Utility of near infrared light to determine tissue oxygenation during hepato-biliary surgery.

Near-infrared spectrophotometry assesses cerebral oxygen saturation (ScO2) based on the absorption spectra of oxygenated and deoxygenated hemoglobin, and the translucency of biological tissue, in the near-infrared band. There is increasing evidence that optimising cerebral oxygenation, guided by ScO2, is associated with improved outcomes in a variety of high risk surgical settings. However, in patients with liver disease, bilirubin can potentially render cerebral oximetry inaccurate. As a result, measurement of cerebral oxygen saturation is rarely undertaken in patients undergoing hepatobiliary surgery. We prospectively measured baseline and intraoperative cerebral oxygen saturation in patients undergoing major pancreatic surgery. Indices including bilirubin, sodium, platelets and maximum amplitude on thromboelastography were associated with low baseline ScO2. However, those patients with low ScO2 (≤51%) maintained a similar trend in cerebral oximetry values both at induction and intraoperatively to those with a normal ScO2. We conclude that the pattern of cerebral oximetry is similar in patients undergoing major pancreatic surgery regardless of their underlying liver dysfunction. Therefore, cerebral oximetry may have a role in monitoring neurological function in this high risk group of patients.

Overexpression of the cellular retinoic acid binding protein-I (CRABP-I) results in a reduction in differentiation-specific gene expression in F9 teratocarcinoma cells.

Treatment of F9 teratocarcinoma stem cells with retinoic acid (RA) causes their irreversible differentiation into extraembryonic endoderm. To elucidate the role of the cellular retinoic acid binding protein-I (CRABP-I) in this differentiation process, we have generated several different stably transfected F9 stem cell lines expressing either elevated or reduced levels of functional CRABP-I protein. Stably transfected lines expressing elevated levels of CRABP-I exhibit an 80-90% reduction in the RA induced expression of retinoic acid receptor (RAR) beta, laminin B1, and collagen type IV (alpha 1) mRNAs at low exogenous RA concentrations, but this reduction is eliminated at higher RA concentrations. Thus, greater expression of CRABP-I reduces the potency of RA in this differentiation system. Moreover, transfection of a CRABP-I expression vector into F9 cells resulted in five- and threefold decreases in the activation of the laminin B1 RARE (retinoic acid response element) and the RAR beta RARE, respectively, as measured from RARE/CAT expression vectors in transient transfection assays. These results support the idea that CRABP-I sequesters RA within the cell and thereby prevents RA from acting to regulate differentiation specific gene expression. Our data suggest a mechanism whereby the level of CRABP-I can regulate responsiveness to RA during development.

Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.

F9 embryonic teratocarcinoma stem cells differentiate into an epithelial cell type called extraembryonic endoderm when treated with retinoic acid (RA), a derivative of retinol (vitamin A). This differentiation is presumably mediated through the actions of retinoid receptors, the RARs and RXRs. To delineate the functions of each of the different retinoid receptors in this model system, we have generated F9 cell lines in which both copies of either the RAR alpha gene or the RAR gamma gene are disrupted by homologous recombination. The absence of RAR alpha is associated with a reduction in the RA-induced expression of both the CRABP-II and Hoxb-1 (formerly 2.9) genes. The absence of RAR gamma is associated with a loss of the RA-inducible expression of the Hoxa-1 (formerly Hox-1.6), Hoxa-3 (formerly Hox-1.5), laminin B1, collagen IV (alpha 1), GATA-4, and BMP-2 genes. Furthermore, the loss of RAR gamma is associated with a reduction in the metabolism of all-trans-RA to more polar derivatives, while the loss of RAR alpha is associated with an increase in metabolism of RA relative to wild-type F9 cells. Thus, each of these RARs exhibits some specificity with respect to the regulation of differentiation-specific gene expression. These results provide an explanation for the expression of multiple RAR types within one cell type and suggest that each RAR has specific functions.

Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.

A study of chronic i.v. dosing of all-trans-retinoic acid (all-trans-RA) was performed to determine whether induction of the capacity-limited elimination process for all-trans-RA occurred with long-term drug administration. Because up-regulation of the cellular retinoic acid-binding proteins (CRABP) may act to bind all-trans-RA intracellularly, the amount of CRABP in skin biopsy samples obtained during and following the course of all-trans-RA administration was also determined. Four adult rhesus monkeys received 50 mg/m2 of all-trans-RA by bolus i.v. injection daily for 8 consecutive days and again for one additional dose following a 7-day period without drug. The plasma disappearance curve of all-trans-RA was characterized by a plateau phase, the duration of which decreased during the period of chronic drug administration, followed by a terminal exponential decay phase, which is consistent with a capacity-limited (saturable) elimination process. The Vmax of this process increased from 0.06 mumol/min on the first day to 0.17 mumol/min by the eighth day of all-trans-RA administration, consistent with induction of an enzymatic process. The amount of CRABP measured in skin biopsy specimens was rapidly induced, increasing to approximately 3-fold baseline levels by day 3 of all-trans-RA administration. It remained at this level throughout the period of chronic drug administration but diminished following the 7-day period without drug. These findings suggest that an intermittent schedule of administration for all-trans-RA has potential advantages over a continuous administration schedule. A period of time without drug administration would allow for return of plasma drug clearance toward baseline levels and down-regulation of CRABP, which could result in higher plasma drug concentrations and possibly less cytoplasmic binding of drug.

