Cerebral haemodynamic changes during propofol-remifentanil or sevoflurane anaesthesia: transcranial Doppler study under bispectral index monitoring

Background. Sevoflurane or propofol–remifentanil-basedanaesthetic regimens represent modern techniques for neurosurgicalanaesthesia. Nevertheless, there are potential differences relatedto their activity on the cerebrovascular system. The magnitudeof such difference is not completely known. Methods. In total 40 patients, treated for spinal or maxillo-facialdisorders, were randomly allocated to either i.v. propofol–remifentanilor inhalational sevoflurane anaesthesia. Transcranial Dopplerwas used to assess changes in cerebral blood flow velocity,carbon dioxide reactivity, cerebral autoregulation and the bispectralindex to assess the depth of anaesthesia. Results. Time-averaged mean flow velocity (MFV) was significantlyreduced after induction of anaesthesia in both sevoflurane andpropofol–remifentanil groups (P<0.001). At deeper levelsof anaesthesia, MFV increased in the sevoflurane group, suggestingan uncoupling flow/metabolism, whereas it was further reducedin the propofol–remifentanil group (P<0.001). Indicesof cerebral autoregulation were reduced in patients with high-dosesevoflurane whereas autoregulation was preserved in patientsanaesthetized with propofol–remifentanil (P<0.001).Higher CO₂ concentrations impaired cerebral autoregulation inthe sevoflurane group but not in patients anaesthetized withpropofol–remifentanil. Conclusions. Propofol–remifentanil anaesthesia induceda dose-dependent low-flow state with preserved cerebral autoregulation,whereas sevoflurane at high doses provided a certain degreeof luxury perfusion.     

Remifentanil and nitrous oxide reduce changes in cerebral blood flow velocity in the middle cerebral artery caused by pain

Background. Cerebral blood flow is affected by painful stimuli,and analgesic agents may alter the response of cerebral bloodflow to pain. We set out to quantify the effects of remifentaniland nitrous oxide on blood flow changes caused by experimentalpain. Methods. We simulated surgical pain in 10 conscious volunteersusing increasing mechanical pressure to the tibia. We measuredchanges in cerebral blood flow velocity in the middle cerebralartery (CBFV_MCA) caused by the pain, using transcranial Dopplersonography. We gave increasing doses of remifentanil (0.025,0.05 and 0.1 µg kg^–1 min^–1)or nitrous oxide [20%, 35% and 50% end-tidal concentration (FE'_N2O)]and compared these effects on blood flow changes. Results. Nitrous oxide increased CBFV_MCA only when given at50% FE'_N2O. Remifentanil did not affect CBFV_MCA. Pain increasedCBFV_MCA. Both agents attenuated this pain-induced change inCBFV_MCA with the exception of nitrous oxide at 20% FE'_N2O. Conclusions. Inhalation of nitrous oxide or adminstration ofremifentanil attenuated pain-induced changes in CBFV_MCA. Br J Anaesth 2003: 90: 296–9     

Effects of magnesium sulphate on cerebral haemodynamics in healthy volunteers: a transcranial Doppler study

Background. Magnesium is increasingly being considered as aneuroprotective agent. We aimed to study its effects on middlecerebral artery blood flow velocity (V_mca), cerebral autoregulationand cerebral vascular reactivity to carbon dioxide (CRCO₂) inhealthy volunteers. Methods. Fifteen healthy volunteers were recruited. Using transcranialDoppler ultrasonography, V_mca was recorded continuously. Thestrength of autoregulation was assessed by the transient hyperaemicresponse test, and the CRCO₂ was measured by assessing changesin V_mca to the induced changes in end-tidal carbon dioxide.I.V. infusion of magnesium sulphate was then started (loadingdose of 16 mmol followed by an infusion at the rate of 2.7 mmolh^–1) for 45 min. The cerebral haemodynamic variables weremeasured again near the end of the infusion of magnesium sulphate. Results. Total serum magnesium levels were doubled by the infusionregimen. However, there were no significant changes in V_mca,strength of autoregulation, or CRCO₂. Five of the volunteersreported marked nausea and two developed significant hypotensionduring the loading dose. Conclusions. Infusion of magnesium sulphate, in a dose thatdoubles its concentration in plasma, does not affect V_mca, strengthof autoregulation or CRCO₂ in healthy volunteers. However, itcan be associated with nausea and hypotension. Br J Anaesth 2003; 91: 273–5     

