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1.
Colorectal Dis ; 19(6): O186-O195, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28258664

ABSTRACT

AIM: Epidural analgesia reduces the surgical stress response. However, its effect on pro- and anti-inflammatory cytokines in the genesis of inflammation following major abdominal surgery remains unclear. Our main objective was to elucidate whether perioperative epidural analgesia prevents the inflammatory response following colorectal cancer surgery. METHODS: Ninety-six patients scheduled for open or laparoscopic surgery were randomized to epidural analgesia (group E) or patient-controlled intravenous analgesia (group P). Surgery and anaesthesia were standardized in both groups. Plasma cortisol, insulin and serum cytokines [interleukin 1ß (IL-1ß), IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumour necrosis factor α, interferon γ, granulocyte-macrophage colony-stimulating factor, prostaglandin E2 and vascular endothelial growth factor] were measured preoperatively (T0), 1-6 h postoperatively (T1) and 3-5 days postoperatively (T2). Mixed model analysis was used, after logarithmic transformation when appropriate, for analyses of cytokines and stress markers. RESULTS: >There were no significant differences in any serum cytokine concentration between groups P and E at any time point except for IL-10 which was 87% higher in group P [median and range 4.1 (2.3-9.2) pg/ml] compared to group E [2.6 (1.3-4.7) pg/ml] (P = 0.002) at T1. There was no difference in plasma cortisol and insulin between the groups at any time point after surgery. A significant difference in median serum cytokine concentration was found between open and laparoscopic surgery with higher levels of IL-6, IL-8 and IL-10 at T1 in patients undergoing open surgery compared to laparoscopic surgery. No difference in serum cytokine concentration was detected between the groups or between the surgical technique at T2. CONCLUSIONS: Open surgery, compared to laparoscopic surgery, has greater impact on these inflammatory mediators than epidural analgesia vs intravenous analgesia.


Subject(s)
Analgesia, Epidural/methods , Analgesia, Patient-Controlled/methods , Analgesics/administration & dosage , Pain Management/methods , Pain, Postoperative/drug therapy , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/surgery , Cytokines/blood , Digestive System Surgical Procedures/adverse effects , Female , Humans , Hydrocortisone/blood , Insulin/blood , Laparoscopy/adverse effects , Male , Middle Aged , Pain, Postoperative/blood , Postoperative Period , Prospective Studies , Treatment Outcome
2.
Br J Anaesth ; 107(2): 164-70, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21586443

ABSTRACT

BACKGROUND: There is some evidence that epidural analgesia (EDA) reduces tumour recurrence after breast and prostatic cancer surgery. We assessed whether EDA reduces long-term mortality after colorectal cancer surgery. METHODS: All patients having colorectal cancer surgery between January 2004 and January 2008 at Linköping and Örebro were included. Exclusion criteria were: emergency operations, laparoscopic-assisted colorectal resection, and stage 4 cancer. Statistical information was obtained from the Swedish National Register for Deaths. Patients were analysed in two groups: EDA group or patient-controlled analgesia (PCA group) as the primary method of analgesia. RESULTS: A total of 655 patients could be included. All-cause mortality for colorectal cancer (stages 1-3) was 22.7% (colon: 20%, rectal: 26%) after 1-5 yr of surgery. Multivariate regression analysis identified the following statistically significant factors for death after colon cancer (P<0.05): age (>72 yr) and cancer stage 3 (compared with stage 1). A similar model for rectal cancer found that age (>72 yr) and the use of PCA rather than EDA and cancer stages 2 and 3 (compared with stage 1) were associated with a higher risk for death. No significant risk of death was found for colon cancer when comparing EDA with PCA (P=0.23), but a significantly increased risk of death was seen after rectal cancer when PCA was used compared with EDA (P=0.049) [hazards ratio: 0.52 (0.27-1.00)]. CONCLUSIONS: We found a reduction in all-cause mortality after rectal but not colon cancer in patients having EDA compared with PCA technique.


Subject(s)
Analgesia, Epidural , Anesthesia, Epidural , Colonic Neoplasms/surgery , Pain, Postoperative/prevention & control , Rectal Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Analgesia, Patient-Controlled/methods , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Neoplasm Staging , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Sweden/epidemiology , Young Adult
3.
J Physiol Pharmacol ; 62(1): 119-24, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21451217