Role of the Ha-ras (RasH) oncogene in mediating progression of the tumor cell phenotype (review).

Recent experimental evidence indicates that the c-Ha-ras (rasH) oncogene may be causally involved in the etiology and evolution of specific human neoplasms. In addition, cultured cells transformed by the rasH oncogene can induce both a tumorigenic and a metastatic phenotype when expressed in appropriate cultured cells. To begin to define the molecular and biochemical mechanism(s) by which the rasH oncogene induce their effects on expression of the transformed state we have employed a cloned rat embryo fibroblast (CREF) cell line. Transformation of CREF cells with wild-type 5 adenovirus (Wt) results in transformed cells which display anchorage-independence and an increased saturation density in monolayer culture, but are non-tumorigenic in both athymic nude mice and syngeneic Fischer rats. In contrast, when CREF cells are transformed with mutant type 5 adenoviruses, such as H5hrl, or the ElA transforming gene from hrl (0-4.5), tumors are induced in both nude mice and syngeneic rats. However, hrl (0-4.5)-transformed CREF cells are not metastatic following intravenous injection into the tail vein of syngeneic rats. Insertion of an activated T24 rasH oncogene or a wild-type v-rasH oncogene into CREF, wt-transformed CREF or hrl (0-4.5)-transformed CREF cells results in acquisition of a metastatic phenotype by these cells. A mutant v-rasH oncogene (mutant 116K), which is defective in GTP binding and the induction of transformation of NIH 3T3 cells, does not induce transformation in CREF cells, but it can progress wt-transformed CREF cells to a tumorigenic-non-metastatic state. Employing this model system which displays well-defined and stable stages in the tumor cell progression lineage, we have analyzed the potential role of changes in the phosphatidylinositol (PI) cycle and phospholipase A2 (PLA2) enzyme activity during progression to a tumorigenic and metastatic phenotype. An increase in PI cycle intermediates (primarily inositol triphosphate; IP3) were observed only in the wt-transformed and hrl (0-4.5)-transformed CREF cell lines transfected with the rasH oncogene. In the case of PLA2, all rasH-transformed CREF cell lines displayed increased activity. In contrast, CREF cells transformed only by Ad5 (Wt or hrl (0-4.5)) or the 116K v-rasH oncogene did not display increased PLA2 activity similar to that observed in rasH transfected cells. Since one important metabolite generated by PLA2 is arachidonic acid, which is converted into prostaglandins and leukotrienes by cyclooxygenase or lipooxygenase, respectively, the levels of prostaglandin E2 (PGE2) in the various cell lines were monitored.(ABSTRACT TRUNCATED AT 400 WORDS)

Cyclizine and droperidol have comparable efficacy and side effects during patient-controlled analgesia.

BACKGROUND: Post-operative nausea and vomiting (PONV) is common, especially following gynaecological surgery. Patient-controlled analgesia (PCA) is frequently complicated by nausea. We assessed PONV, pain and sedation in patients receiving cyclizine or droperidol during PCA following abdominal hysterectomy in a double-blind trial. METHODS: Thirty women were randomised to receive either cyclizine 0.7 mg/kg or droperidol 0.04 mg/kg during surgery followed by PCA containing morphine sulphate with cyclizine 2 mg or droperidol 0.05 mg per demand. Blinded observers scored levels of nausea, sedation, anxiety and pain. RESULTS: Pain scores, PCA usage and supplemental antiemetic requirements were comparable. Nausea and sedation scores were similar in both groups. Two patients in each group developed refractory PONV. Pre-operative anxiety scores were similar and decreased comparably over time. Patients developing refractory emetic sequelae had a higher incidence of previous PONV. Previous PONV also predicted lower PCA medication intake despite similar demand rates, suggesting increased usage during lock-out periods. CONCLUSION: Prophylactic cyclizine and droperidol have similar efficacy during PCA. Neither is associated with perioperative anxiety. A minority of patients have refractory PONV during PCA. Previous PONV may predict less efficient PCA usage.

