Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation.

Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is underscored by the list of diseases resulting from changes in transporter expression and activity. However, despite numerous structural studies of the transporters revealing both zinc binding sites and motifs important for transporter function, the exact molecular mechanisms regulating ZIP and ZnT activities are still not clear. For example, protein phosphorylation was found to regulate ZIP7 activity resulting in the release of Zn2+ from intracellular stores leading to phosphorylation of tyrosine kinases and activation of signaling pathways. In addition, sequence analyses predict all 24 human zinc transporters to be phosphorylated suggesting that protein phosphorylation is important for regulation of transporter function. This review describes how zinc transporters are implicated in a number of important human diseases. It summarizes the current knowledge regarding ZIP and ZnT transporter structures and points to how protein phosphorylation seems to be important for the regulation of zinc transporter activity. The review addresses the need to investigate the role of protein phosphorylation in zinc transporter function and regulation, and argues for a pressing need to introduce quantitative phosphoproteomics to specifically target zinc transporters and proteins involved in zinc signaling. Finally, different quantitative phosphoproteomic strategies are suggested.

Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1. METHOD: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. RESULTS: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. CONCLUSION: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance.

Risk factors for lymph node metastases in women with endometrial cancer: A population-based, nation-wide register study-On behalf of the Swedish Gynecological Cancer Group.

The role of lymphadenectomy in the management of early endometrial cancer remains controversial. In the recent ESMO-ESGO-ESTRO guidelines, lymphadenectomy is recommended for patients with endometrioid adenocarcinoma Grade 3 with deep myometrial invasion, but complete agreement was not achieved. In Sweden, DNA aneuploidy has been included as a high-risk factor. The aim of our study was to evaluate the impact of tumor histology, FIGO grade, DNA ploidy and myometrial invasion (MI) on occurrence of lymph node metastasis (LNM) in patients with endometrial cancer. The study design is a retrospective cohort study based on prospectively recorded register data. Endometrial cancer patients registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2015 with FIGO Stages I-III and verified nodal status were included. Data on DNA ploidy, histology, FIGO grade and MI were included in multivariable log-binomial regression analyses with LNM as dependent variable. 1,165 cases fulfilled the inclusion criteria. The multivariable analyses revealed increased risk of LNM in patients with tumors with MI ≥ 50% (risk ratio [RR] = 4.1; 95% confidence interval [CI] 3.0-5.6), nonendometrioid compared to endometrioid histology (RR 1.8; CI 1.4-2.4) and FIGO Grade 3 compared to Grade 1-2 tumors (RR 1.5; CI 1.1-2.0). No statistically significant association between DNA ploidy status and LNM was detected. This population-based, nation-wide study in women with endometrial cancer confirms a strong association between MI ≥ 50%, nonendometrioid histology and FIGO Grade 3, respectively, and LNM. DNA ploidy should not be included in the preoperative decision making of removing nodes or not.

Changing Metrics of Organ Procurement Organization Performance in Order to Increase Organ Donation Rates in the United States.

The shortage of deceased-donor organs is compounded by donation metrics that fail to account for the total pool of possible donors, leading to ambiguous donor statistics. We sought to assess potential metrics of organ procurement organizations (OPOs) utilizing data from the Nationwide Inpatient Sample (NIS) from 2009-2012 and State Inpatient Databases (SIDs) from 2008-2014. A possible donor was defined as a ventilated inpatient death ≤75 years of age, without multi-organ system failure, sepsis, or cancer, whose cause of death was consistent with organ donation. These estimates were compared to patient-level data from chart review from two large OPOs. Among 2,907,658 inpatient deaths from 2009-2012, 96,028 (3.3%) were a "possible deceased-organ donor." The two proposed metrics of OPO performance were: (1) donation percentage (percentage of possible deceased-donors who become actual donors; range: 20.0-57.0%); and (2) organs transplanted per possible donor (range: 0.52-1.74). These metrics allow for comparisons of OPO performance and geographic-level donation rates, and identify areas in greatest need of interventions to improve donation rates. We demonstrate that administrative data can be used to identify possible deceased donors in the US and could be a data source for CMS to implement new OPO performance metrics in a standardized fashion.

Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013.

BACKGROUND: Although the incidence of severe local anaesthetic systemic toxicity (LAST) has been declining, the risk of LAST still remains. There are no national treatment guidelines for LAST in Finland. We performed a national survey of the occurrence of LAST and its treatment in 2011-2013. METHODS: A structured electronic questionnaire was sent to the anaesthesia department chiefs of all Finnish public hospitals (n = 45) in spring 2014. We collected information about the occurrence and outcome of LASTs and existence of treatment protocols. RESULTS: The questionnaire response rate was 100% covering approximately 95% of all regional anaesthesias managed by anaesthesiologists in Finnish hospitals. The total number of regional anaesthesias, excluding spinal anaesthesia, performed by anaesthesiologists was approximately 211,700 during the survey period. Fifteen cases of LAST were reported (0.7 : 10,000); all patients recovered without negative sequelae. Fourteen patients, in five of whom ultrasound guidance had been applied, developed central nervous system toxicity symptoms and only one cardiac symptoms. Lipid emulsion was given to this latter patient, and to four of the other 14. The relative risk (95% confidence intervals) for occurrence of LAST in non-academic hospital vs. university hospitals was 3.3 (1.0-10.3; P = 0.04). Treatment protocols for LAST included lipid emulsion in 47% of the departments. CONCLUSIONS: The incidence of LAST in Finland is very low. Several departments have adopted lipid emulsion treatment for LAST despite lack of national recommendations and knowledge of the possible mechanism of action.

National critical incident reporting systems relevant to anaesthesia: a European survey.

BACKGROUND: Critical incident reporting is a key tool in the promotion of patient safety in anaesthesia. METHODS: We surveyed representatives of national incident reporting systems in six European countries, inviting information on scope and organization, and intelligence on factors determining success and failure. RESULTS: Some systems are government-run and nationally conceived; others started out as small, specialty-focused initiatives, which have since acquired a national reach. However, both national co-ordination and specialty enthusiasts seem to be necessary for an optimally functioning system. The role of reporting culture, definitional issues, and dissemination is discussed. CONCLUSIONS: We make recommendations for others intending to start new systems and speculate on the prospects for sharing patient safety lessons relevant to anaesthesia at European level.

CTAD Task Force Paper: Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.

Neoadjuvant chemotherapy prior to pelvic exenteration in patients with recurrent cervical cancer: single institution experience.

OBJECTIVES: The aim of the study is to evaluate the response to neoadjuvant chemotherapy (NACHT) of patients with recurrent cervical cancer who were poor candidates for pelvic exenteration (PE), and the impact on DFS and OS. METHODS: A retrospective data collection extracted from medical records of 61 patients submitted to pelvic exenteration was performed: 30 underwent up-front exenterative procedure whereas 31 received NACHT. RESULTS: The median tumor size was significantly (P=0.0006) larger in the NACHT group compared to the up-front PE one (43.9 mm vs 28 mm), and a significant (P=0.04) higher percentage of patients (45 vs 20%) had lateral pelvic wall invasion in the NACHT group. No statistically significant difference in early and late complications was observed in the two groups. Median overall survival in study population was 42.9 months (95% CI: 22.2, 180.8). Median overall survival times as well as recurrence free survival times were not significantly different between NACHT (42.9 months and 36.1 months for OS and DFS respectively) vs. No NACHT (111.9 months and 48.1 months for OS and DFS respectively). There was an overall significant difference in DFS between negative and positive margins but the curves were similar for NACHT and up-front PE groups stratified by resection margin status. CONCLUSIONS: In our series, though small and retrospective, NACHT prior to PE represents a feasible therapeutic option without intra-operative and early post-operative mortality or worsening of early and late complication rate and with acceptable long-term survival and DFS for recurrent cervical cancer patients who are poor candidates for up-front pelvic exenteration.

Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: the Cache County Study.