ABSTRACT

Neuronal intracellular transport is performed by motor proteins, which deliver vesicles, organelles and proteins along cytoskeletal tracks inside the neuron. We have previously shown that the anesthetic propofol causes dose- and time-dependent, reversible retraction of neuronal neurites. We hypothesize that propofol alters the vesicular transport of cortical neurons due to this neurite retraction. Primary cultures of co-cultivated rat cortical neurons and glial cells were exposed to either 2 µM propofol, control medium or the lipid vehicle, in time-response experiments. Reversibility was tested by washing propofol off the cells. The role of the GABA(A) receptor (GABA(A)R) was assessed with the GABA(A)R antagonist gabazine. Vesicles were tracked using differential interference contrast video microscopy. Propofol caused a retrograde movement in 83.4±5.2% (mean±S.E.M.) of vesicles, which accelerated over the observed time course (0.025±0.012 µm.s⁻¹). In control medium, vesicles moved predominantly anterograde (84.6±11.1%) with lower velocity (0.011±0.004 µm.s⁻¹). Cells exposed to the lipid vehicle showed the same dynamic characteristics as cells in control medium. The propofol-induced effect on vesicle transport was reversible and blocked by the GABA(A)R antagonist gabazine in low concentration. Our results show that propofol causes a reversible, accelerating vesicle movement toward the neuronal cell body that is mediated via synaptic GABA(A)R. We have previously reported that propofol initiates neurite retraction, and we propose that propofol causes vesicle movement by retrograde flow of cytoplasm from the narrowed neurite.


Subject(s)
Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Neurons/drug effects , Neurons/metabolism , Propofol/pharmacology , Transport Vesicles/drug effects , Animals , Cells, Cultured , Cerebral Cortex/cytology , Molecular Motor Proteins/metabolism , Neurites/metabolism , Neuroglia/metabolism , Neurons/cytology , Pyridazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism
4.
Br J Anaesth ; 104(3): 305-12, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20150346

ABSTRACT

BACKGROUND: Major adverse cardiac events (MACEs) are a common cause of death after non-cardiac surgery. Despite evidence for the benefit of aspirin for secondary prevention, it is often discontinued in the perioperative period due to the risk of bleeding. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in order to compare the effect of low-dose aspirin with that of placebo on myocardial damage, cardiovascular, and bleeding complications in high-risk patients undergoing non-cardiac surgery. Aspirin (75 mg) or placebo was given 7 days before surgery and continued until the third postoperative day. Patients were followed up for 30 days after surgery. RESULTS: A total of 220 patients were enrolled, 109 patients received aspirin and 111 received placebo. Four patients (3.7%) in the aspirin group and 10 patients (9.0%) in the placebo group had elevated troponin T levels in the postoperative period (P=0.10). Twelve patients (5.4%) had an MACE during the first 30 postoperative days. Two of these patients (1.8%) were in the aspirin group and 10 patients (9.0%) were in the placebo group (P=0.02). Treatment with aspirin resulted in a 7.2% absolute risk reduction [95% confidence interval (CI), 1.3-13%] for postoperative MACE. The relative risk reduction was 80% (95% CI, 9.2-95%). Numbers needed to treat were 14 (95% CI, 7.6-78). No significant differences in bleeding complications were seen between the two groups. CONCLUSIONS: In high-risk patients undergoing non-cardiac surgery, perioperative aspirin reduced the risk of MACE without increasing bleeding complications. However, the study was not powered to evaluate bleeding complications.


Subject(s)
Aspirin/administration & dosage , Cardiovascular Diseases/prevention & control , Perioperative Care/methods , Platelet Aggregation Inhibitors/administration & dosage , Postoperative Complications/prevention & control , Aged , Aged, 80 and over , Aspirin/adverse effects , Blood Loss, Surgical , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Postoperative Hemorrhage/chemically induced
5.
Br J Anaesth ; 103(2): 206-12, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19525507

ABSTRACT

BACKGROUND: The aim of this investigation was to assess the incidence of elevated N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) and its relation to outcome defined as perioperative adverse cardiac events and all-cause mortality in high-risk patients undergoing non-elective surgery for hip fracture. METHODS: A cohort of patients with hip fractures were extracted from a prospective observational study of high-risk patients (ASA class III or IV) undergoing emergency surgery. NT-proBNP and troponin I were measured before operation. An NT-proBNP > or = 3984 ng litre(-1) was set as the cut-off level for significance. Perioperative adverse cardiac events and 30 day and 3 month mortality were recorded. RESULTS: Sixty-nine subjects were included. Thirty-four subjects (49%) had an NT-proBNP > or = 3984 ng litre(-1) before surgery. Thirty-four subjects (49%) had a perioperative adverse cardiac event. Of these, 22 subjects (65%) had NT-proBNP above the diagnostic threshold compared with 12 subjects (34%) who had an NT-proBNP below the diagnostic threshold (P=0.01). Preoperative NT-proBNP > or = 3984 ng litre(-1) [odds ratio (OR) 3.0; 95% confidence interval (CI) 1.0-8.9] and congestive heart failure (OR 3.0; 95% CI 1.0-9.0) were independent predictors of perioperative adverse cardiac events. A total of eight subjects (12%) died within 30 days after operation. CONCLUSIONS: There is a high incidence of elevated NT-proBNP in subjects undergoing non-elective hip fracture surgery. Preoperative NT-proBNP is a valuable predictor of cardiac complications in the perioperative period.