Patients' knowledge of perioperative care.

BACKGROUND: Patient knowledge of perioperative care, particularly the role of the anaesthetist, appears limited. AIM: This study investigated patients' knowledge of common medical terms, of their surgical care, of the role of the anaesthetist, and their preoperative fears and concerns about postoperative pain. We examined the changes in their knowledge base as a result of the pre-anaesthetic visit and their inpatient stay. METHODS: Three hundred patients were surveyed on three separate occasions, before a routine pre-anaesthetic visit, two to three hours after this visit and on the day of discharge from hospital. RESULTS: Patients' knowledge of medical terms, their surgical procedure, and the role of the anaesthetist in their perioperative care were limited. There was little change following either the pre-anaesthetic visit or postoperative convalescence. Misconceptions, about such issues as postoperative pain, appeared to increase by the end of their hospital stay. Male patients, older patients and patients in lower socio-economic groups had poorer knowledge. A significant proportion of patients remained unaware that the anaesthetist was medically qualified. CONCLUSIONS: Patients' knowledge of perioperative care is limited, with very little change during hospital stay. Novel educational approaches may be required to increase basic medical knowledge.

Instructions for ambulatory surgery--patient comprehension and compliance.

Ambulatory surgery has proliferated as a result of increasing inpatient costs. Its high level of safety has resulted in its extension to less healthy, often elderly patients. Patient compliance with instructions is essential to avoid morbidity. We aimed to identify subgroups potentially at risk due to non-compliance. A confidential questionnaire was administered to 220 consecutive daycase patients. Data included: patient demographics, duration of fasting, taking of medications that morning, importance of fasting and medication instructions, mode of post-discharge transport, and whether they had someone to stay with them that night. Seven (3.5 per cent) patients admitted to non-compliance with fasting instructions, with 8 per cent considering these instructions non-essential. Thirteen of 59 patients on medications took them against instructions, with 9 patients considering the instructions non-essential. Eight patients admitted intending to drive home; 7 per cent admitted to having no one to stay with them on the night of surgery. A significantly minority of patients (particularly male) admit to non-compliance with ambulatory surgery instructions; these figures may be underestimates. Absence of anaesthetic/medical input and lack of reinforcement probably contribute to non-compliance. Some medication-related non-compliance may be appropriate (e.g. antianginals, antihypertensives) and may reflect conflicting instructions given to the patient. The stopping of all medications prior to ambulatory surgery needs revision. Older patients living alone may not be suitable candidates for ambulatory anaesthesia.

Extreme heatstroke causing fulminant hepatic failure requiring liver transplantation: a case report.

INTRODUCTION: Exertional heatstroke with liver involvement is a rare and potentially fatal condition. In this setting, fulminant hepatic failure (FHF) occurs as a result of severe hypoxic hepatitis. CASE REPORT: We report the case of a young male athlete who developed exertional heatstroke associated with rhabdomyolysis and hypoxic hepatitis while running the final stages of an ultra-marathon (62 km). The patient rapidly developed multiorgan failure, including fulminant hepatic failure, requiring intensive care admission for mechanical ventilation, hemodialysis, and inotropic support. He failed to improve with supportive measures and underwent an emergency hepatectomy followed by orthotopic liver transplant, after which he recovered completely. CONCLUSIONS: We discuss the rationale for liver transplantation in this setting, possible alternative treatments, and the pathophysiology of fulminant liver failure in this rare case.

Alcoholic liver disease in the intensive care unit: outcomes and predictors of prognosis.

BACKGROUND: An increasing number of patients with alcoholic liver disease (ALD) are being referred for critical care support, but limited information is available on their short- and medium-term outcomes. This study aimed to determine mortality rates, identify optimal predictors of prognosis, and determine the appropriate time to apply these predictors in patients with ALD admitted to intensive care unit (ICU). METHODS: In this retrospective study, patients admitted to ICU between 2009 and 2012 with a primary diagnosis of ALD were included. Survival was calculated using the Kaplan-Meier method, risk factors for death determined by logistic regression analysis, and discriminative capacity of models using receiver operating characteristic curves. RESULTS: Of 170 patients admitted with liver disease, 62 met the inclusion criteria. Survival rates in the ICU, in hospital, and at 6 months were 40.3% (95% confidence interval [CI], 30.7%-49.9%), 35.5% (95% CI, 25.35%-45.65%), and 29% (95% CI, 19.4%-38.6%), respectively. Multiple linear regression analysis of day 1 variables produced an equation with Sequential Organ Failure Assessment score and lactate as significant predictors of mortality; this model had an area under the receiver operating characteristic curve of 0.93. A score greater than 12 in this model correlated with a mortality of more than 80% at all time points and was more accurate than any other score examined. CONCLUSION: Patients admitted to ICU with ALD have a very high inhospital mortality. A combination of the established Sequential Organ Failure Assessment score and lactate provided the most accurate predictor of outcome on day of admission and at all subsequent time points.

