The reported successful use of IV lipid emulsions in local anesthetic intoxications is thought to be due to lipid sequestration of local anesthetics. However, controlled efficacy studies were ...lacking, and other mechanisms of action have also been suggested. We investigated the effect of lipid infusion on plasma concentrations and cardiovascular effects of 2 local anesthetics differing in lipophilicity, bupivacaine, and mepivacaine.
Bupivacaine (n = 20) or mepivacaine (n = 20) was infused into a central vein of anesthetized (isoflurane 1%, Fio(2) 0.21) pigs until mean arterial blood pressure decreased to 50% from baseline. Isoflurane was discontinued and Fio(2) was increased to 1.0. Ten pigs in each local anesthetic group were treated with 20% lipid emulsion (ClinOleic®), and 10 pigs with Ringer's solution: 1.5 mL/kg in 1 minute followed by an infusion of 0.25 mL · kg(-1) · min(-1) for 29 minutes. Five additional pigs were infused bupivacaine and Intralipid®. Total and nonlipid-bound local anesthetic concentrations were determined from repeated blood samples.
There were no overall differences in total or nonlipid-bound plasma local anesthetic concentrations between the lipid and Ringer's groups. However, plasma median total bupivacaine concentration was 21% and 23% higher at 20 and 30 minutes, respectively, in the lipid group (P = 0.016 without Holm-Bonferroni correction). There was also no overall difference between lipid and Ringer's groups in the rate of recovery of hemodynamic and electrocardiographic variables. Median mean arterial blood pressure in the lipid group with bupivacaine intoxication was 16 mm Hg and 15 mm Hg higher than in the corresponding Ringer's group at 10 and 15 minutes, respectively (P = 0.016 and P = 0.021, respectively, without Holm-Bonferroni correction). Intralipid® also caused no difference between total plasma and nonlipid-bound concentrations of bupivacaine with no apparent enhancement of recovery.
Lipid emulsion neither had any measurable effect on the disposition of the studied local anesthetics in plasma, nor did it improve the rate of recovery from intoxication by either local anesthetic as measured by hemodynamic variables.
Abstract Study objective Comparison of local anesthetic infiltration (LAI), spinal anesthesia (SPIN) and total intravenous anesthesia (TIVA) for open inguinal herniorrhaphy. We hypothesized that ...patients receiving LAI could be discharged faster than SPIN and TIVA patients. Design Randomized, prospective trial. Setting University hospital day-surgery center. Patients 156 adult male patients (ASA 1–3) undergoing day-case open inguinal herniorrhaphy. Interventions Patients were randomized to either LAI (lidocaine + ropivacaine), SPIN (bupivacaine + fentanyl) or TIVA (propofol + remifentanil). Perioperative Ringer infusion was 1.5 mL/h. Urinary bladder was scanned before and after surgery. Interviews were performed on postoperative days 1, 7 and 90. Measurements Duration of surgery, duration of the patients' stay in the operating room and time until their readiness for discharge home. Patient satisfaction and adverse effects were registered. Main results Surgery lasted longer in LAI group (median 40 min) than in SPIN group (35 min) ( P = .003) and TIVA group (33 min) ( P < .001). Although surgery was shortest in TIVA group, TIVA patients stayed longer in the operating room than LAI patients ( P = .001). Time until readiness for discharge was shorter in LAI group (93 min) than in TIVA (147 min) and SPIN (190 min) groups ( P < .001). Supplementary lidocaine infiltration was given to 32 LAI patients, and IV fentanyl to 29 LAI and 4 SPIN patients. Ephedrine was required in 34 TIVA, 5 LAI and 5 SPIN patients. One SPIN and three LAI patients had to be given TIVA and another SPIN patient LAI to complete the operations. Urinary retention was absent. Discomfort in the scar (26%) three months postoperatively was not anesthesia-related. Conclusions Logistically, LAI was superior because of the fastest recovery postoperatively. The anesthetic techniques were adequate for surgery in all but a few LAI and SPIN patients. Lack of urinary retention was probably related to the small IV infusion volumes.
Intravenous lipid emulsion has been suggested as treatment for local anaesthetic toxicity, but the exact mechanism of action is still uncertain. Controlled studies on the effect of lipid emulsion on ...toxic doses of local anaesthetics have not been performed in man. In randomized, subject‐blinded and two‐phase cross‐over fashion, eight healthy volunteers were given a 1.5 ml/kg bolus of 20% Intralipid® (200 mg/ml) or Ringer's acetate solution intravenously, followed by a rapid injection of lidocaine 1.0 mg/kg. Then, the same solution as in the bolus was infused at a rate of 0.25 ml/kg/min. for 30 min. Electroencephalography (EEG) was recorded, and 5 min. after lidocaine injection, the volunteers were asked to report subjective symptoms. Total and un‐entrapped lidocaine plasma concentrations were measured from venous blood samples. EEG band power changes (delta, alpha and beta) after the lidocaine bolus were similar during lipid and during Ringer infusion. There were no differences between infusions in the subjective symptoms of central nervous system toxicity. Lidocaine was only minimally entrapped in the plasma by lipid emulsion, but the mean un‐entrapped lidocaine area under concentration–time curve from 0 to 30 min. was clearly smaller during lipid than Ringer infusion (16.4 versus 21.3 mg × min/l, p = 0.044). Intravenous lipid emulsion did not influence subjective toxicity symptoms nor affect the EEG changes caused by lidocaine.
Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on ...plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well‐perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid® (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain amitriptyline concentration by 25% (p = 0.038) and amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial amitriptyline tissue distribution, was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid‐rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.
P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been ...identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values.
Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing.
The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (chi2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome.
The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.
The TASK-3 channel is an acid-sensitive two-pore-domain K+ channel, widely expressed in the brain and probably involved in regulating numerous neuronal populations. Here, we characterized the ...behavioral and pharmacological phenotypes of TASK-3 knockout (KO) mice. Circadian locomotor activity measurements revealed that the nocturnal activity of the TASK-3 KO mice was increased by 38% (P < 0.01) compared with wild-type littermate controls, light phase activity being similar. Although TASK-3 channels are abundant in cerebellar granule cells, the KO mice performed as well as the wild-type mice in walking on a rotating rod or along a 1.2-cm-diameter beam. However, they fell more frequently from a narrower 0.8-cm beam. The KO mice showed impaired working memory in the spontaneous alternation task, with the alternation percentage being 62 +/- 3% for the wild-type mice and 48 +/- 4% (P < 0.05) for the KO mice. Likewise, during training for the Morris water-maze spatial memory task, the KO mice were slower to find the hidden platform, and in the probe trial, the female KO mice visited fewer times the platform quadrant than the male KO and wild-type mice. In pharmacological tests, the TASK-3 KO mice showed reduced sensitivity to the inhalation anesthetic halothane and the cannabinoid receptor agonist WIN55212-2 mesylate (R)-(+)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo1,2,3-de-1,4-benzoxazin-6-yl-1-naphthalenylmethanone mesylate but unaltered responses to the alpha2 adrenoceptor agonist dexmedetomidine, the i.v. anesthetic propofol, the opioid receptor agonist morphine, and the local anesthetic lidocaine. Overall, our results suggest important contributions of TASK-3 channels in the neuronal circuits regulating circadian rhythms, cognitive functions, and mediating specific pharmacological effects.
Arterial blood gas (ABG) analysis is the traditional method for measuring the partial pressure of carbon dioxide. In mechanically ventilated patients a continuous noninvasive monitoring of
would ...obviously be attractive. In the current study, we present a novel formula for noninvasive estimation of arterial carbon dioxide. Eighty-one datasets were collected from 19 anesthetized and mechanically ventilated pigs. Eleven animals were mechanically ventilated without interventions. In the remaining eight pigs the partial pressure of carbon dioxide was manipulated. The new formula (Formula 1) is PaCO₂ = PETCO₂ + k(PETO₂ - PaO₂) where PaO₂ was calculated from the oxygen saturation. We tested the agreements of this novel formula and compared it to a traditional method using the baseline PaCO₂ - ETCO₂ gap added to subsequently measured, end-tidal carbon dioxide levels (Formula 2). The mean difference between PaCO₂ and calculated carbon dioxide (Formula 1) was 0.16 kPa (±SE 1.17). The mean difference between PaCO₂ and carbon dioxide with Formula 2 was 0.66 kPa (±SE 0.18). With a mixed linear model excluding cases with cardiorespiratory collapse, there was a significant difference between formulae (
< 0.001), as well as significant interaction between formulae and time (
< 0.001). In this preliminary animal study, this novel formula appears to have a reasonable agreement with PaCO₂ values measured with ABG analysis, but needs further validation in human patients.
In recent years, several older (first intrathecal use in the 1950s, 1960s, and 1970s) local anesthetics have been investigated as spinal anesthetics in ambulatory surgery because these drugs are ...claimed to cause less transient neurologic symptoms (TNS) than lidocaine which was the main spinal anesthetic for surgery of short-duration for decades. The review covers the current literature.
Several recent reports have dealt with the short-acting chloroprocaine and articaine and the intermediate-duration-acting prilocaine. Mepivacaine, another intermediate-acting drug, was applied in one trial only. Various dosages of these drugs either alone or with a small dose of fentanyl were compared with each other, with lidocaine, or with the currently most commonly used low-dose bupivacaine technique. The recovery from both motor and sensory block was usually reasonably fast. However, occasionally recovery after mepivacaine and prilocaine was prolonged which fits ill in a fast-flow ambulatory setting. TNS cases were very rarely reported.
The newest results corroborate (at least for chloroprocaine, articaine, and prilocaine) previous data that these drugs provide reliable and mostly well tolerated spinal blocks associated with an apparently smaller risk for postanesthesic TNS as compared with lidocaine. Further studies are warranted regarding broader indications, possible usefulness of adjuvants, and for the exploration of the side-effect profiles in detail. To what extent the observed revival of these older, rather well characterized local anesthetics leads to a wider use of spinal anesthesia in the ambulatory setting remains to be seen. This is also dependent on various organizational and local traditional factors.
: The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ...ovarian cancer patients. Thirty‐eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.
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