Cerebral and lung kinetics of morphine in conscious sheep after short intravenous infusions

Background. The analgesic effects of morphine are delayed relativeto its concentration in blood. The rate of equilibration ofmorphine between blood and brain may contribute to this delay,but the kinetics of this process have not been modelled. Thiswas determined in conscious instrumented sheep. The lung kineticsof morphine were also determined given their importance in definingsystemic kinetics after i.v. bolus administration. Methods. Sheep were given short i.v. infusions of morphine (30mg over 4 min). Cerebral kinetics were inferred from arterio–sagittalsinus concentration gradients and cerebral blood flow, and lungkinetics from the pulmonary artery–aortic gradient andcardiac output. These data were fitted to flow- and membrane-limitedmodels of the kinetics in each organ. Results. Morphine had minimal cardiovascular effects, did notalter cerebral blood flow and caused insignificant respiratorydepression. Lung kinetics were best described by a single distributionvolume (2036 ml) with a first-order loss (1370 ml min^–1),which was attributed to deep distribution. The cerebral kineticsof morphine were characterized by a significant permeabilitybarrier. Permeability across the barrier (7.44 ml min^–1)was estimated with good precision, and was approximately one-fifthof the nominal cerebral blood flow. The distribution volumeof morphine in the brain was estimated with less precision,but was described by a brain:blood partition coefficient ofapproximately 1.4. The time required for 50% equilibration betweenbrain and blood concentrations was approximately 10.3 min. Conclusion. The cerebral equilibration of morphine was relativelyslow, and was characterized by significant membrane limitation. Br J Anaesth 2003; 90: 750–8     

Detection of cerebral hypoperfusion with bispectral index during paediatric cardiac surgery

Background. The bispectral index (BIS) may indicate changesin cerebral activity when the cerebral circulation is affectedby acute hypotension. Methods. We measured BIS and cerebral haemoglobin saturation(Sr_O2) by near-infrared spectroscopy in 10 children undergoingcardiac surgery. Results. We noted 14 episodes of simultaneous decreases in Sr_O2and BIS during acute hypotension in five children. An acutedecrease in BIS, which coincided with a decrease in Sr_O2 suggestinga reduction in cerebral blood flow, was associated with acuteslowing of the raw EEG waveforms. Conclusions. Our findings suggest that an acute decrease inBIS during acute hypotension indicates cerebral hypoperfusion,and that cerebral hypoperfusion caused by hypotension may occurfrequently during paediatric cardiac surgery. Br J Anaesth 2003; 90: 694–8     

Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac

Background. Non-selective cyclooxygenase (COX) inhibitors ornon-steroidal anti- inflammatory drugs (NSAIDs) are frequentlyomitted for perioperative pain relief because of potential side-effects.COX-2-selective inhibitors may have a more favourable side-effectprofile. This study tested the hypothesis that the COX-2-selectiveinhibitor rofecoxib has less influence on platelet functionthan the NSAID diclofenac in gynaecological surgery. In addition,analgesic efficacy and side-effects of the two drugs were compared. Methods. In this single-centre, prospective, double-blind, activecontrolled study, women undergoing vaginal hysterectomy (n=25)or breast surgery (n=25) under general anaesthesia receivedpreoperatively 50 mg of rofecoxib p.o. followed 8 and 16 h laterby two doses of placebo or three doses of diclofenac 50 mg p.o.at the same time points. We assessed arachidonic acid-stimulatedplatelet aggregation before and 4 h after the first dose ofstudy medication, estimated intraoperative blood loss, and haemoglobinloss until the first morning after surgery. Analgesic efficacy,use of rescue analgesics, and side-effects were also recorded. Results. In the rofecoxib group, stimulated platelet aggregationwas disturbed less (P=0.02), and estimated intraoperative bloodloss (P=0.01) and the decrease in haemoglobin were lower (P=0.01).At similar pain ratings, the use of anti-emetic drugs was lessin the rofecoxib group (P=0.03). Conclusion. Besides having a smaller effect on platelet aggregation,one oral dose of rofecoxib 50 mg given before surgery providedpostoperative analgesia similar to that given by three dosesof diclofenac 50 mg and was associated with less use of anti-emeticsand less surgical blood loss in gynaecological surgery comparedwith diclofenac. Br J Anaesth 2004; 92: 523–31     