Subject(s)
Hip Fractures/surgery , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Aged , Aged, 80 and over , Biomarkers/blood , Cardiovascular Diseases/etiology , Emergencies , Female , Hip Fractures/blood , Humans , Male , Postoperative Complications , Preoperative Care/methods , Prognosis , Prospective Studies
6.
Acta Anaesthesiol Scand ; 53(8): 986-94, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19388892

ABSTRACT

BACKGROUND: The aim of this study was to determine the incidence of myocardial damage and left ventricular myocardial dysfunction and their influence on outcome in high-risk patients undergoing non-elective surgery. METHODS: In this prospective observational study, 211 patients with American Society of Anesthesiologists classification III or IV undergoing emergent or urgent surgery were included. Troponin I (TnI) was measured pre-operatively, 12 and 48 h post-operatively. Pre-operative N-terminal fragment of B-type natriuretic peptide (NT-proBNP), as a marker for left ventricular systolic dysfunction, was analyzed. The diagnostic thresholds were set to TnI >0.06 microg/l and NT-proBNP >1800 pg/ml, respectively. Post-operative major adverse cardiac events (MACE), 30-day and 3-months mortality were recorded. RESULTS: Elevated TnI levels were detected in 33% of the patients post-operatively. A TnI elevation increased the risk of MACE (35% vs. 3% in patients with normal TnI levels, P<0.001) and 30-day mortality (23% vs. 7%, P=0.003). Increased concentrations of NT-proBNP were seen in 59% of the patients. Elevated NT-proBNP was an independent predictor of myocardial damage post-operatively, odds ratio, 6.2 [95% confidence interval (CI) 2.1-18.0] and resulted in an increased risk of MACE (21% vs. 2.5% in patients with NT-proBNP < or = 1800 pg/ml, P<0.001). CONCLUSION: Myocardial damage is common in a high-risk population undergoing unscheduled surgery. These results suggest a close correlation between myocardial damage in the post-operative period and increased concentration of NT-proBNP before surgery. The combinations of TnI and NT-proBNP are reliable markers for monitoring patients at risk in the peri-operative period as well as useful tools in our risk assessment pre-operatively in emergency surgery.


Subject(s)
Emergency Medical Services , Heart Diseases/diagnosis , Surgical Procedures, Operative , Aged , Aged, 80 and over , Biomarkers , Endpoint Determination , Female , Heart Diseases/mortality , Heart Diseases/pathology , Heart Function Tests , Humans , Male , Myocardium/pathology , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Predictive Value of Tests , ROC Curve , Risk , Surgical Procedures, Operative/mortality , Survival Analysis , Troponin I/blood
7.
Br J Anaesth ; 101(3): 374-9, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18587139

ABSTRACT

BACKGROUND: The mechanism by which anaesthetic agents produce general anaesthesia is not yet fully understood. Retraction of neurites is an important function of individual neurones and neural plexuses during normal and pathological conditions, and it has been shown that such a retraction pathway exists in developing and mature neurones. We hypothesized that propofol decreases neuronal activity by causing retraction of neuronal neurites. METHODS: Primary cultures of rat cortical neurones were exposed in concentration- and time-response experiments to 0.02, 0.2, 2, and 20 microM propofol or lipid vehicle. Neurones were pretreated with the GABA(A) receptor (GABA(A)R) antagonist, bicuculline, the myosin II ATPase activity inhibitor, blebbistatin, and the F-actin stabilizing agent, phalloidin, followed by administration of propofol (20 microM). Changes in neurite retraction were evaluated using time-lapse light microscopy. RESULTS: Propofol caused a concentration- and time-dependent reversible retraction of cultured cortical neurone neurites. Bicuculline, blebbistatin, and phalloidin completely inhibited propofol-induced neurite retraction. Images of retracted neurites were characterized by a retraction bulb and a thin trailing membrane remnant. CONCLUSIONS: Cultured cortical rat neurones retract their neurites after exposure to propofol in a concentration- and time-dependent manner. This retraction is GABA(A)R mediated, reversible, and dependent on actin and myosin II. Furthermore, the concentrations and times to full retraction and recovery correspond to those observed during propofol anaesthesia.


