Publications by authors named "Peter Gerner"

59 Publications

Anaesthetic care of patients undergoing primary hip and knee arthroplasty: consensus recommendations from the International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) based on a systematic review and meta-analysis.

Br J Anaesth 2019 Sep 24;123(3):269-287. Epub 2019 Jul 24.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Background: Evidence-based international expert consensus regarding anaesthetic practice in hip/knee arthroplasty surgery is needed for improved healthcare outcomes.

Methods: The International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) systematic review, including randomised controlled and observational studies comparing neuraxial to general anaesthesia regarding major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, genitourinary, thromboembolic, neurological, infectious, and bleeding complications. Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, from 1946 to May 17, 2018 were queried. Meta-analysis and Grading of Recommendations Assessment, Development and Evaluation approach was utilised to assess evidence quality and to develop recommendations.

Results: The analysis of 94 studies revealed that neuraxial anaesthesia was associated with lower odds or no difference in virtually all reported complications, except for urinary retention. Excerpt of complications for neuraxial vs general anaesthesia in hip/knee arthroplasty, respectively: mortality odds ratio (OR): 0.67, 95% confidence interval (CI): 0.57-0.80/OR: 0.83, 95% CI: 0.60-1.15; pulmonary OR: 0.65, 95% CI: 0.52-0.80/OR: 0.69, 95% CI: 0.58-0.81; acute renal failure OR: 0.69, 95% CI: 0.59-0.81/OR: 0.73, 95% CI: 0.65-0.82; deep venous thrombosis OR: 0.52, 95% CI: 0.42-0.65/OR: 0.77, 95% CI: 0.64-0.93; infections OR: 0.73, 95% CI: 0.67-0.79/OR: 0.80, 95% CI: 0.76-0.85; and blood transfusion OR: 0.85, 95% CI: 0.82-0.89/OR: 0.84, 95% CI: 0.82-0.87.

Conclusions: Recommendation: primary neuraxial anaesthesia is preferred for knee arthroplasty, given several positive postoperative outcome benefits; evidence level: low, weak recommendation.

Recommendation: neuraxial anaesthesia is recommended for hip arthroplasty given associated outcome benefits; evidence level: moderate-low, strong recommendation. Based on current evidence, the consensus group recommends neuraxial over general anaesthesia for hip/knee arthroplasty.

Trial Registry Number: PROSPERO CRD42018099935.
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http://dx.doi.org/10.1016/j.bja.2019.05.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678169PMC
September 2019

Factors associated with hospital admission after rotator cuff repair: the role of peripheral nerve blockade.

J Clin Anesth 2015 Nov 17;27(7):566-73. Epub 2015 Aug 17.

Department of Anesthesiology, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA; Department of Anesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University, Salzburg, Austria. Electronic address:

Study Objective: The objective was to analyze the impact of a peripheral nerve block in addition to general anesthesia on hospital admission after surgical rotator cuff repair.

Design: This was a population-based outcome study. The cost effectiveness of ambulatory rotator cuff repair relies on the discharge of patients on the day of surgery. As the impact of a peripheral nerve block in addition to general anesthesia on this outcome is unknown, we sought to elucidate this subject using population-based data.

Patients And Methods: Information on patients undergoing rotator cuff surgery under general anesthesia with or without the addition of a peripheral nerve block (GN vs G) from a retrospective database provided by Premier Perspective, Inc, Charlotte, NC (http://www.premierinc.com), was analyzed. Using multilevel multivariable regressions, we evaluated the independent impact of the type of anesthesia on the outcomes hospital admission, combined major complications, and increased hospital costs.

Results: We identified 27,201 patients who underwent surgical rotator cuff repair. Approximately 89% (24,240) of patients were discharged on the day of surgery, whereas 11% (2961) were admitted to the hospital. The admission rates for the GN group were 9.1% and 11.2% for the G group (P=.0001). The multivariable regression models showed that patients with the addition of a peripheral nerve block had 18% less risk of being admitted to the hospital (relative risk [RR]=0.82; 95% confidence interval [CI], 0.74-0.91; P=.0003) compared with those without this intervention. Differences in risk for combined major complications (RR=1.00; 95% CI, 0.83-1.20; P=.9751) or increased hospital costs (RR=0.97; 95% CI, 0.93-1.02; P=.2538) were nonsignificant.

Discussion: For patients undergoing surgical rotator cuff repair under general anesthesia, the addition of a peripheral nerve block may be associated with a reduction in the need for postoperative hospital admission after ambulatory surgery. Although the reason for this finding has to remain speculative, better pain control may play a role.
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http://dx.doi.org/10.1016/j.jclinane.2015.07.008DOI Listing
November 2015

Additives to local anesthetics for peripheral nerve blocks or local anesthesia: a review of the literature.

Pain Manag 2015 ;5(2):117-28

Department of Anesthesiology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA.