Effects of desflurane on cerebral autoregulation

The aim of this study was to determine the effects of desflurane,at 1 and 1.5 MAC, on cerebral autoregulation. Data were analysedfrom eight patients undergoing non-neurosurgical procedure.The blood flow velocity in the middle cerebral artery was measuredby transcranial Doppler ultrasound and cerebral autoregulationwas assessed by the transient hyperaemic response test. Partialpressure of the end-tidal carbon dioxide (PE'_CO2) and mean arterialpressure were measured throughout the study. Anaesthesia wasinduced with propofol and was maintained with desflurane atend-tidal concentrations of 7.4% (1 MAC) or 10.8% (1.5 MAC).The order of administration of the desflurane concentrationswas determined randomly and a period of 15 min was allowed forequilibration at each concentration. The transient hyperaemicresponse tests were performed before induction of anaesthesiaand after equilibration with each concentration of desflurane.An infusion of phenylephrine was used to maintain pre-inductionmean arterial pressure and ventilation was adjusted to maintainthe pre-induction value of PE'_CO2 throughout the study. Twoindices derived from the transient hyperaemic response test(the transient hyperaemic response ratio and the strength ofautoregulation) were used to assess cerebral autoregulation.Desflurane resulted in a marked and significant impairment incerebral autoregulation; at concentrations of 1.5 MAC, autoregulationwas almost abolished. Br J Anaesth 2001; 87: 193–7     

Cerebral haemodynamics in pregnancy and pre-eclampsia as assessed by transcranial Doppler ultrasonography

Background. Altered cerebral circulation, as reported duringnormal pregnancy, and in patients with pre-eclampsia, can beassociated with changes in cerebral vascular reactivity and/orcerebral autoregulation. The aim of our study was to performa comparative assessment of cerebral haemodynamics, includingvascular reactivity and autoregulation, in pre-eclamptic patients,healthy pregnant women, and healthy non-pregnant women. Methods. Thirty patients with pre-eclampsia were recruited.Age- and height-matched healthy pregnant (n=30) and non-pregnantcontrol (n=30) groups were also recruited. Monitoring includedtranscranial Doppler ultrasonography, end-tidal carbon dioxideand non-invasive arterial pressure measurement. Cerebral autoregulationwas assessed by performing the transient hyperaemic response(THR) test. The cerebrovascular reactivity to carbon dioxide(CRCO₂) was assessed by measuring middle cerebral artery bloodflow velocity (MCAFV) after induced changes in end-tidal carbondioxide. Estimated cerebral perfusion pressure (eCPP) and criticalclosing pressure (CrCP) were calculated using established formulae.Statistical analysis included ANOVA with Tukey’s pairwisecomparisons. Results. Mean arterial pressure (MAP) was increased in pre-eclampsia(P<0.05). Mean MCAFV was lower in healthy pregnancy (P<0.05),but in pre-eclampsia it was similar to the non- pregnant group.When compared with the non-pregnant group, mean eCPP was higherin the healthy pregnant and pre-eclamptic groups (P<0.05).There were no meaningful differences in cerebral autoregulationor CRCO₂. Conclusions. Healthy pregnancy increases eCPP, presumably bydecreasing CrCP. In pre-eclampsia, eCPP is maintained at thesame level as in healthy pregnancy despite an increased MAP.Pre-eclampsia has no significant effect on cerebral autoregulationor CRCO₂. Br J Anaesth 2002; 89: 687–92     

Extrapolation to zero-flow pressure in cerebral arteries to estimate intracranial pressure