Acute respiratory distress syndrome: current concepts and future directions.

Acute respiratory distress syndrome is one of the leading causes of death in critically ill patients. Recent advances in supportive care have led to a moderate improvement in mortality. In particular, a much lower mortality rate than expected was evident in the severest category of patients (requiring extracorporeal membrane oxygenation) in Australia during the recent H1N1 pandemic. Though improvements in supportive care may have provided some benefit, there remains an absence of effective biological agents that are necessary to achieve further incremental reduction in mortality. This article will review the evidence available for current treatment strategies and discuss future research directions that may eventually improve outcomes in this important global disease.

Randomised controlled trials: important but overrated?

Practising physicians individualise treatments, hoping to achieve optimal outcomes by tackling relevant patient variables. The randomised controlled trial (RCT) is universally accepted as the best means of comparison. Yet doctors sometimes wonder if particular patients might benefit more from treatments that fared worse in the RCT comparisons. Such clinicians may even feel ostracised by their peers for stepping outside treatments based on RCTs and guidelines. Are RCTs the only acceptable evaluations of how patient care can be assessed and delivered? In this controversy we explore the interpretation of RCT data for practising clinicians facing individualised patient choices. First, critical care anaesthetists John Boylan and Brian Kavanagh emphasise the dangers of bias and show how Bayesian approaches utilise prior probabilities to improve posterior (combined) probability estimates. Secondly, Jane Armitage, of the Clinical Trial Service Unit in Oxford, argues why RCTs remain essential and explores how the quality of randomisation can be improved through systematic reviews and by avoiding selective reporting.

The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells.

The CRABP-I and CRABP-II proteins are high affinity cytoplasmic retinoic acid-binding proteins. In undifferentiated F9 teratocarcinoma stem cells, only the CRABP-I protein is expressed at detectable levels. We have previously shown that overexpression of the CRABP-I protein in stably transfected F9 stem cell lines results in a lower sensitivity to a given external concentration of retinoic acid relative to that of untransfected F9 cells; in contrast, reduced CRABP-I expression in CRABP-I cDNA anti-sense transfected lines is associated with increased sensitivity of these lines to retinoic acid. These three types of cell lines were cultured in the presence of 50 nM [3H]retinoic acid, and the metabolism of retinoic acid was followed over the next 24 h. The results demonstrate that CRABP-I has the ability to alter both the levels and types of RA metabolites produced in the cytoplasm of differentiating embryonic stem cells. Moreover, the level of CRABP-I determines the rate of RA metabolism to 4-oxo-RA such that the higher the CRABP-I level, the faster the metabolism of [3H]retinoic acid. This is the first reported connection between the level of CRABP-I expression and intracellular RA metabolism.

The auditory steady state response during sufentanil anaesthesia.

The auditory steady state response (ASSR) is a sinusoidal evoked potential elicited by rapidly repeated auditory stimuli. The ASSR was recorded in eight patients during high-dose sufentanil anaesthesia for cardiac surgery in order to assess its usefulness as a measure of the level of consciousness. The electroencephalogram (EEG) was recorded for comparison. The ASSR was present before induction in all patients. It was attenuated severely or possibly abolished with loss of consciousness, and reappeared at low amplitude 5-10 min later and remained attenuated until the end of surgery. The amplitude increased with early signs of awakening in the Intensive Care Unit. With few exceptions, changes in the simultaneously recorded EEG were similar to those of the ASSR. The ASSR deserves further evaluation as a tool for monitoring level of consciousness during high-dose opioid anaesthesia.

The long-latency auditory evoked potential as a measure of the level of consciousness during sufentanil anesthesia.

The long-latency auditory evoked potential was recorded during opioid anesthesia to evaluate its usefulness for assessing the level of consciousness. Eight patients undergoing coronary artery surgery under high-dose sufentanil anesthesia following a lorazepam premedication were tested. Four waves were studied: the N1, P2, P3, and the slow wave (SW). The amplitude of N1 and that of the SW were reduced by sufentanil, but the differences did not reach significance. The amplitude and latency of P2 and the latency of the SW were significantly reduced. The P3, which is possibly a specific indicator for consciousness, was present before induction and absent during anesthesia. There was no conscious recall for intraoperative events. Preservation of the N1, P2, and SW, which are abolished by nonopioid general anesthetics, suggests that auditory processing proceeds further during anesthesia with sufentanil. However, no electrophysiologic evidence of consciousness was found during sufentanil anesthesia.