A multitude of studies have focused on individual additives to local anesthetics and their effect on quality, onset, duration, spread and selectivity, as well as the potential toxic effects of their use. This review aims to give a broad overview of the current evidence in this developing field, based on beneficial and adverse effects of these drugs. We discuss the limitations of the available data and hope to convey implications and future perspectives for clinicians and researchers alike.
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http://dx.doi.org/10.2217/pmt.15.2DOI Listing
January 2016

Ropivacaine 0.375% vs. 0.75% with prilocaine for intermediate cervical plexus block for carotid endarterectomy: A randomised trial.

Eur J Anaesthesiol 2015 Nov;32(11):781-9

From the Department of Anaesthesiology, Perioperative Medicine and Intensive Care (AK, JN, OS, PG), Department of Laboratory Medicine (TKF), and Department of Vascular and Endovascular Surgery, Paracelsus Medical University, Salzburg, Austria (NM).

Background: Carotid endarterectomy is widely performed under regional anaesthesia. Ultrasound guidance is increasingly used in many regional anaesthetic procedures to improve safety and efficacy, and because it can reduce the amount of local anaesthetic required. Despite this, an ideal approach and dosing regimen for cervical plexus block remain elusive.

Objective: The aim of this study was to compare two different concentrations of ropivacaine in terms of analgesic adequacy, haemodynamic effects and plasma concentration using an ultrasound-guided triple approach for intermediate cervical plexus blockade.

Design: A randomised, placebo-controlled, blinded study.

Setting: University Clinic Salzburg, Department of Anaesthesiology, Perioperative Medicine and Intensive Care, Paracelsus Medical University, Salzburg, Austria, from 16 November 2012 to 17 September 2013.

Patients: Forty-six patients prospectively randomised to receive ultrasound-guided intermediate cervical block with either 20 ml ropivacaine 0.75% or 20 ml ropivacaine 0.375% each with 20 ml prilocaine 1%.

Intervention: After subcutaneous infiltration, blocks were performed using ultrasound-guided infiltration below the sternocleidomastoid muscle, and ultrasound-guided infiltration of the carotid sheath. Ropivacaine and prilocaine plasma concentrations were measured at intervals.

Main Outcome: The primary study endpoint was the volume of supplementary lidocaine 1% required to achieve adequate surgical anaesthesia. Perioperative haemodynamic variables and pain scores were recorded.

Results: There was no statistical difference in the volume of supplementary lidocaine given: 5.0 (±3.63) ml in the ropivacaine 0.375% group and 5.17 (±2.76) ml in the ropivacaine 0.75% group (P = 0.846). Pain scores were similarly low across both groups. Measured concentrations of ropivacaine and prilocaine did not reach toxic levels in either group. Levels of ropivacaine were approximately two-fold higher in the 0.75% group [mean area under the curve (AUC) 10 531.11 (±2912.84) vs. 5264.34 ng (±1594.69), P < 0.0001]. Perioperative cardiovascular stability was excellent in both groups. There were no serious block-related complications.

Conclusion: An ultrasound-guided intermediate block provides adequate anaesthesia for carotid thrombendarterectomy with a little need for supplementary local anaesthetic. Use of 0.375% ropivacaine provided similarly effective analgesia as 0.75%, but resulted in significantly lower plasma concentrations.

Trial Registration: The study was registered at the European Clinical Trial Database (Eudra CT No.: 2012-002769) as well as at ClinicalTrials.gov (NCT01759940).
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http://dx.doi.org/10.1097/EJA.0000000000000243DOI Listing
November 2015

Utility of intraoperative lung ultrasonography.

A A Case Rep 2015 Mar;4(6):71-4

From the Departments of *Anesthesiology, Perioperative Medicine and General Intensive Care Medicine and †Surgery, Salzburg General Hospital, Salzburg, Austria; ‡Paracelsus Medical University, Salzburg, Austria; and §Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A patient with an endobronchial tumor and critical airway obstruction developed hypoxia and hypercarbia and, subsequently, cardiac arrest during a palliative laser core-out excision. The differential diagnosis included tension pneumothorax, as well as airway obstruction due to swelling of residual tumor or to blood clots. In this case, empiric needle decompression could have had deleterious consequences. Immediate bedside lung ultrasonography provided real-time information leading to the stabilization of the patient. This case provides compelling motivation for anesthesiologists to acquire this easily learned skill.
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http://dx.doi.org/10.1213/XAA.0000000000000123DOI Listing
March 2015

The Qualitative Hyperalgesia Profile: A New Metric to Assess Chronic Post-Thoracotomy Pain.

Open Pain J 2013 ;6:190-198

Pain Research Center, Brigham & Women's Hospital, Boston MA 02115, USA.