Background. Cerebral perfusion pressure (CPP) is commonly calculatedfrom the difference between arterial blood pressure (AP) andintracranial pressure (ICP). ICP can be considered the effectivedownstream pressure of the cerebral circulation. Consequently,cerebral circulatory arrest would occur when AP equals ICP.Estimation of AP for zero-flow pressure (ZFP) may thus allowestimation of ICP. We estimated ZFP from cerebral pressure–flowvelocity relationships so that ICP could be measured by transcranialDoppler sonography. Methods. We studied 20 mechanically ventilated patients withsevere head injury, in whom ICP was monitored by epidural pressuretransducers. AP was measured with a radial artery cannula. Bloodflow velocity in the middle cerebral artery (V_MCA) ipsilateralto the site of ICP measurement was measured with a 2 MHz transcranialDoppler probe. All data were recorded by a microcomputer fromanalogue–digital converters. ZFP was extrapolated by regressionanalysis of AP–V_MCA plots and compared with simultaneousmeasurements of ICP. Results. ZFP estimated from AP–V_MCA plots was linearlyrelated to ICP over a wide range of values (r=0.93). There wasno systematic difference between ZFP and ICP. Limit of agreement(2 SD) was 15.2 mm Hg. Short-term variations in ICP wereclosely followed by changes in ZFP. Conclusion. Extrapolation of cerebral ZFP from instantaneousAP–V_MCA relationships enables detection of severely elevatedICP and may be a useful and less invasive method for CPP monitoringthan other methods. Br J Anaesth 2003; 90: 291–5     

Cerebral ischaemia during cardiac surgery in children detected by combined monitoring of BIS and near-infrared spectroscopy

Background. Children frequently suffer transient cerebral ischaemiaduring cardiac surgery. We measured cerebral ischaemia in childrenduring cardiac surgery by combining two methods of monitoring. Methods. We studied 65 children aged between 5 months and 17yr having surgery to correct non-cyanotic heart disease usinghypothermic cardiopulmonary bypass (CPB). During surgery, wemeasured the Bispectral Index (BIS) and regional cerebral haemoglobinoxygen saturation (Sr_O2) with near-infrared spectroscopy (NIRS).Cerebral ischaemia was diagnosed if both Sr_O2 and BIS decreasedabruptly when acute hypotension occurred. In each patient, therelationship between Sr_O2 and arterial blood pressure (AP) wasindicated by a plot of mean Sr_O2 against simultaneous mean AP. Results. We noted 72 episodes of cerebral ischaemia in 38 patients.Sixty-three ischaemic events were during CPB. Cerebral ischaemiawas less frequent in older patients. Cerebral ischaemia wasmore common and more frequent in children under 4 yr old. Haematocritduring CPB was lower and Sr_O2 was more dependent on AP in childrenunder 4 yr. Conclusions. Children less than 4 yr of age are more likelyto have cerebral ischaemia caused by hypotension during cardiacsurgery. Ineffective cerebral autoregulation and haemodilutionduring CPB may be responsible. Br J Anaesth 2004: 92: 662–9     

Effects of ephedrine, dobutamine and dopexamine on cerebral haemodynamics: transcranial Doppler studies in healthy volunteers