Subject(s)
Anesthetics, Intravenous/pharmacology , Neurites/drug effects , Propofol/pharmacology , Anesthetics, Intravenous/antagonists & inhibitors , Animals , Bicuculline/pharmacology , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Dose-Response Relationship, Drug , GABA Antagonists/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Neurites/ultrastructure , Phalloidine/pharmacology , Propofol/antagonists & inhibitors , Rats , Rats, Sprague-Dawley
8.
Acta Anaesthesiol Scand ; 51(9): 1184-9, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17850559

ABSTRACT

AIM: Interaction with the gamma-aminobutyric acid receptor (GABA(A)R) complex is recognized as an important component of the mechanism of many anaesthetic agents, including propofol. The aims of this study were to investigate the effect of propofol on GABA(A)R, to determine whether exposure of neurones to propofol influences the localization of GABA(A)R within the cell and to look for cytoskeletal changes that may be connected with activation, such as the mitogen-activated protein kinase (MAPK) pathway. METHODS: Primary cortical cell cultures from rat, with and without pre-incubation with the GABA(A)R antagonist bicuculline, were exposed to propofol. The cells were lysed and separated into membrane and cytosolic fractions. Immunoblot analyses of filamentous actin (F-actin), the GABA(A)beta(2)-subunit receptor and extracellular signal-regulated kinase-1/2 (ERK-1/2) were performed. RESULTS: Propofol triggers an increase in GABA(A)R, actin content and ERK-1/2 phosphorylation in the cytosolic fraction. In the membrane fraction, there is a decrease in GABA(A)beta(2)-subunit content and an increase in both actin content and ERK-1/2 phosphorylation. The GABA(A)R antagonist bicuculline blocks the propofol-induced changes in F-actin, ERK and GABA(A)beta(2)-subunit content, and ERK-1/2 phosphorylation. CONCLUSION: We believe that propofol triggers a dose-dependent internalization of the GABA(A)beta(2)-subunit. The increase in internal GABA(A)beta(2)-subunit content exhibits a close relationship to actin polymerization and to an increase in ERK-1/2 activation. Actin contributes to the internalization sequestering of the GABA(A)beta(2)-subunit.


Subject(s)
Actins/drug effects , Anesthetics, Intravenous/pharmacology , Extracellular Signal-Regulated MAP Kinases/drug effects , Neurons/drug effects , Propofol/pharmacology , Receptors, GABA-A/drug effects , Animals , Bicuculline/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , GABA Antagonists/pharmacology , Neurons/chemistry , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism
9.
Acta Anaesthesiol Scand ; 48(9): 1071-9, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15352951

ABSTRACT

BACKGROUND: The aim of this study was to evaluate the significance of elevated postoperative Troponin T (TnT) levels in an elderly population undergoing non-cardiac surgery. METHODS: Five hundred and forty-six consecutive patients aged 70 years or older undergoing non-cardiac surgery of >30-min duration were enrolled in this prospective, observational study. A postoperative TnT measurement was obtained on the 5th to 7th postoperative day. Troponin T values greater than 0.02 ng ml(-1) were considered positive. Patients were followed over a 1-year period, and mortality and non-fatal cardiac events (acute myocardial infarction and coronary interventions) were recorded. RESULTS: Troponin T concentrations greater than 0.02 ng ml(-1) were detected in 53 of the study subjects (9.7%). Eleven per cent of the patients with elevated TnT had electrocardiographic or clinical signs of myocardial ischemia. One year after surgery, 17 (32%) of the patients with abnormal TnT concentrations had died. In a multivariate Cox regression analysis adjusting for baseline and perioperative data, a TnT value >0.02 ng ml(-1) was an independent correlate of the mortality adjusted hazard ratio (HR): 14.9 (95% CI 3.7-60.3). Other independent predictors of death were tachycardia (HR, 14.9 95% CI 3.45-64.8), ASA 4 (HR, 8.1 95% CI 1.3-50.0), reoperation (HR, 6.4 95% CI 1.1-36.9), and use of diuretics (HR, 4.2 95% CI 1.3-13.8). CONCLUSION: We conclude that elevated TnT levels in the postoperative period confer a 15-fold increase in mortality during the first year after surgery. Our findings also provide evidence that silent myocardial ischemia is common in an elderly population. Routine perioperative surveillance for TnT might therefore be of use in detecting patients at an increased risk of mortality during the first postoperative year.


Subject(s)
Postoperative Complications/diagnosis , Surgical Procedures, Operative/adverse effects , Troponin T/blood , Aged , Anesthesia , Cause of Death , Endpoint Determination , Female , Follow-Up Studies , Heart Diseases/epidemiology , Heart Diseases/mortality , Humans , Male , Postoperative Complications/mortality , Predictive Value of Tests , Prognosis , Prospective Studies
10.
Acta Anaesthesiol Scand ; 47(2): 157-64, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12631044