OBJECTIVES: To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). DESIGN: Survival analysis of time to dementia, AD, or VaD onset. SETTING: Population-based study. PARTICIPANTS: 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. MEASUREMENTS: The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-squared statistics, t-tests, and Cox proportional hazard ratios were used to assess associations. RESULTS: The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE ε4 allele, lower Mini-Mental State Examination, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, whereas hallucinations were a risk factor for VaD. CONCLUSIONS: These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD.

Hyperbaric articaine with or without fentanyl in spinal anaesthesia: patient and observer blinded comparison.

BACKGROUND: The rapid and short-acting local anaesthetic articaine is a feasible spinal anaesthetic for day-case open inguinal herniorrhaphy (OIH). We hypothesised that similarly to other spinal local anaesthetics, the addition of fentanyl may prolong articaine spinal analgesia without prolonging motor block. METHODS: We performed a randomised, controlled study in 100 adult patients undergoing OIH. Spinal anaesthesia was induced by injecting hyperbaric articaine 72 mg with (Group A + F) or without (Group A) fentanyl 10 µg with the patient in lateral decubitus position. The distribution of sensory block was tested using pinprick and controlled by tilting the operating table 10 up or down. Motor block testing was based on the patient's ability to flex knees and ankles. Rescue analgesic was intravenous (i.v.) fentanyl. Pain scores were registered, and i.v. paracetamol 1 g was given as the first post-operative analgesic. RESULTS: There were no differences (A + F vs. A) in the maximum median extension of the sensory block (T5 vs. T5), mean duration of sensory block ≥ T10 (76 min vs. 73 min), or total duration of sensory (146 min vs. 146 min) or motor block (99 min vs. 107 min). Fewer patients in Group A + F needed fentanyl (5 vs. 14, P < 0.05) perioperatively or paracetamol (3 vs. 18, P < 0.001) post-operatively. CONCLUSION: Fentanyl 10 µg added to spinal hyperbaric articaine improved analgesia and reduced analgesic consumption during and after OIH. Fentanyl did not prolong motor block or delay recovery.

Chloroprocaine 40 mg produces shorter spinal block than articaine 40 mg in day-case knee arthroscopy patients.

BACKGROUND: Articaine and chloroprocaine have recently gained interest as short-acting spinal anaesthetics. Based on previous work comparing articaine 60 mg with chloroprocaine 40 mg, we hypothesised that articaine 40 mg and chloroprocaine 40 mg would produce similar spinal anaesthesa regarding block onset, maximal spread, and recovery. METHODS: In this randomised, double-blind study, adult patients (18-70 years, American Society of Anaesthesiologists physical status I-III, BMI < 36 kg/m(2) ) scheduled for day-case knee arthroscopy received either articaine 40 mg (20 mg/ml) (group A40, n = 16) or chloroprocaine 40 mg (20 mg/ml) (group C40, n = 18) intrathecally. Telephone interviews were performed on the first and seventh postoperative day to disclose possible side effects, e.g. transient neurological symptoms (TNS). RESULTS: The groups were comparable regarding demographic data, onset and maximal spread of spinal anaesthesia, and duration of surgery. Surgery could be performed successfully under spinal anaesthesia except once in A40 (insufficient block) and once in C40 (prolonged surgery). Complete recovery was significantly slower in A40 vs. C40 for both motor block (105 (94/120) vs. 75 (71/90) min) [P < 0.001, Mann-Whitney U-test (MW-U)] and sensory block [135 (109/176) vs. 105 min (90/124)] (P < 0.02, MW-U), respectively [data are median (25th/75th percentiles)]. One patient from A40 showed mild TNS. CONCLUSION: Both A40 and C40 provided mainly adequate spinal anaesthesia for day-case knee arthroscopy. While onset and maximal spread were comparable, the recovery from motor block was clearly faster with chloroprocaine after equivalent doses of spinal articaine and chloroprocaine.

The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.

Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans.