Background. Sympathomimetic drugs are assumed to have no directeffects on cerebral haemodynamics on the basis of animal experiments;there is little evidence of their direct effects in humans.This study aimed to address this issue. Methods. The effects of ephedrine, dobutamine, and dopexamineon cerebral autoregulation, cerebral vascular reactivity tocarbon dioxide, estimated cerebral perfusion pressure, and zeroflow pressure (ZPF) were studied in 10 healthy volunteers usingtranscranial Doppler ultrasound. The strength of autoregulationwas measured using the transient hyperaemic response test. Thereactivity to carbon dioxide was measured as the change in middlecerebral artery flow velocity with a step change in end-tidalcarbon dioxide. For the estimated cerebral perfusion pressureand the ZFP, established formulae were used which utilized instantaneousvalues of arterial pressure and middle cerebral artery flowvelocity. Measurements were made at baseline and after i.v.infusion of the study drug to an endpoint of 25% increase inmean arterial pressure (MAP) (ephedrine, dobutamine) or cardiacindex (dopexamine). Results. There was no significant change in the strength ofautoregulation (from (mean (SD)) 1.07 (0.16) to 1.07 (0.18);from 1.07 (0.16) to 1.03 (0.19); from 1.04 (0.12) to 1.04 (0.25)),reactivity to carbon dioxide (from 40% (8) to 36 (10); from37 (12) to 37 (11); from 45 (12) to 43 (11)) with ephedrine,dobutamine, or dopexamine, respectively. Despite a clinicallysignificant increase in MAP with ephedrine and dobutamine anda clinically significant increase in cardiac index with dopexamine,the estimated cerebral perfusion pressure did not change significantly(from 81 (38) to 60 (16) mm Hg with ephedrine; from 67 (22)to 63 (11) mm Hg with dobutamine; from 87 (27) to 79 (17) mmHg with dopexamine). The ZFP increased significantly with ephedrine(from 29 (10) to 44 (11) mm Hg) and dobutamine (from 35 (14)to 43 (10) mm Hg) but not dopexamine (from 3 (23) to 11 (22)mm Hg). Conclusions. Sympathomimetic agents do not significantly changecerebrovascular homeostasis as assessed by the transient hyperaemicresponse test, reactivity to carbon dioxide and estimated cerebralperfusion pressure. Br J Anaesth 2004; 92: 39–44     

Preservation of static and dynamic cerebral autoregulation after mild hypothermic cardiopulmonary bypass

Background. Dysfunction of cerebral autoregulation might contributeto neurological morbidity after cardiac surgery. In this study,our aim was to assess the preservation of cerebral autoregulationafter cardiac surgery involving cardiopulmonary bypass (CPB). Methods. Dynamic and static components of cerebral autoregulationwere evaluated in 12 patients undergoing coronary artery bypassgraft surgery, anaesthetized with midazolam, fentanyl, and propofol,and using mild hypothermic CPB (31–33°C). Arterialpressure (ABP), central venous pressure (CVP), and blood flowvelocity in the middle cerebral artery (CBFV) were recorded.The cerebral perfusion pressure (CPP) was calculated as a differencebetween mean ABP and CVP. Rapid decrease of CPP was caused bya sudden change of patients' position from Trendelenburg toreverse Trendelenburg. Cerebral vascular resistance (CVR) wascalculated by dividing CPP by CBFV. Index of static cerebralautoregulation (CAstat) was calculated as the change of CVRrelated to change of CPP during the manoeuvre. Dynamic rateof autoregulation (RoRdyn) was determined as the change in CVRper second during the first 4 s immediately after a decreasein CPP, related to the change of CPP. Measurements were obtainedafter induction of anaesthesia, and 15, 30, and 45 min aftertermination of CPB. Results. No significant changes were found in CAstat or RoRdynafter CPB. Significant changes in CVR could be explained byconcomitant changes in body temperature and haematocrit. Conclusion. Autoregulation of cerebral blood flow remains preservedafter mild hypothermic CPB.      

Effects of temperature and haematocrit on the relationships between blood flow velocity and blood flow in a vessel of fixed diameter

Background. To determine whether temperature and haematocrit(Hct) alter the relationship between blood flow (BF) and bloodflow velocity (BFV). Methods. Using a transcranial Doppler apparatus, we measuredthe peak velocity of whole blood cells pumped by a cardiopulmonarybypass (CPB) circuit, through a 0.15-cm internal diameter segmentof rigid tubing. BF and BFV relationships were obtained at temperaturesof 19, 28, and 37°C and at Hct of 0.05, 0.22, 0.39, and0.54, by altering CPB flow over a range from 10 to 100 cc/min.Linear regression analysis was performed. Results. The relationship between velocity and flow for thepooled Hct data was y=(0.43)x+0.86, r²=0.998 and 95% CI (0.999–1)whereas the association for the temperature data was y=(0.42)x+0.02,r²=0.9998 and 95% CI (0.999–0.9997). Changes of bloodviscosity had no effect on velocity at a given flow rate. Thecombined effect of Hct and temperature on velocity for the relationshipwith flow is expressed by: y=1.3+2.4x. Conclusion. In fixed diameter vessels with laminar flow, thelinear relationship between flow and velocity is not affectedby changes in temperature and Hct in clinical ranges. Theseresults are explained by the Fahraeus–Lindquist effect.They support the use of transcranial Doppler sonography to estimatecerebral blood flow in infants who may have large variationsof Hct and/or temperature during bypass. Br J Anaesth 2002; 88: 277–9     

Does the opioid-sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient?