ABSTRACT

BACKGROUND: Propofol is known to interact with the gamma-aminobutyric acidA (GABA(A)) receptor, however, activating the receptor alone is not sufficient for producing anaesthesia. METHODS: To compare propofol and GABA, their interaction with the GABAA receptor beta subunit and actin were studied in three cellular fractions of cultured rat neurons using Western blot technique. RESULTS: Propofol tyrosine phosphorylated the GABA(A) receptor beta2 (MW 54 and 56 kDa) and beta3 (MW 57 kDa) subtypes. The increase was shown in both the cytoskeleton (beta2(54) and beta2(56) subtypes) and the cell membrane (beta2(54) and beta3 subtypes). Concurrently the 56 kDa beta2 subtype was reduced in the cytosol. Propofol, but not GABA, also tyrosine phosphorylated actin in the cell membrane and cytoskeletal fraction. Without extracellular calcium available, the amount of actin decreased in the cytoskeleton, but tyrosine phosphorylation was unchanged. GABA caused increased tyrosine phosphorylation of beta2(56) and beta3 subtypes in the membrane and both beta2 subtypes in the cytoskeleton but no cytosolic tyrosine phosphorylation. CONCLUSION: The difference between propofol and GABA at the GABA(A) receptor was shown to take place in the membrane, where the beta2(54) was increased by propofol and instead the beta2(56) subtype was increased by GABA. Only propofol also tyrosine phosphorylated actin in the cell membrane and cytoskeletal fraction. This interaction between the GABAA receptor and actin might explain the difference between anaesthesia and physiological neuronal inhibition.


Subject(s)
Actins/drug effects , Anesthesia , Anesthetics, Intravenous/pharmacology , Propofol/pharmacology , Receptors, GABA-A/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology , Sleep/physiology , gamma-Aminobutyric Acid/pharmacology , Animals , Blotting, Western , Cell Membrane/drug effects , Cells, Cultured , Cytoskeleton/drug effects , Cytosol/drug effects , Indicators and Reagents , Neurons/drug effects , Neurons/ultrastructure , Phosphorylation , Precipitin Tests , Protein Subunits , Rats , Subcellular Fractions/drug effects , Subcellular Fractions/ultrastructure , Tyrosine/metabolism
11.
Acta Physiol Scand ; 175(3): 227-35, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12100362

ABSTRACT

Propofol, an intravenous anaesthetic, has been shown to interact with the beta-subunit of the gamma-amino butyric acid(A) (GABA(A)) receptor and also to cause changes in [Ca2+]i. The GABA(A) receptor, a suggested target for anaesthetics, is known to be regulated by kinases. We have investigated if tyrosine kinase is involved in the intracellular signal system used by propofol to cause anaesthesia. We used primary cell cultured neurones from newborn rats, pre-incubated with or without a tyrosine kinase inhibitor before propofol stimulation. The effect of propofol on tyrosine phosphorylation and changes in [Ca2+]i were investigated. Propofol (3 microg mL(-1), 16.8 microM) increased intracellular calcium levels by 122 +/- 34% (mean +/- SEM) when applied to neurones in calcium free medium. This rise in [Ca2+]i was lowered by 68% when the cells were pre-incubated with the tyrosine kinase inhibitor herbimycin A before exposure to propofol (P < 0.05). Propofol caused an increase (33 +/- 10%) in tyrosine phosphorylation, with maximum at 120 s, of the beta-subunit of the GABA(A)-receptor. This tyrosine phosphorylation was decreased after pre-treatment with herbimycin A (44 +/- 7%, P < 0.05), and was not affected by the absence of exogenous calcium in the medium. Tyrosine kinase participates in the propofol signalling system by inducing the release of calcium from intracellular stores and by modulating the beta-subunit of the GABA(A)-receptor.


Subject(s)
Calcium/metabolism , Neurons/drug effects , Neurons/metabolism , Propofol/pharmacology , Protein-Tyrosine Kinases/metabolism , Receptors, GABA-A/metabolism , Animals , Benzoquinones , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Lactams, Macrocyclic , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinones/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Reference Values , Rifabutin/analogs & derivatives
12.
Acta Anaesthesiol Scand ; 45(10): 1215-20, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11736672

ABSTRACT

BACKGROUND: It has previously been shown that propofol in clinically relevant concentrations induces a calcium-dependent conformational change in the cytoskeleton. The aim of this study was to further clarify the effect of propofol on the actin cytoskeleton and to determine if this conformational change is mediated by the interaction between the GABA(A)-receptor and propofol. METHODS: Primary cultured cortical neurons from newborn rats were treated with propofol 3 microg x ml(-1) in a time-response titration, with and without preincubation with the GABA(A)-receptor antagonist, bicuculline. Actin-protein content was detected by Western blot analysis and the cellular content of F-actin measured by a spectrophotometric technique. RESULTS: Propofol triggers a relatively slow statistically significant increase in the intracellular F-actin content, maximum after 20-min incubation (160%+/-16.3) (mean+/-SEM) P<0.05. The propofol-induced increase in F-actin was effectively blocked by bicuculline. The increase in intracellular actin content after exposure to propofol as well as the effect of bicuculline were verified by Western blot analysis. CONCLUSION: The present study shows that propofol triggers a time-dependent change of actin. Since this reorganization can be blocked effectively by a GABA(A)-receptor antagonist, this suggests that the GABA(A)-receptor is involved in the pathway leading to cytoskeletal reorganization after propofol treatment. The actin polymerization reached its maximum after 20 min. Therefore, we believe that the propofol-induced changes might be connected with slower cellular responses such as cell-to-cell interaction and/or channel regulation.