Intravenous lipid emulsion is the recommended treatment for severe local anaesthetic intoxication. Lipid emulsion may entrap lipid soluble drugs by functioning as a 'lipid sink', but its effect on bupivacaine pharmacokinetics remains unknown. In this randomised, double-blind, crossover study, eight healthy male volunteers were infused bupivacaine 0.5mg.kg(-1) intravenously over 20 min, followed by an infusion of either intravenous lipid emulsion or Hartmann's solution for 30 min. At 20 and 30 min after the start of the infusion, the total plasma bupivacaine concentration was lower while receiving lipid emulsion than Hartmann's solution (mean difference 111 (95% CI 55-167) µg.l(-1) and 75 (95% CI 26-124 µg.l(-1) at 20 and 30 min, respectively; p<0.02). However, there were no differences in un-entrapped (non-lipid bound) or free (non-protein bound) bupivacaine plasma concentrations during the infusion. Intravenous lipid emulsion infusion reduced the context-sensitive half-life of total plasma bupivacaine from 45 (95% CI 32-76)min to 25 (95% CI 20-33)min; p=0.01. We observed no significant adverse effects of lipid emulsion. In conclusion, lipid emulsion may slightly increase the rate of bupivacaine tissue distribution. No 'lipid sink' effect was observed with the non-toxic dose of bupivacaine used.

Responses of immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures.

AIM: To report several types of response of immature permanent teeth with infected necrotic pulp tissue and either apical periodontitis or abscess to revascularization procedures. METHODOLOGY: Twenty immature permanent teeth with infected necrotic pulp tissue and either apical periodontitis or abscesses from 20 patients were included. The teeth were isolated with rubber dam, and pulp chambers was accessed through the crowns. The canals were gently irrigated with 5.25% sodium hypochlorite with minimal mechanical debridement. Calcium hydroxide was used as an inter-appointment intracanal medicament and placed into the coronal half of the canal space. After resolution of clinical signs and symptoms, bleeding was induced into the canal space from the periapical tissues using K-files. The coronal canal space was sealed with a mixture of mineral trioxide aggregate (MTA) and saline solution. The access cavity was filled with composite resin. These immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscesses were followed up from 6 to 26 months. RESULTS: Five types of responses of these immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures were observed: type 1, increased thickening of the canal walls and continued root maturation; type 2, no significant continuation of root development with the root apex becoming blunt and closed; type 3, continued root development with the apical foramen remaining open; type 4, severe calcification (obliteration) of the canal space; type 5, a hard tissue barrier formed in the canal between the coronal MTA plug and the root apex. CONCLUSIONS: Based on this case series, the outcome of continued root development was not as predictable as increased thickening of the canal walls in human immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess after revascularization procedures. Continued root development of revascularized immature permanent necrotic teeth depends on whether the Hertwig's epithelial root sheath survives in case of apical periodontitis/abscess. Severe pulp canal calcification (obliteration) by hard tissue formation might be a complication of internal replacement resorption or union between the intracanal hard tissue and the apical bone (ankylosis) in revascularized immature permanent necrotic teeth.

Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection.

Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s-B12) on end-of-treatment response (ETR) in patients with chronic HCV. Ninety-nine treatment naïve HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s-B12) was analysed in samples collected before treatment start. Pretreatment s-B12 levels were correlated to ETR using univariate analysis. S-B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s-B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s-B12 levels ≤ 360 pm, 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s-B12 > 360 pm, one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s-B12 > 360 vs ≤ 360 pm: OR 28.6 CI 2.31-354, P = 0.008. Fibrosis stage 3-4 vs 0-2: OR 0.29 CI 0.074-1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87-83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048-0.91 P = 0.034. Standard interferon vs pegylated-interferon: OR 0.079, CI 0.0091-0.68 P = 0.019. Age and gender were not correlated to ETR. S-B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti-HCV treatment.

A case-control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A.