Thoracotomy often results in chronic pain, characterized by resting pain and elevated mechano-sensitivity. This paper defines complex behavioral responses to tactile stimulation in rats after thoracotomy, shown to be reversibly relieved by systemic morphine, in order to develop a novel qualitative "pain" score. A deep incision and 1 hour of rib retraction in male Sprague-Dawley rats resulted in reduced threshold and a change in the locus of greatest tactile (von Frey filament) sensitivity, from the lower back to a more rostral location around the wound site, and extending bilaterally. The fraction of rats showing nocifensive responses to mild stimulation (10 gm) increased after thoracotomy (from a pre-operative value of 0/10 to 8/10 at 10 days post-op), and the average threshold decreased correspondingly, from 15 gm to ∼4 gm. The nature of the nocifensive responses to tactile stimulation, composed pre-operatively only of no response (Grade 0) or brief contractions of the local subcutaneous muscles (Grade I), changed markedly after thoracotomy, with the appearance of new behaviors including a brisk lateral "escape" movement and/or a 180° rotation of the trunk (both included as Grade II), and whole body shuddering, and scratching and squealing (Grade III). Systemic morphine (2.5 mg/kg, i.p.) transiently raised the threshold for response and reduced the frequency of Grade II and III responses, supporting the interpretation that these represent pain. The findings support the development of a Qualitative Hyperalgesic Profile to assess the complex behavior that indicates a central integration of hyperalgesia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932053PMC
http://dx.doi.org/10.2174/1876386301306010190DOI Listing
January 2013

Dexmedetomidine added to ropivacaine extends the duration of interscalene brachial plexus blocks for elective shoulder surgery when compared with ropivacaine alone: a single-center, prospective, triple-blind, randomized controlled trial.

Reg Anesth Pain Med 2014 Jan-Feb;39(1):37-47

From the *Department of Anesthesiology, Perioperative Medicine, and Critical Care Medicine, Paracelsus Medical University, Salzburg, Austria; †Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI; ‡Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria; and §Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI.

Background And Objectives: Research suggests that the addition of dexmedetomidine to local anesthetics can prolong peripheral nerve blocks; however, clinical safety data are limited, and interscalene blocks have not been studied. The present study was designed to test the hypothesis that dexmedetomidine added to ropivacaine would safely enhance the duration of analgesia without adverse effects when compared with ropivacaine alone.

Methods: We conducted a single-center, prospective, randomized, triple-blind, controlled trial of 62 patients undergoing elective shoulder surgery under general anesthesia with an interscalene block. Patients underwent ultrasound-guided interscalene blocks using either 12 mL of 0.5% ropivacaine or 0.5% ropivacaine plus 150-µg dexmedetomidine. The primary outcomes were self-reported duration of the nerve block and safety assessment (adverse effects and neurological sequelae). Data were analyzed in a blinded fashion.

Results: The median duration of the nerve block was 18 hours (95% confidence interval, 18-20) in the dexmedetomidine group and 14 hours (95% confidence interval, 14-16) in the ropivacaine group (P = 0.0001). Dexmedetomidine also lowered pain scores for the first 14 hours postoperatively and significantly hastened the time to sensory (P = 0.04) and motor (P = 0.002) block onset. Dexmedetomidine lowered heart rate but blood pressures were stable. Plasma levels of ropivacaine were not different between groups, and plasma dexmedetomidine levels were relatively low. There were no adverse events or neurological sequelae.

Conclusions: Dexmedetomidine added to ropivacaine for interscalene blocks increased the duration of the nerve block and improved postoperative pain. These additional efficacy and safety data should encourage further study of peripheral perineural dexmedetomidine in humans.
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http://dx.doi.org/10.1097/AAP.0000000000000033DOI Listing
August 2014

Ephedrine shows synergistic motor blockade when combined with bupivacaine or lidocaine for spinal anesthesia in a rat model.

Anesth Analg 2013 Apr 4;116(4):944-8. Epub 2013 Mar 4.

Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Dr., Room H3687, MC 5640, Stanford, CA 94305, USA.

Background: Ephedrine is a direct/indirect vasoactive drug. In addition, it also possesses intrinsic local anesthetic properties, mainly due to its sodium-channel blockage. We investigated whether ephedrine demonstrates a synergistic effect with bupivacaine and lidocaine when injected via a spinal catheter into the spinal space of rats.

Methods: Spinal catheters were surgically placed in 47 rats (n = 8 per group; 7 rats were excluded.) Bupivacaine, lidocaine, and ephedrine in various concentrations and constant volumes (60 μL) were injected into the spinal catheters to determine the equipotency of each drug. Ephedrine in combination with either bupivacaine or lidocaine was then injected into the spinal catheters.

Results: Ephedrine demonstrated statistically significant synergistic effects with bupivacaine as well as with lidocaine in fixed combinations. The combination index reflecting a synergistic effect was 0.792 (95% confidence interval: 0.665-0.919) for ephedrine + bupivacaine and 0.663 (95% confidence interval: 0.532-0.794) for ephedrine + lidocaine.

Conclusion: Ephedrine combined with either bupivacaine or lidocaine acted synergistically to block motor function and has the potential to reduce the amount of local anesthetic needed for spinal block. The synergistic effect of ephedrine in combination with local anesthetics is an interesting pharmacological phenomenon that warrants further clinical evaluation.
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http://dx.doi.org/10.1213/ANE.0b013e3182834662DOI Listing
April 2013

Local anesthetic-induced inhibition of human neutrophil priming: the influence of structure, lipophilicity, and charge.