Subject(s)
Actins/metabolism , Anesthetics, Intravenous/pharmacology , Neurons/metabolism , Propofol/pharmacology , Actins/drug effects , Animals , Animals, Newborn , Bicuculline/pharmacology , Cells, Cultured , Cerebral Cortex/anatomy & histology , Dose-Response Relationship, Drug , GABA Antagonists/pharmacology , Immunoblotting , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/physiology , Spectrometry, Fluorescence
13.
Br J Anaesth ; 82(4): 596-602, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10472230

ABSTRACT

The effects of diazepam, which acts at GABAA receptors to enhance the effects of GABA, and ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, on local rates of cerebral glucose utilization (ICMRglc) were examined in unrestrained rats. Four groups were studied: vehicle-injected controls; and ketamine-treated, diazepam-treated and combined ketamine- and diazepam-treated animals. Ketamine alone produced a heterogeneous pattern of changes in ICMRglc (e.g. significant increases in the corpus callosum, olfactory tubercle and the entire Papez circuit, in addition to other limbic areas, and significant decreases in lateral habenula and some components of the auditory system). Diazepam alone statistically significantly decreased ICMRglc in the brain as a whole and in most areas of the cerebral cortex, thalamus and limbic system. The most remarkable effects of the two drugs administered together on ICMRglc occurred in the limbic system where the dramatic increases observed with ketamine alone were prevented by treatment with diazepam.


Subject(s)
Anesthetics, Dissociative/pharmacology , Anti-Anxiety Agents/pharmacology , Brain/drug effects , Diazepam/pharmacology , Glucose/metabolism , Ketamine/pharmacology , Animals , Behavior, Animal/drug effects , Brain/metabolism , Drug Interactions , Male , Rats , Rats, Sprague-Dawley
14.
Acta Physiol Scand ; 165(1): 33-8, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10072094

ABSTRACT

The mechanisms behind oxygen mediated changes in tissue blood flow remain unsettled. Today these are thought to (from experiments on separate vessels and other tissues than the brain) operate through the vessels themselves, probably by involvement of the endothelium in the distal parts of the vascular tree. The aim of this study was to investigate how hyperoxaemia affects the cerebrocortical capillary blood flow distribution in order to gain further knowledge of oxygen mediated blood flow regulating mechanisms. The experiments were performed on seven ventilated anaesthetized pigs. A multiwire Clark-type microelectrode, placed on the brain surface (motor cortex), was used for capillary blood flow (hydrogen clearance) and oxygen pressure measurements, both of which were made at normoxaemia (arterial PO2 14.4 kPa) and hyperoxaemia (arterial PO2 50.4 kPa)(the animals serving as their own control). Blood pressure, arterial PCO2 and pH remained unchanged throughout the experiments. During hyperoxaemia a 11% reduction in the cerebrocortical capillary blood flow was found (P < 0.001). This flow reduction was seen mainly in two capillary blood flow classes (6/7 animals). In parallel a heterogeneous increase in the cerebrocortical oxygen pressures from 4.5 to 10.1 kPa (mean) (P < 0.001) was found. These results show that hyperoxaemia causes a selective reduction in capillary blood flow affecting capillaries at specific flow levels. A finding that suggests, for the brain, that both the oxygen sensor and effect mechanism is situated distally, in the vascular tree.


Subject(s)
Brain/blood supply , Cerebrovascular Circulation , Hyperoxia/physiopathology , Hyperoxia/veterinary , Animals , Blood Flow Velocity , Blood Pressure/physiology , Capillaries/physiology , Hydrogen-Ion Concentration , Microelectrodes , Oxygen/blood , Swine , Vasoconstriction/physiology
15.
Br J Anaesth ; 83(3): 467-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10655921

ABSTRACT

Propofol depresses both cerebral oxygen consumption and glucose utilization. We tested the hypothesis that these well described effects on brain metabolism are manifest by a reduction in neuronal acid production in vitro. The rate of extracellular acidification in primary cell cultures of rat cortical neurones was measured using a novel instrument (silicon microphysiometer) after stimulation with propofol 0.3, 3 and 30 micrograms ml-1. Intralipid 10% served as a control. Propofol 3 micrograms ml-1 caused a mean decrease of 1.51 (SEM 0.71)% in baseline acidification rate, which was significantly greater than that produced by 0.3 microgram ml-1 or Intralipid alone (P < 0.05). The reduction after stimulation with propofol 30 micrograms ml-1 was 4.68 (0.35)% of baseline rates and this in turn was significantly greater than that elicited by propofol 3 or 0.3 microgram ml-1, or Intralipid (P < 0.001). We have confirmed the depressant effect of propofol on cerebral metabolism and established that propofol inhibits neuronal acid excretion in vitro.