Background. The aim of this prospective, double-blind, randomized,placebo-controlled clinical trial was to investigate the opioid-sparingeffects of rectal diclofenac following total abdominal hysterectomy. Methods. Forty ASA I–II patients, aged 20–60 yr,were randomized to receive identical-looking suppositories ofeither diclofenac 75 mg or placebo, twice daily. All patientswere given a standardized anaesthetic, with intravenous morphinevia a patient-controlled analgesia device and either diclofenacor placebo for postoperative analgesia. Results. The median 24 h morphine consumption (interquartilerange) was significantly higher (P=0.02) in the placebo group[59 (45–85) mg] than in the diclofenac group [31 (14–65)mg]. In comparison with the placebo group, there were significantreductions in total pain score in the diclofenac group at rest(P=0.04) and on movement (P<0.01). Total (SD) sedation scorewas significantly lower (P=0.04) in the diclofenac group [90(73) mm] than in the placebo group [148 (89) mm]. Total (interquartilerange) nausea score was significantly lower (P<0.01) in thediclofenac group [14 (0–53) mm] than in the placebo group[64 (30–109) mm]. There was no significant differencebetween the two groups of patients in episodes of vomiting ornumber of rescue antiemetics. Conclusions. Rectal diclofenac reduces morphine consumption,improves postoperative analgesia, and reduces the incidenceof adverse effects such as sedation and nausea. Br J Anaesth 2002; 88: 714–16     

Cerebral embolization during cardiac surgery: impact of aortic atheroma burden

Background. Aortic atheromatous disease is known to be associatedwith an increased risk of perioperative stroke in the settingof cardiac surgery. In this study, we sought to determine therelationship between cerebral microemboli and aortic atheromaburden in patients undergoing cardiac surgery. Methods. Transoesophageal echocardiographic images of the ascending,arch and descending aorta were evaluated in 128 patients todetermine the aortic atheroma burden. Transcranial Doppler (TCD)of the right middle cerebral artery was performed in order tomeasure cerebral embolic load during surgery. Using multivariatelinear regression, the numbers of emboli were compared withthe atheroma burden. Results. After controlling for age, cardiopulmonary bypass timeand the number of bypass grafts, cerebral emboli were significantlyassociated with atheroma in the ascending aorta (R²=0.11, P=0.02)and aortic arch (P=0.013). However, there was no associationbetween emboli and descending aortic atheroma burden (R²=0.05,P=0.20). Conclusions. We demonstrate a positive relationship betweenTCD-detected cerebral emboli and the atheromatous burden ofthe ascending aorta and aortic arch. Previously demonstratedassociations between TCD-detectable cerebral emboli and adversecerebral outcome may be related to the presence of significantaortic atheromatous disease. Br J Anaesth 2003; 91: 656–61     

Dopexamine reverses colonic but not gastric mucosal perfusion defects in lethal endotoxin shock

