A randomized double-blind clinical trial of a continuous 96-hour levobupivacaine infiltration after open or laparoscopic colorectal surgery for postoperative pain management--including clinically important changes in protein binding.

BACKGROUND: Continuous local anesthetic infiltration has been used for pain management after open colorectal surgery. However, its application to patients undergoing laparoscopic colorectal surgery has not been examined. The aim of this prospective, randomized, double-blind, placebo-controlled clinical trial was to study the use of a commercial infiltration device in patients undergoing open or laparoscopic colorectal surgery, along with plasma concentrations of levobupivacaine, its acute-phase binding protein (alpha-1 acid glycoprotein, AAG), and the stress marker, cortisol. METHODS: Eligible patients were randomized (2:1) to receive a continuous infiltration of either levobupivacaine or placebo using a commercial device (ON-Q PainBuster) inserted in the preperitoneal layer at the end of surgery. Blood was sampled for determination of levobupivacaine and AAG and cortisol concentrations. Other outcomes measured were pain scores, morbidity and mortality, time to bowel movement, mobilization, and length of hospitalization. RESULTS: In patients having open surgery, the levobupivacaine treatment showed a trend toward reduced total opioid consumption. No patients reported adverse effects attributable to levobupivacaine, despite 11 patients having concentrations at some time(s) during the 96-hour infiltration of up to 5.5 mg/L exceeding a putative toxicity threshold of 2.7 mg/L. AAG concentrations measured postsurgery increased by a mean of 55% (P < 0.001) at 48 hours. Cortisol concentrations also increased significantly by a mean of 191% at 1 hour. CONCLUSIONS: Continuous local anesthetic infiltration may be more beneficial in open surgery. The threshold for adverse effects from highly bound local anesthetic drugs established in healthy volunteers is of limited usefulness in clinical scenarios in which AAG concentration increases in response to surgical stress. Hence, there is scope to adopt higher doses to enhance therapeutic benefit.

Measuring the unbound concentration fails to resolve analytic interferences in digoxin immunoassays.

Therapeutic drug monitoring of digoxin is well established in the clinical management of cardiac patients treated with the drug. Recently, target concentrations have been revised in patients with congestive heart failure to 0.5 to 0.8 microg/L, challenging the sensitivity limits of most immunoassays. These widely used methods are often criticized, particularly on specificity grounds resulting from interference from exogenous and endogenous sources. One solution to remove higher molecular weight interference has been to ultrafilter plasma samples before assaying. The present study included 261 patient digoxin samples and compared two commercial ultrafiltration devices (Centrifree and Micrcon) that share the same separation membrane (YM-30). The results showed widely discordant apparent unbound digoxin concentrations in the ultrafiltrate from these devices with a Deming regression line of Centrifree = 1.31 x Micrcon + 0.042 (95% confidence interval for slope of 1.237 to 1.391) and apparent unbound fractions ranging from 15% to 610% of the unfiltered plasma digoxin concentrations, suggesting that ultrafiltration did not resolve such interference issues. The concept of measuring lower unbound digoxin concentrations as a result of lower therapeutic range for total (bound plus unbound) digoxin will also render most immunoassays insensitive and inappropriately calibrated. There is a strong imperative to review digoxin monitoring practices in the light of current clinical imperatives for both specificity and sensitivity reasons.

Comparison of the reintroduced MEIA assay with HPLC-MS/MS for the determination of whole-blood sirolimus from transplant recipients.

Therapeutic monitoring with dosage individualization of sirolimus drug therapy is standard clinical practice for organ transplant recipients. For several years sirolimus monitoring has been restricted as a result of lack of an immunoassay. The recent reintroduction of the microparticle enzyme immunoassay (MEIA) for sirolimus on the IMx analyser has the potential to address this situation. This study, using patient samples, has compared the MEIA sirolimus method with an established HPLC-tandem mass spectrometry method (HPLC-MS/MS). An established HPLC-UV assay was used for independent cross-validation. For quality control materials (5, 11, 22 microg/L), the MEIA showed acceptable validation criteria based on intra- and inter-run precision (CV) and accuracy (bias) of <8% and <13%, respectively. The lower limit of quantitation was found to be approximately 3 microg/L. The performance of the immunoassay was compared with HPLC-MS/MS using EDTA whole-blood samples obtained from various types of organ transplant recipients (n = 116). The resultant Deming regression line was: MEIA =1.3 x HPLC-MS/MS + 1.3 (r = 0.967, S(y/x) = 1) with a mean bias of 49.2% +/- 23.1% (range, -2.4% to 128%; P<0.001). The reason for the large and variable bias was not explored in this study, but the sirolimus-metabolite cross-reactivity with the MEIA antibody could be a substantive contributing factor. Whereas the MEIA sirolimus method may be an adjunct to sirolimus dosage individualization in transplant recipients, users must consider the implications of the substantial and variable bias when interpreting results. In selected patients where difficult clinical issues arise, reference to a specific chromatographic method may be required.