Several genes that modify risk of factor VIII (FVIII) inhibitors in haemophilia A patients have been identified. Aside from the underlying mutations that cause haemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators including IL10, TNFα and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk. We sought to confirm previous observations on FVIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal FVIII gene polymorphisms affect inhibitor risk in caucasians. We studied 915 caucasian, severe haemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls). Genes were analysed using 368 tagging single nucleotide polymorphisms starting 20 kb 5' and ending 10 kb 3' of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated. Haplotypes that increased inhibitor risk were found in IL10 (OR = 1.33, P = 0.04), IL12 (OR = 1.31, P = 0.04) and IL1α (OR = 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR = .69, P = 0.008) and IL1ß (OR = 0.75, P = 0.02). One rare haplotype in the FVIII gene increased the risk of inhibitor development by nearly fourfold (OR = 3.8, P = 0.004). We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare FVIII haplotype in caucasians that is associated with increased inhibitor risk.

Pharmacokinetics of ropivacaine in patients with chronic renal failure.

BACKGROUND: As ropivacaine and its metabolites are excreted by the kidneys, we studied their disposition in subjects with renal dysfunction. METHODS: Twenty patients with moderate or severe renal insufficiency and 10 healthy volunteers received ropivacaine 1 mg kg(-1) i.v. over 30 min. The concentrations of ropivacaine and its main metabolites, pipecoloxylidide (PPX) and 3-hydroxy-ropivacaine, were measured in plasma and urine for 16-48 h. The relationship between pharmacokinetic parameters and creatinine clearance (CL(CR)) was assessed. A model for estimating non-renal clearance of a metabolite of ropivacaine is described. RESULTS: Renal dysfunction had little or no influence on the pharmacokinetics of ropivacaine. The median plasma concentrations of unbound ropivacaine were similar in uraemic and non-uraemic subjects. Renal clearance of PPX correlated significantly with CL(CR) (R(2)=0.81). Lack of correlation between total PPX exposure, expressed as area under the total plasma concentration-time curve from zero to infinity, and CL(CR) suggests that the clearance of PPX also includes non-renal elimination. However, in two uraemic patients, there was increased exposure to PPX resulting from low non-renal elimination. CONCLUSIONS: The pharmacokinetics of ropivacaine is not affected by renal failure. Although the renal clearance of PPX correlates with CL(CR), non-renal elimination seems to compensate for reduced renal clearance in most patients. PPX may accumulate in plasma during long-term postoperative infusions, in particular in patients with co-existing low non-renal elimination. Systemic toxicity is still unlikely because PPX is markedly less toxic than ropivacaine.

Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial.

BACKGROUND: In this prospective, randomized, double-blind, placebo-controlled study, we investigated the effect of pregabalin on oxycodone consumption, postoperative confusion, and pain in elderly cardiac surgery patients. METHODS: Seventy patients, aged ≥75 yr, were randomized to receive either 150 mg of pregabalin before operation and 75 mg of pregabalin twice daily for 5 postoperative days or placebo. Pain intensity was measured with the Verbal Rating Scale (VRS). When pain intensity was ≥2 on the VRS, patients received oxycodone either i.v. (0.05 mg kg(-1)) or orally (0.10-0.15 mg kg(-1)). Postoperative confusion was measured with the Confusion Assessment Method for the intensive care unit (CAM-ICU). Postoperative pain was assessed by a telephone interview 1 and 3 months after operation. RESULTS: Cumulative consumption of parenteral oxycodone during 16 h after extubation was reduced by 44% and total oxycodone consumption from extubation to the end of the fifth postoperative day was reduced by 48% in the pregabalin group. Time to extubation was 138 min shorter and CAM-ICU scores were significantly lower on the first postoperative day in the placebo group, although there was no significant difference with respect to the Mini-Mental State Examination or the Richmond Agitation Sedation Score. The incidence of pain during movement was significantly lower in the pregabalin group at 3 months postoperative. CONCLUSIONS: The administration of pregabalin reduced postoperative opioid consumption after cardiac surgery reduced the incidence of confusion on the first postoperative day and increased time to extubation when compared with placebo. Three months after operation, patients in the pregabalin group experienced less pain during movement.