Subject(s)
Anesthetics, Intravenous/pharmacology , Cerebral Cortex/drug effects , Propofol/pharmacology , Animals , Cell Culture Techniques , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Emulsions , Extracellular Space/metabolism , Fat Emulsions, Intravenous/pharmacology , Hydrogen-Ion Concentration/drug effects , Phospholipids , Potentiometry , Rats , Rats, Sprague-Dawley , Soybean Oil
16.
Reg Anesth Pain Med ; 23(4): 402-8, 1998.
Article in English | MEDLINE | ID: mdl-9690594

ABSTRACT

BACKGROUND AND OBJECTIVES: When given intracutaneously, capsaicin can cause burning pain by central propagation in thin afferents, as well as neurogenic vasodilatation, reflecting antidromic conduction in the same fibers. We wanted to test the hypothesis that an intravenous regional block (IVRA) inhibits these two phenomena to a similar degree. METHODS: Sixteen healthy volunteers participated. A bilateral IVRA was performed by simultaneously injecting mepivacaine in one arm and normal saline in the other in a randomized, double-blind manner. Ten minutes after release of the tourniquet, neurogenic inflammation was inflicted in each forearm by intracutaneous capsaicin. Microvascular skin blood flow was measured with a laser Doppler perfusion imager. The area of the flare and the flow therein were measured, taking into account the change in baseline caused by mepivacaine treatment and the postischemic hyperemia. Pain was repeatedly evaluated by visual analog scale. RESULTS: The reactive hyperemia following arterial occlusion was less in the mepivacaine-treated arm 10 minutes after tourniquet release (P=.026). Intracutaneous capsaicin elicited a flare in both arms. The area of the flare was smaller 10 minutes after capsaicin (P=.009) in the mepivacaine-treated arm. There was no difference between the arms concerning the mean blood flow within the flare or in ischemic or capsaicin-induced pain. CONCLUSIONS: Mepivacaine, given as an IVRA, had no effect on the post-IVRA sensory function of thin afferents but differentially decreased the spread of the capsaicin-induced flare.


Subject(s)
Anesthesia, Conduction , Anesthesia, Intravenous , Anesthetics, Local/pharmacology , Capsaicin/administration & dosage , Mepivacaine/pharmacology , Vasodilation/drug effects , Adult , Double-Blind Method , Female , Humans , Inflammation/chemically induced , Injections, Intradermal , Laser-Doppler Flowmetry , Male , Middle Aged , Neurons, Afferent/drug effects , Pain/chemically induced , Pain Measurement
17.
Am J Physiol ; 274(5): E852-9, 1998 05.
Article in English | MEDLINE | ID: mdl-9612243

ABSTRACT

We have examined the effects of a surgical level of thiopental anesthesia in adult male rats on local rates of cerebral protein synthesis with the quantitative autoradiographic L-[1-14C]leucine method. The relative contribution of leucine derived from protein breakdown to the intracellular precursor amino acid pool for protein synthesis was found to be statistically significantly decreased in the anesthetized rats compared with controls. In the brain as a whole and in 30 of the 35 brain regions examined, rates of protein synthesis were decreased (1-11%) in the anesthetized rats. Decreases were statistically significant (P < or = 0.05) in the brain as a whole and in six of the regions, and they approached statistical significance in an additional 13 regions, indicating a tendency for a generalized but small effect.


Subject(s)
Anesthesia , Brain/metabolism , Nerve Tissue Proteins/biosynthesis , Thiopental , Amino Acids/metabolism , Animals , Homeostasis/physiology , Leucine/metabolism , Male , Rats , Rats, Sprague-Dawley , Reference Values , Tissue Distribution
18.
Br J Anaesth ; 81(6): 957-9, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10211025

ABSTRACT

The concentration of propofol in and surrounding the human brain during propofol anaesthesia is unknown. We measured simultaneously the concentration of propofol in cerebrospinal fluid (CSF) from an indwelling intraventricular catheter and the concentration in arterial blood in five neurosurgical patients before, during induction (at 2.5 and 5 min) and during a maintenance propofol infusion (at 15 and 30 min). After induction of anaesthesia with propofol 2 mg kg-1, anaesthesia was maintained with an infusion of 8 mg kg-1 h-1 for 15 min and then reduced to 6 mg kg-1 h-1. The plasma concentration of propofol increased rapidly during induction and reached a plateau concentration of mean 2.24 (SD 0.66) micrograms ml-1 after 5 min. The concentration of propofol in CSF showed a slower increase during induction and remained almost constant at 35.5 (19.6) ng ml-1 at 15-30 min after induction. The CSF concentration of propofol that we measured was 1.6% of the plasma concentration and consistent with the high protein binding of the drug in plasma.


