury, including subarachnoid hemorrhage (n = 10), intracerebral and/or intraventricular hemorrhage (n = 4), or closed head trauma (n = 2) who received morphine intravenously after being fitted with cerebrospinal fluid ventriculostomy and peripheral arterial catheters. INTERVENTIONS: We correlated the cerebrospinal fluid distribution of morphine, morphine-3-glucuronide, and morphine-6-glucuronide with the cerebrospinal fluid and plasma concentration of the proinflammatory cytokine interleukin-6 and the passive marker of blood-brain barrier permeability, albumin. MEASUREMENTS AND MAIN RESULTS: Acute brain injury produced a robust inflammatory response in the central nervous system as reflected by the elevated concentration of interleukin-6 in cerebrospinal fluid. Penetration of morphine metabolites into the central nervous system increased in proportion to the neuroinflammatory response as demonstrated by the positive correlation between cerebrospinal fluid interleukin-6 exposure and the area under the curve cerebrospinal fluid/plasma ratio for morphine-3-glucuronide (r = .49, p < .001) and morphine-6-glucuronide (r = .51, p < .001). In contrast, distribution of morphine into the brain was not linked with cerebrospinal fluid interleukin-6 exposure (r = .073, p = .54). Albumin concentrations in plasma and cerebrospinal fluid were consistently in the normal range, indicating that the physical integrity of the blood-brain barrier was likely undisturbed. CONCLUSIONS: Our results suggest that central nervous system inflammation following acute brain injury may selectively inhibit the activity of specific drug efflux transporters within the blood-brain barrier. This finding may have significant implications for patients with neuroinflammatory conditions when administered centrally acting drugs normally excluded from the brain by such transporters.

Large bowel obstruction in pregnancy: a rare entity, an unusual cause.

BACKGROUND: Large bowel obstruction is a rare and difficult diagnosis in pregnancy. Common causes are caecal and sigmoid volvulus and less common pseudo-obstruction. An infrequent cause of large bowel obstruction from an adhesive band in pregnancy causing diagnostic difficulty is reported. METHODS: Report of an unusual cause of large bowel obstruction in pregnancy. RESULTS: Diagnostic colonoscopy confirmed large bowel obstruction at the level of sigmoid. Laparotomy revealed this to be from a single band adhesion originating from the site of previous appendicectomy. Division of the band resolved the obstruction. CONCLUSIONS: A high index of suspicion is necessary for the diagnosis of large bowel obstruction in pregnancy especially in women with previous history of abdominal or pelvic surgery. Colonoscopy is helpful avoiding radiation to foetus and mother. Prompt surgical intervention reduces risks and maximises chances for a favourable outcome for both mother and child.

Palliative and end-of-life care for patients with cardiopulmonary diseases: American College of Chest Physicians position statement.

Acute and chronic pulmonary and cardiac diseases often have a high mortality rate, and can be a source of significant suffering. Palliative care, as described by the Institute of Medicine, "seeks to prevent, relieve, reduce or soothe the symptoms of disease or disorder without effecting a cure... Palliative care in this broad sense is not restricted to those who are dying or those enrolled in hospice programs." The American College of Chest Physicians strongly supports the position that such palliative and end-of-life care of the patient with an acute devastating or chronically progressive pulmonary or cardiac disease and his/her family should be an integral part of cardiopulmonary medicine. This care is best provided through an interdisciplinary effort by competent and experienced professionals under the leadership of a knowledgeable and compassionate physician. To that end, it is hoped that this statement will serve as a framework within which physicians may develop their own approach to the management of patients requiring palliative care.

Drug absorption, distribution, metabolism and excretion considerations in critically ill adults.

INTRODUCTION: All critically ill patients require medication to treat organ dysfunction. However, the pharmacokinetics of drugs used to treat these patients is complex due to frequent alterations in drug absorption, distribution, metabolism, and excretion (ADME). AREAS COVERED: This review examines pharmacokinetic aspects of drug administration for adult intensive care unit (ICU) patients. Specifically, the authors examine the ADME changes that occur and which should be considered by clinicians when delivering drug therapy to critically ill patients. EXPERT OPINION: Dosage pharmacokinetics determined from single-dose or limited-duration administration studies in healthy volunteers may not apply to critically ill patients. Organ dysfunction among these patients may be due to pre-existing disease or the effects of a systemic or locoregional inflammatory response precipitated by their illness. Alterations in pharmacokinetics observed among the critically ill include altered bioavailability after enteral administration, increased volume of distribution and blood-brain barrier permeability and changes in P-glycoprotein and cytochrome P450 enzyme function. However, the effect of these changes on clinically important outcomes remains uncertain and poorly studied. Future investigations should examine not only pharmacokinetic changes among the critically ill, but also whether recognition of these changes and alterations in drug therapy directed as a consequence of their observation alters patient outcomes.

Heparin-induced thrombocytopenia in medical surgical critical illness.

BACKGROUND: In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3,746 critically ill patients, 17 patients (0.5%) developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to a lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (five vs 12 patients, P = .14), which was statistically significant (three vs 12 patients, P = .046) in a prespecified per-protocol analysis that excluded patients with DVT at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis may reduce HIT frequency in patients in the ICU. METHODS: In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to the study drug and other open-label heparin, to determine whether the study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT. RESULTS: HIT-associated thrombosis occurred in 10 of 17 patients (58.8%) (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P = .020), including less seroconversion (P = .058) and less breakthrough of thrombocytopenia/thrombosis (P = .032). Antiplatelet factor 4/heparin IgG antibodies by enzyme-linked immunosorbent assay were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%, P < .001). One patient with HIT-associated DVT died after UFH bolus (anaphylactoid reaction), whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH. CONCLUSIONS: The lower risk of HIT in patients in the ICU receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.