Reg Anesth Pain Med 2013 Jan-Feb;38(1):9-15

Department of Anesthesiology, University Hospital Maastricht, The Netherlands.

Background And Objectives: Local anesthetics (LAs) are widely known for inhibition of voltage-gated sodium channels underlying their antiarrhythmic and antinociceptive effects. However, LAs have significant immunomodulatory properties and were shown to affect human neutrophil functions independent of sodium-channel blockade. Previous studies suggest a highly selective interaction between LAs and the α-subunit of G protein-coupled receptors of the Gq/G11 family as underlying mechanism. Providing a detailed structure function analysis, this study aimed to determine the active parts within the LA molecule responsible for the effects on human neutrophil priming.

Methods: Human neutrophils were incubated with structurally different LAs for 60 minutes, followed by priming and activation using either platelet-activating factor or lysophosphatidic acid and N-formyl-methionyl-L-leucyl-L-phenylalanine. Superoxide anion generation was determined, using the cytochrome c reduction assay.

Results: Differences in priming inhibition of human neutrophils between LAs were smaller than expected, although significant. Ester-linked LAs blocked priming responses more effectively than did amide LAs. Furthermore, the inhibitory potency of LAs on priming decreased with an increase of their respective octanol-buffer coefficient, and inhibition did not correlate with sodium-channel-blocking potency. Charge was not crucially required for priming inhibition, yet it played a role in effect size.

Conclusions: Local anesthetics significantly attenuated Gαq-protein-mediated neutrophil priming. The most potent inhibition was achieved by ester compounds, inversely correlated with their octanol-buffer coefficient, and enhanced by permanent charges within the LA molecule. No correlation to their potency of blocking sodium channels was found.
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http://dx.doi.org/10.1097/AAP.0b013e31827a3cbeDOI Listing
August 2013

Demographics and perioperative outcome in patients with depression and anxiety undergoing total joint arthroplasty: a population-based study.

Psychosomatics 2013 Mar-Apr;54(2):149-57. Epub 2012 Nov 27.

Department of Anesthesiology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY, USA.

Background: Depression and anxiety are highly prevalent psychiatric disorders. However, little is known about their impact on outcomes in the perioperative setting. This study is intended to gain insight into epidemiology and effects on perioperative morbidity, mortality, length of hospital stay, discharge and cost.

Methods: We obtained the National Inpatient Sample from the Hospital Cost and Utilization Project for each year between 2000 and 2008. Entries indicating the performance of primary total hip and knee arthroplasty were identified and separated into four groups: (1) those with concomitant diagnosis of depression or (2) anxiety, (3) both, and (4) none of these diagnoses. The incidence of major complications, non-routine discharge, length, and cost of hospitalization were assessed. Regression analysis was performed to identify if psychiatric comorbidity was an independent risk factor for each outcome.

Results: We identified 1,212,493 patients undergoing arthroplasty between 2000 and 2008. The prevalence of depression and anxiety significantly increased over time. Patients with either condition had higher hospital charges, rates of non-routine discharges and comorbidity index. Depression or anxiety were associated with significantly decreased adjusted odds for in-hospital mortality (OR = 0.53, p = 0.0147; OR = 0.58, p = 0.0064). The risk of developing a major complication was slightly lower in patients with depression, anxiety or both (OR=0.95, p = 0.0738; OR = 0.95, p = 0.0259; OR = 0.94, p = 0.7349).

Conclusions: Patients suffering from depression, anxiety, or both require more healthcare resources in a perioperative setting. However, lower short-term mortality in spite of higher comorbidity burden and without extensive changes in perioperative complication profile indicates better outcome for this group of patients.
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http://dx.doi.org/10.1016/j.psym.2012.08.009DOI Listing
January 2014

Comparative perioperative outcomes associated with neuraxial versus general anesthesia for simultaneous bilateral total knee arthroplasty.

Reg Anesth Pain Med 2012 Nov-Dec;37(6):638-44

Department of Anesthesiology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA.

Background And Objectives: The influence of the type of anesthesia on perioperative outcomes after bilateral total knee arthroplasty (BTKA) remains unknown. Therefore, we examined a large sample of BTKA recipients, hypothesizing that neuraxial anesthesia would favorably impact on outcomes.

Methods: We identified patient entries indicating elective BTKA between 2006 and 2010 in a national database; subgrouped them by type of anesthesia: general (G), neuraxial (N), or combined neuraxial-general (NG); and analyzed differences in demographics and perioperative outcomes.

Results: Of 15,687 identified procedures, 6.8% (n = 1066) were performed under N, 80.1% (n = 12,567) under G, and 13.1% (n = 2054) under NG. Comparing N to G and NG, patients in group N were, on average, younger (63.9, 64.6, and 64.8 years; P = 0.030) but did not differ in overall comorbidity burden. Patients in group N required blood product transfusions significantly less frequently (28.5%, 44.7%, 38.0%; P < 0.0001). In-hospital mortality, 30-day mortality, and complication rates tended to be lower in group N, without reaching statistical significance. After adjusting for covariates, N and NG were associated with 16.0% and 6.0% reduction in major complications compared with G, but only the reduced odds for the requirement of blood transfusions associated with N reached statistical significance (N vs G: odds ratio, 0.52 [95% CI, 0.45-0.61], P < 0.0001; NG vs G: odds ratio, 0.77 [95% CI, 0.69-0.86], P < 0.0001).