Subject(s)
Anesthesia , Anesthetics, Intravenous/cerebrospinal fluid , Propofol/cerebrospinal fluid , Adult , Aged , Anesthetics, Intravenous/blood , Female , Humans , Male , Middle Aged , Neurosurgical Procedures , Propofol/blood
19.
Acta Anaesthesiol Scand ; 41(8): 1047-53, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9311405

ABSTRACT

BACKGROUND: Opioid receptors have been demonstrated on peripheral afferent nerves throughout the body. The aim of the present study was to compare the effects of intravenous and intraperitoneal administration of morphine with regard to pain, postoperative morphine requirement, and recovery after major abdominal surgery, and to describe the pharmacokinetics of intraperitoneal morphine in humans. METHODS: In a double-blind manner, 30 patients scheduled for major abdominal surgery were randomized to either 50 mg of morphine intravenously (i.v.) or 50 mg of morphine intraperitoneally (i.p.) before operation. Pain was measured on a visual analogue scale and morphine requirements were registered for 3 days. Recovery was measured as time to oral intake of food, time to flatulence and days in hospital. Plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations were determined during the first 4 h after morphine administration. RESULTS: During the first postoperative hours there was less pain at rest (P = 0.02) and on coughing (P = 0.004) in the intravenous group. The requirement of additional morphine (P = 0.016) was lower in the intravenous group during the first postoperative day. No major differences in recovery were seen. The plasma concentrations of morphine measured as area under the curve (AUC) during the first 4 h were similar, but the intravenous group showed significantly higher concentrations of the active metabolite morphine-6-glucuronide, (P = 0.016), indicating a difference in pharmacokinetics after intraperitoneal compared to intravenous administration of morphine. CONCLUSION: Intraperitoneal administration of 50 mg of morphine before major abdominal surgery is less efficient in reducing pain and postoperative morphine requirements than the same amount of morphine given intravenously.


Subject(s)
Analgesics, Opioid/administration & dosage , Morphine/administration & dosage , Pain, Postoperative/prevention & control , Premedication , Adult , Aged , Analgesics, Opioid/pharmacokinetics , Double-Blind Method , Female , Humans , Infusions, Intravenous , Infusions, Parenteral , Male , Middle Aged , Morphine/pharmacokinetics , Pain Measurement
20.
Reg Anesth ; 22(2): 131-6, 1997.
Article in English | MEDLINE | ID: mdl-9089854

ABSTRACT

BACKGROUND AND OBJECTIVES: It has been suggested that the potency of epidural morphine might be explained by spinal metabolism to the active and potent metabolite morphine-6-glucuronide (M6G). The main objective of this study was to describe the early pharmacokinetics of epidurally administered, morphine with special attention to the appearance of the glucuronated metabolites in cerebrospinal fluid (CSF). METHODS: Morphine was administered epidurally to eight patients scheduled for major abdominal surgery. The concentrations of morphine and its 6-glucuronide and 3-glucuronide metabolites were monitored in blood and CSF at 10, 30, 60, and 120 minutes and 10 and 24 hours. Postoperative pain was estimated on a visual analog scale, and analgesia requirements (administered by a patient-controlled technique) were recorded. RESULTS: Only traces of the metabolites were found in CSF and in only two patients throughout the 24 hours. Both metabolites appeared rapidly (within 30 minutes) in plasma in all patients and were found in plasma throughout the study period. Morphine concentration peaked in CSF within 30 minutes at a very high level; in plasma, it peaked at 10 minutes. No correlation was seen between initial or later concentrations of morphine in CSF and postoperative pain or morphine requirements. CONCLUSIONS: No evidence of spinal metabolism of morphine could be found. Rapid distribution of morphine to CSF and plasma occurred after epidural administration. No value of initial CSF morphine concentrations for prediction of analgesic requirements could be demonstrated.


Subject(s)
Analgesics, Opioid/blood , Analgesics, Opioid/cerebrospinal fluid , Morphine Derivatives/blood , Morphine Derivatives/cerebrospinal fluid , Morphine/blood , Morphine/cerebrospinal fluid , Abdomen/surgery , Adult , Aged , Analgesia, Epidural , Analgesics, Opioid/administration & dosage , Female , Humans , Injections, Epidural , Male , Middle Aged , Morphine/administration & dosage
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