Sedation for critically ill or injured adults in the intensive care unit: a shifting paradigm.

As most critically ill or injured patients will require some degree of sedation, the goal of this paper was to comprehensively review the literature associated with use of sedative agents in the intensive care unit (ICU). The first and selected latter portions of this article present a narrative overview of the shifting paradigm in ICU sedation practices, indications for uninterrupted or prolonged ICU sedation, and the pharmacology of sedative agents. In the second portion, we conducted a structured, although not entirely systematic, review of the available evidence associated with use of alternative sedative agents in critically ill or injured adults. Data sources for this review were derived by searching OVID MEDLINE and PubMed from their first available date until May 2012 for relevant randomized controlled trials (RCTs), systematic reviews and/or meta-analyses and economic evaluations. Advances in the technology of mechanical ventilation have permitted clinicians to limit the use of sedation among the critically ill through daily sedative interruptions or other means. These practices have been reported to result in improved mortality, a decreased length of ICU and hospital stay and a lower risk of drug-associated delirium. However, in some cases, prolonged or uninterrupted sedation may still be indicated, such as when patients develop intracranial hypertension following traumatic brain injury. The pharmacokinetics of sedative agents have clinical importance and may be altered by critical illness or injury, co-morbid conditions and/or drug-drug interactions. Although use of validated sedation scales to monitor depth of sedation is likely to reduce adverse events, they have no utility for patients receiving neuromuscular receptor blocking agents. Depth of sedation monitoring devices such as the Bispectral Index (BIS©) also have limitations. Among existing RCTs, no sedative agent has been reported to improve the risk of mortality among the critically ill or injured. Moreover, although propofol may be associated with a shorter time to tracheal extubation and recovery from sedation than midazolam, the risk of hypertriglyceridaemia and hypotension is higher with propofol. Despite dexmedetomidine being linked with a lower risk of drug-associated delirium than alternative sedative agents, this drug increases risk of bradycardia and hypotension. Among adults with severe traumatic brain injury, there are insufficient data to suggest that any single sedative agent decreases the risk of subsequent poor neurological outcomes or mortality. The lack of examination of confounders, including the type of healthcare system in which the investigation was conducted, is a major limitation of existing pharmacoeconomic analyses, which likely limits generalizability of their results.

Knockdown of microRNA-21 inhibits proliferation and increases cell death by targeting programmed cell death 4 (PDCD4) in pancreatic ductal adenocarcinoma.

OBJECTIVE: This study aims to examine the expression of a panel of five microRNAs (miRNA) in pancreatic ductal adenocarcinoma (PDAC) and the functional effect of miR-21 inhibition in PDAC cell lines. BACKGROUND: miRNA are short, non-coding RNA molecules, which play important roles in several cellular processes by silencing expression of their target genes through translational repression or mRNA degradation. They are often aberrantly expressed in cancer, and this dysregulation can promote carcinogenesis by altering the expression of tumour suppressor or oncogenes. METHODS: miRNA expression levels were measured in 24 PDAC tumour/matched adjacent normal tissue samples and three PDAC cell lines using reverse transcription polymerase chain reaction. Levels of cell proliferation and death and expression of programmed cell death 4 (PDCD4; tumour suppressor) were studied in PDAC cells (MIA-Pa-Ca-2) in the absence or presence of a miR-21 inhibitor. RESULTS: PDAC primary tissues and cell lines displayed a consistent upregulation of miR-21 (P < 0.0001) and downregulation of both miR-148a (P < 0.0001) and miR-375 (P < 0.0001) relative to adjacent normal tissue. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). Inhibition of miR-21 in MIA-Pa-Ca-2 PDAC cells led to reduced cell proliferation (P < 0.01) and increased cell death (P < 0.01), with simultaneous increase in levels of the tumour suppressor, PDCD4 (P < 0.01). CONCLUSION: miRNA expression profiles may be used as biomarkers for detecting pancreatic cancer. Moreover, miR-21 could be a predictor of disease progression and a possible therapeutic target in part by upregulating PDCD4 in pancreatic cancer.

Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil-lymphocyte versus platelet-lymphocyte ratio.

BACKGROUND: The objective of this study was to investigate whether the preoperative hematologic markers, the platelet-lymphocyte ratio (PLR), or the neutrophil-lymphocyte ratio (NLR) ratio are significant prognostic indicators in resected pancreatic ductal adenocarcinoma. METHODS: A total of 84 patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma over a 10-year period were identified from a retrospectively maintained database. RESULTS: The preoperative NLR was found to be a significant prognostic marker (P = .023), whereas PLR had no significant relationship with survival (P = .642) using univariate Cox survival analysis. The median overall survival in patients with an NLR of < or =3.0 (n = 55) was 13.7, 17.0 months in those with an NLR of 3.0 to 4.0 (n = 17) and 5.9 months in patients with a value of >4.0 (n = 12) (log rank, P = .016). The NLR retained its significance on multivariate analysis (P = .039) along with resection margin status (P = .001). CONCLUSION: The preoperative NLR represents a significant independent prognostic indicator in patients with resected pancreatic ductal adenocarcinoma, whereas PLR does not.