Conclusions: Neuraxial anesthesia for BTKA is associated with significantly lower rates of blood transfusions and, by trend, decreased morbidity. Although by itself the effect may be limited, N might be used within a multimodal approach to reduce complications after BTKA.
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http://dx.doi.org/10.1097/AAP.0b013e31826e1494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653590PMC
April 2013

In Zucker diabetic fatty rats, subclinical diabetic neuropathy increases in vivo lidocaine block duration but not in vitro neurotoxicity.

Reg Anesth Pain Med 2012 Nov-Dec;37(6):601-6

Department of Anesthesiology, Academic Medical Center, University of Amsterdam, the Netherlands.

Background And Objectives: Application of local anesthetics may lead to nerve damage. Increasing evidence suggests that risk of neurotoxicity is higher in patients with diabetic peripheral neuropathy. In addition, block duration may be prolonged in neuropathy. We sought to investigate neurotoxicity in vitro and block duration in vivo in a genetic animal model of diabetes mellitus type 2.

Methods: In the first experiments, neurons harvested from control Zucker diabetic fatty (ZDF) rats were exposed to acute (24 hours) or chronic (72 hours) hyperglycemia, followed by incubation with lidocaine 40 mM (approximately 1%). In a second experiment, neurons harvested from control ZDF rats, or diabetic ZDF rats, were incubated with lidocaine, with or without SB203580, an inhibitor of the p38 mitogen-activated protein kinase. Finally, we performed sciatic nerve block (lidocaine 2%, 0.2 mL) in control or diabetic ZDF rats and measured motor and nociceptive block duration.

Results: In vitro, neither acute nor chronic hyperglycemia altered neurotoxic properties of lidocaine. In vitro, incubation of neurons with lidocaine resulted in a slightly decreased survival ratio when neurons were harvested from diabetic (57% ± 19%) as compared with control (64% ± 9%) rats. The addition of SB203580 partly reversed this enhanced neurotoxic effect and raised survival to 71% ± 12% in diabetic neurons and 66% ± 9% in control rats, respectively. In vivo, even though no difference was detected at baseline testing, motor block was significantly prolonged in diabetic as compared with control rats (137 ± 16 vs 86 ± 17 min).

Conclusions: In vitro, local anesthetic neurotoxicity was more pronounced on neurons from diabetic animals, but the survival difference was small. In vivo, subclinical neuropathy leads to substantial prolongation of block duration. We conclude that early diabetic neuropathy increases block duration, whereas the observed increase in toxicity was small.
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http://dx.doi.org/10.1097/AAP.0b013e3182664afbDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480545PMC
April 2013

Trends in in-hospital major morbidity and mortality after total joint arthroplasty: United States 1998-2008.

Anesth Analg 2012 Aug 31;115(2):321-7. Epub 2012 May 31.

Department of Anesthesiology, New York Presbyterian Hospital-Weill Cornell, New York, NY, USA.

Background: The use of total joint arthroplasties is increasing worldwide. In this work we aim to elucidate recent trends in demographics and perioperative outcomes of patients undergoing total hip (THA) or total knee arthroplasty (TKA).

Methods: Data from the US Nationwide Impatient Sample between 1998 and 2008 were gathered for primary THAs and TKAs. Trends in patient age, comorbidity burden, length of hospitalization, frequency of major perioperative complications, and in-hospital mortality were analyzed. In-hospital outcomes were reported as events per 1000 inpatient days to account for changes in length of hospitalization over time. Deyo index, discharge status, and the interaction effect of time and discharge status were included in the adjusted trend analysis for morbidity.

Results: Between 1998 and 2008, the average age of patients undergoing TKA and THA decreased by 2 to 3 years (P < 0.001). The average length of stay decreased by approximately 1 day over the time interval studied (P < 0.001). The percentage of patients being discharged home declined from 29.7% to 25.4% after TKA and from 29.3% to 24.2% after THA, in favor of dispositions to long- and short-term care facilities (P < 0.0001). Comorbidity burden as measured by the Deyo comorbidity index increased by 35% and 30% for TKA and THA patients, respectively (P < 0.0001). After TKA, there was an increase in the incidence of the following major complications: pulmonary embolism (coefficient estimate [CE] 0.069; 95% confidence interval [CI], 0.059-0.079; P < 0.0001), sepsis (CE 0.034; 95% CI, 0.014-0.054; P = 0.001), nonmyocardial infarction cardiac complications (CE 0.038; 95% CI, 0.035-0.041; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.031-0.047; P < 0.0001). After THA, there was an increase in the incidence of the following major complications: pulmonary embolism (CE 0.031; 95% CI, 0.012-0.049; P = 0.001), sepsis (CE 0.060; 95% CI, 0.039-0.081; P < 0.0001), nonmyocardial infarction cardiac complications (CE 0.040; 95% CI, 0.036-0.043; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.029-0.048). In-hospital mortality declined after both TKA (CE -0.059; 95% CI, -0.077 to -0.040; P < 0.0001) and THA (CE -0.068; 95% CI, -0.086 to -0.051; P < 0.0001).