Background. Whilst dopexamine appears to increase overall splanchnicblood flow in postoperative and septic patients, the effectson gastric mucosal perfusion are controversial and based onconcomitantly increasing mucosal to arterial PCO₂ gradients(PdCO₂). We hypothesized that dopexamine alters splanchnic bloodflow distribution and metabolism during experimental endotoxinshock and modifies the inflammatory response induced by endotoxin. Methods. In an experiment with anaesthetized normovolaemic,normoventilated pigs, 21 animals were randomized into: (i) subacutelethal endotoxin shock for 14 h (n=7 at baseline); (ii)endotoxin shock with dopexamine infusion (aiming to exceed baselinecardiac output, n=7); or (iii) controls (n=7). Regional bloodflow and metabolism were monitored. Results. Endotoxin produced a hypodynamic phase followed bya normo/hyperdynamic, hypotensive phase. Despite increasingsystemic blood flow in response to dopexamine, proportionalsplanchnic blood flow decreased during the hypodynamic phase.Dopexamine gradually decreased fractional coeliac trunk flow,while fractional superior mesenteric arterial flow increased.Dopexamine induced early arterial hyperlactataemia and augmentedthe gastric PdCO₂ gradient while colonic luminal lactate releaseand colonic PdCO₂ gradient were reversed. Dopexamine did notmodify the inflammatory response as evaluated by arterial IL-1ßand IL-6 concentrations. Conclusions. Dopexamine protects colonic, but not gastric mucosalepithelium in experimental endotoxin shock. This may be relatedto redistribution of blood flow within the splanchnic circulation. Br J Anaesth 2003; 91: 878–85     

Propacetamol augments inhibition of platelet function by diclofenac in volunteers

Background. Acetaminophen (paracetamol) enhances the analgesiceffect of non-steroidal anti-inflammatory drugs (NSAIDs). Acetaminophenis a weak inhibitor of cyclooxygenase (COX), and its combinationwith an NSAID may augment COX inhibition-related side effects. Methods. Ten healthy male volunteers (21–30 yr) were givendiclofenac 1.1 mg kg^–1 alone, a combination of propacetamol30 mg kg^–1 (which is hydrolysed to 50% acetaminophen)and diclofenac 1.1 mg kg^–1 or placebo intravenously ina double blind, crossover study. Platelet function was assessedat 5 min, 90 min and 22–24 h by photometric aggregometry,platelet function analyser (PFA-100^TM) and by measuring therelease of thromboxane B₂ (TxB₂). Analgesia was assessed withthe cold pressor test. Results. Platelet aggregation induced with arachidonic acidwas fully inhibited by both diclofenac alone and the combinationat the end of the 30-min drug infusion. Propacetamol augmentedthe inhibition by diclofenac at 90 min (P=0.014). At 22–24h, platelet function had fully recovered. TxB₂ release was inhibitedby the combination of propacetamol and diclofenac at 90 minin comparison with diclofenac alone (P=0.027). PFA-100^TM detectedno difference in platelet function between these two groups.No analgesic effect was detected with the cold pressor test. Conclusions. The combination of propacetamol and diclofenacinhibits platelet function more than diclofenac alone. Thisshould be considered when assessing the risk of surgical bleeding. Br J Anaesth 2003; 91: 357–62     

Effects of levobupivacaine and ropivacaine on rat sciatic nerve blood flow

Background. Ischaemia is one of the causative mechanisms ofperipheral nerve injury, a documented complication of regionalanaesthesia. Local anaesthetics per se and/or vasopressor adjuvantsmay account for changes in peripheral nerve blood flow. Theaim of this study was to test the effects of levobupivacaineand ropivacaine in a rat sciatic nerve model with respect tolocal blood flow and histopathological changes. Methods. Forty-eight female Sprague–Dawley rats were anaesthetizedfor left sciatic nerve exposure. After baseline nerve bloodflow measurement with a laser Doppler flowmeter, 0.2 ml of oneof the following solutions was applied topically to the nervein a random fashion: saline 0.9%; lidocaine 10 mg ml^–1;levobupivacaine 2.5 mg ml^–1; levobupivacaine 5 mg ml^–1;levobupivacaine 7.5 mg ml^–1; ropivacaine 2 mg ml^–1;ropivacaine 7.5 mg ml^–1; and ropivacaine 7.5 mg ml^–1plus epinephrine 5 µg ml^–1; all in saline 0.9%.Nerve blood flow was evaluated at 5-min intervals up to 30 minafter local application of anaesthetic solution. Three animalsper group were killed for histological evaluation 48 h later.Multiple one-way analyses of variance followed by Scheffé'spost hoc test was used for statistical analysis. P<0.05 wasconsidered significant. Results. Local anaesthetics at all concentrations tested causedsignificant reduction in nerve blood flow. The combination ofropivacaine 7.5 mg ml^–1 plus epinephrine did not reducenerve blood flow to a greater extent than ropivacaine 7.5 mgml^–1 alone. Low concentrations of levobupivacaine (2.5and 5 mg ml^–1) reduced nerve blood flow to the same extentas lidocaine 10 mg ml^–1. No significant histological changeswere observed at 48 h. Conclusion. Despite acute reductions in peripheral nerve bloodflow, significant histopathological changes were not observedin this rat sciatic nerve model after topical application oflevobupivacaine and ropivacaine at concentrations relevant toclinical practice.     

Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial

Background. Risks and costs of allogeneic blood transfusionsmandate strategies to reduce blood loss in surgery. The objectiveof this study was to assess the efficacy of antifibrinolytictreatment in reducing perioperative blood loss during totalknee replacement. Methods. A double-blind, randomized and placebo-controlled clinicaltrial was carried out on 127 patients undergoing total kneereplacement. Patients in the study group received tranexamicacid 10 mg kg^–1 i.v. just before the tourniquet was deflatedand 3 h later, or epsilon-aminocaproic acid 100 mg kg^–1before tourniquet deflation followed by continuous perfusion(1 g h^–1) during 3 h. External perioperative blood losswas measured and total blood loss was calculated. The numberof patients transfused and number of packed red cell (PRC) unitstransfused was recorded and possible postoperative thromboemboliccomplications were investigated. Results. Total blood loss [mean (SD)] was 1099 ml (535) in thegroup that received antifibrinolytic agents and 1784 ml (660)in the control group (P<0.001). Five patients (7.5%) in thestudy group and 23 (38.3%) in the control group (P<0.001)received blood transfusions; the first group received a meanof 0.10 PRC unit per patient and the second, 0.58 (P<0.001).Mean reduction in haemoglobin levels (g dl^–1) betweenpreoperative and fifth day postoperative readings was 2.5 (0.9)in the study group and 3.4 (1.2) in the control group (P<0.001).Clinical assessment did not reveal any thromboembolic complications. Conclusions. Antifibrinolytic agents produce a significant decreasein blood loss in patients undergoing total knee replacement,reflected in a reduction in the number of blood transfusionsrequired.     

Differential modulation of interleukin-6 and interleukin-10 by diclofenac in patients undergoing major surgery

Background. Prostaglandins modulate cytokine release thoughincreases in cAMP, regulating interleukin (IL) 6 and IL-10.Diclofenac inhibits cyclo-oxygenase activity and hence prostaglandinproduction. We hypothesized that diclofenac would affect releaseof IL-6 and IL-10 and modulate the immune response. Methods. In a randomized, double-blind, placebo-controlled study,we investigated the effect of diclofenac in patients undergoingmajor urological surgery. Patients were randomized to receiveeither diclofenac (50 mg orally every 8 h the daybefore surgery and 75 mg i.m. every 12 h on the dayof surgery, n=23) or placebo (n=23). Standardized combined generalanaesthesia and epidural analgesia was administered. Serum IL-6,IL-10 and cortisol were measured before surgery and 30 minand 2, 6, 12 and 24 h after skin incision. Temperature,leucocyte count and C-reactive protein concentration were measuredbefore surgery and after 24 h. Results. IL-6 and IL-10 concentrations increased, reaching peaklevels at 12 and 6 h respectively in both groups. At 12 h,the IL-6 concentration was significantly lower in patients receivingdiclofenac than in those receiving placebo (P=0.003). In contrast,IL-10 concentration at 6 h was higher in diclofenac-treatedpatients (P=0.008), and this was associated with less pyrexia(P=0.03), a lower leucocyte count (P=0.0002) and a lower C-reactiveprotein concentration (P=0.0039). Serum cortisol concentrationwas similar in the two groups of patients until 24 h, whenthe concentration was lower in patients who received diclofenac(P=0.002). Cortisol concentration correlated with IL-6 concentrationat 24 h. Conclusions. Administration of diclofenac was associated withlower IL-6 and higher IL-10 concentrations, and lower leucocytecount, C-reactive protein concentration and temperature. Diclofenacmay have an anti-inflammatory role in major surgery. Br J Anaesth 2002; 88: 797–802