Conclusion: Between 1998 and 2008, trends show increases in several major in-hospital complications after THA and TKA, including pulmonary embolism, sepsis, nonmyocardial infarction cardiac complications, and pneumonia. Despite the increase in complications, declining in-hospital mortality was noted over this period.
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http://dx.doi.org/10.1213/ANE.0b013e31825b6824DOI Listing
August 2012

Epidemiology and risk factors for perioperative mortality after total hip and knee arthroplasty.

J Orthop Res 2012 Nov 19;30(11):1811-21. Epub 2012 Apr 19.

Department of Anesthesiology, Hospital for Special Surgery, New York, 10021 NY, USA.

The perioperative mortality of total knee and hip arthroplasties (TKA, THA) remains a major concern among health care providers and their patients. The increase in utilization of TKA and THA makes it imperative to be aware of factors that are associated with this unfortunate event. Therefore we analyzed the Nationwide Inpatient Sample data from 1998 to 2008 and compared admissions with perioperative mortality to those that survived their hospitalization. An estimated total of 4,438,213 TKA and 2,182,121 THA procedures were performed in the United States between 1998 and 2008. The average mortality rate for TKA was 0.13% and 0.18% for THA, or 0.34 and 0.44 events per 1,000 inpatient days, respectively. Independent risk factors for in-hospital mortality were advanced age, male gender, ethnic minority background, emergency admission as well as a number of comorbidities and complications. Furthermore, we demonstrated that the timing of death occurred earlier after TKA when compared to THA, with 50% of fatalities occurring by day 4 versus day 6 of the hospitalization, respectively. This study provides nationally representative information on risk factors for and timing of perioperative mortality after TKA and THA. Our data can be used to assess the risk for perioperative mortality and to develop targeted intervention to decrease such risk.
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http://dx.doi.org/10.1002/jor.22139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407319PMC
November 2012

Perioperative management of partial face transplantation involving a heparin antibody-positive donor.

J Clin Anesth 2011 Jun;23(4):318-21

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Heparin-induced thrombocytopenia (HIT) is an immunologic condition that may lead to thrombosis. We present a case of face transplantation from a donor who had suffered a severe stroke, possibly from HIT, during cardiac surgery. The procedure was planned to include full heparinization. The anesthesia team was involved in the early planning phase and had detailed access to the donor's medical history; alternative anticoagulation for the donor and recipient was suggested so as to avoid a possible complication.
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http://dx.doi.org/10.1016/j.jclinane.2010.07.004DOI Listing
June 2011

Prolonged cutaneous analgesia with transdermal application of amitriptyline and capsaicin.

Reg Anesth Pain Med 2011 May-Jun;36(3):236-40

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background And Objectives: Capsaicin selectively binds to TRPV1, the vanilloid subtype 1 of the superfamily of transient receptor potential ion channels, which is highly expressed in pain-transmitting C fibers. Recent reports have demonstrated that the coadministration of capsaicin with a local anesthetic (LA) at the rat sciatic nerve elicits a prolonged nociceptive-selective nerve block, suggesting that activation of the TRPV1 receptor may allow LAs to enter the nerve through the TRPV1 pore. In previous studies, we demonstrated that transdermal amitriptyline achieves clinical analgesic effects and is more potent than lidocaine. Here we examine whether the combined application of amitriptyline and capsaicin as a transdermal patch will produce prolonged cutaneous analgesia compared with amitriptyline alone.

Methods: Male Sprague-Dawley rats (weights 250-300 g) were assigned to five treatment groups (n = 6-8 per group). Transdermal patches containing amitriptyline with different concentrations of capsaicin were applied for 3 hrs to rats' shaved backs: 2.5% amitriptyline alone (control group) and in combination with 0.05%, 0.15%, 1%, and 8% capsaicin. Behavioral testing for cutaneous nociception was conducted before drug application and after patch removal using the cutaneous trunci muscle reflex. In addition, skin appearance was assessed to determine irritation by these formulations.

Results: The cutaneous analgesic effect is significantly prolonged when amitriptyline is applied in combination with 8% capsaicin. Amitriptyline alone provided a complete block to pinprick for 4.5 hrs, and the time to full recovery was 96 hrs. Amitriptyline with 8% capsaicin produced a complete block to pinprick for 6 to 9 hrs, and the time to full recovery was 216 hrs (P = 0.002). Amitriptyline alone causes toxic effects in skin, whereas the higher the concentration of capsaicin, the less skin irritation was noted, and the combination of amitriptyline 2.5% with capsaicin 8% caused no adverse skin reactions.

Conclusions: This study demonstrates that the combined application of amitriptyline and capsaicin results in prolonged cutaneous analgesia compared with amitriptyline alone, suggesting that the activation of the TRPV1 channel by capsaicin facilitates the passage of amitriptyline into nociceptors. This transdermal patch achieves far longer cutaneous analgesia than currently available patch applications such as EMLA cream. The mechanism that underlies the lesser skin irritation noted when amitriptyline is combined with higher doses of capsaicin compared with amitriptyline alone is unclear and may be related to a counteraction of amitriptyline-induced vasoconstriction.
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http://dx.doi.org/10.1097/AAP.0b013e31820c2c30DOI Listing
March 2012

Prolonged suppression of postincisional pain by a slow-release formulation of lidocaine.

Anesthesiology 2011 Jan;114(1):135-49

Tufts School of Medicine, Boston, Massachusetts, USA.

Background: Postoperative pain can occur despite nerve blocks during the surgical period. Here we tested Xybrex (Orthocon, Inc., Irvington, NY), a slow-release formulation of lidocaine that blocks rat sciatic nerve for 1-2 days, for its ability to suppress postincisional pain.

Methods: A plantar paw incision was made in rats, either along the midline (Brennan model) or at the lateral edge, 30 min after different treatment groups received either lidocaine (0.2 ml, 2%) or Xybrex implant at the ipsilateral sciatic nerve or Xybrex at the contralateral sciatic nerve. Behavioral testing by von Frey filaments occurred at 2 and 6 h postoperatively and for the next 10 postoperative days. The fractional response (paw withdrawal responses per 10 pokes) was scored at each time.

Results: Mechanosensitivity from the Brennan paw incision was reduced throughout the postoperative period by ipsilateral Xybrex, although lidocaine injection almost had no effect. Contralateral Xybrex had a weaker but still significant antihyperalgesic effect, converging to that from ipsilateral Xybrex at postoperative day 2. Xybrex at the nuchal midline reduced allodynia for only postoperative days 1-3, whereas hyperalgesia was reduced continuously after postoperative day 2. Hyperalgesia from the lateral incision was also reduced by ipsilateral Xybrex but not by contralateral Xybrex.

Conclusions: Implants of slow-release lidocaine formulations are most effective against postincisional pain when placed at the ipsilateral nerve innervating the area of incision. Contralateral nerve implants are somewhat less effective, probably acting by releasing lidocaine into the systemic circulation. There appears to be a differential role of central sensitization between postincisional allodynia and hyperalgesia.
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http://dx.doi.org/10.1097/ALN.0b013e3182001996DOI Listing
January 2011

The relationship between functional sciatic nerve block duration and the rate of release of lidocaine from a controlled-release matrix.

Anesth Analg 2010 Jul 3;111(1):221-9. Epub 2010 Jun 3.

Brigham and Women's Hospital, MRB-611, 75 Francis St., Boston, MA 02115-6110, USA.

Background: Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration.

Methods: Lidocaine concentration was varied in 1 series of formulations (OSB-L) containing a constant amount of release rate modifier. In another series (OST-R), the release rate modifier was varied while the lidocaine content was held constant. Release kinetics were measured in vitro and correlated to the in vivo duration of antinociceptive and motor block effects when the formulation was implanted next to the rat sciatic nerve. In parallel studies, rats receiving different formulations of slow-release lidocaine were fixed by intracardiac perfusion with 4% paraformaldehyde and nerve-muscle tissue taken for histopathological analysis.

Results: In this study, we have demonstrated that the most important variable for effecting functional nerve block, i.e., the blockade of impulses in the relevant fibers of the sciatic nerve, is the rate of lidocaine release at that time. For the OSB-L formulations (lidocaine concentrations of 1.875%, 3.75%, 7.5%, and 15% at a constant release rate modifier of 5%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 0.91 +/- 0.28 and 1.75 +/- 0.61 mg/h, respectively. For the OST-R formulations (16% lidocaine with release rate modifier concentrations of 1.875%, 3.75%, 7.5%, and 15%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 2.33 +/- 1.39 and 4.34 +/- 1.09 mg/h, respectively. The OSB-L formulations showed a dose-dependent increase in block duration proportional to an increase in initial lidocaine concentration, whereas the OST-R formulations showed a nonmonotonic relationship between release rate modifier concentration and block duration. The histopathological studies at 24 hours, 3, 5, or 7 days, and 4 weeks after the implantation revealed inflammatory reactions with degrees correlated with lidocaine content, but limited to the connective tissue and muscle immediately surrounding the implanted material. Despite these observed inflammatory reactions, nociceptive and motor block function returned to normal, preimplantation values in all animals.

Conclusions: Increasing initial lidocaine content proportionately increased the duration of functional sciatic nerve block. However, decreasing the release rate per se does not give a proportional increase in block duration. Instead, there seems to be an optimal, intermediate release rate for achieving the maximum duration of block.
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http://dx.doi.org/10.1213/ANE.0b013e3181dd2690DOI Listing
July 2010

Resiniferatoxin combined with antidepressants preferentially prolongs sensory/nociceptive block in rat sciatic nerve.

Anesth Analg 2010 Jul 2;111(1):207-13. Epub 2010 Jun 2.

Department of Anesthesiology, Mackay Memorial Hospital, 92 Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan.

Background: Current techniques of peripheral nerve block have major limitations, including lack of differentiation between motor and sensory fibers and potential toxicity of local anesthetics. Recent studies have suggested that a nociceptive-selective nerve block can be achieved via a transient receptor potential vanilloid type 1 activator (capsaicin) along with local anesthetics. We hypothesized that the combination of potent transient receptor potential vanilloid type 1 agonist resiniferatoxin (RTX) and selected antidepressants (amitriptyline, doxepin, and fluoxetine, also potent sodium channel blockers) would produce prolonged and predominantly sensory nerve block.

Methods: Rats were anesthetized with isoflurane, and 0.2 mL of amitriptyline, doxepin, or fluoxetine was deposited next to the surgically exposed sciatic nerves (n = 8 per group). Some animals received a second injection containing RTX (n = 8 per group). The effect of nerve block was assessed by neurobehavioral tests of the motor function (extensor postural thrust) and the nocifensive reaction (mechanical pinch).

Results: A single application of RTX produced nociceptive-selective sciatic nerve block, whereas antidepressants produced nociceptive and motor block. The combined administration of RTX and antidepressant resulted in a predominantly nociceptive nerve block. Compared with antidepressants or RTX alone, the combination prolonged the nociceptive nerve block more than the motor block.

Conclusions: The combined application of RTX and antidepressants produced a markedly prolonged nociceptive peripheral nerve block in rat sciatic nerves compared with either agent alone. However, the 2-drug regimen also elicited prolonged blockade of the motor function, although disproportionately less compared with the nociceptive modality, suggesting the existence of nontransient receptor potential vanilloid type 1-mediated mechanisms. The mechanisms through which RTX affects nociceptive signal transduction/transmission have yet to be fully elucidated.
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http://dx.doi.org/10.1213/ANE.0b013e3181e0cc90DOI Listing
July 2010

The effects of resiniferatoxin in an experimental rat thoracotomy model.

Anesth Analg 2010 Jan 21;110(1):228-32. Epub 2009 Nov 21.

Department of Anesthesiology and Pain Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea.

Background: Chronic pain after thoracotomy has been reproduced in a rat model that allows investigation of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that morphine, clonidine, neostigmine, gabapentin, and bupivacaine reduce the incidence of allodynia in the rat postthoracotomy pain model. One purpose of this study was to test whether intercostal injection of resiniferatoxin (RTX) decreased the amount of allodynia in an animal model of chronic postthoracotomy pain. We also tested whether RTX induced a transient mechanical hyperalgesic response in uninjured animals.

Methods: Male Sprague-Dawley rats were anesthetized, and the right fourth and fifth ribs were surgically exposed. The pleura was opened, and the ribs were retracted. Intercostal RTX 0.8 or 8 microg was injected in animals that developed allodynia after surgery; a control group underwent rib retraction and received vehicle only. An additional group of uninjured animals received RTX. Rats were tested for mechanical allodynia at a predetermined area around the incision site for 3 wk.

Results: Allodynia developed in 42% of the animals that underwent thoracotomy. A transient hyperalgesic response was noted in the uninjured group that underwent drug injections. Intercostal RTX did not modify the course of allodynia in injured rats.

Discussion: The current results suggest that intercostal RTX causes a transient hyperalgesic response in uninjured animals and is ineffective in reducing the mechanical allodynia after thoracotomy.
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http://dx.doi.org/10.1213/ANE.0b013e3181c5c89aDOI Listing
January 2010

"Above all, do no harm": hippocrates.

Authors:
Peter Gerner

Anesthesiology 2009 Nov;111(5):938-9

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http://dx.doi.org/10.1097/ALN.0b013e3181bbcd2cDOI Listing
November 2009

Calcium chloride prolongs the effects of lidocaine and bupivacaine in rat sciatic nerve.

Reg Anesth Pain Med 2009 Jul-Aug;34(4):333-9

Department of Anesthesiology, Mackay Memorial Hospital, Mackay Medicine, Nursing and Management College, Taipei, Taiwan.

Background And Objectives: Elevated extracellular calcium ion has been shown to shift the voltage dependence of Na+- and K+-ion channels rightward, making the nerve less excitable. We hypothesized that calcium chloride (CaCl2) when used as an adjuvant prolongs and intensifies the block by local anesthetics (LAs). We investigated the effects of LAs combined with calcium in rat sciatic nerve blockade and in cultured rat GH3 cells expressing Na+ channels. Furthermore, we tested for histologic changes due to CaCl2.

Methods: We anesthetized rats with sevoflurane, exposed the sciatic nerves, and injected 0.2 mL of 1% lidocaine or 0.1% bupivacaine, alone or coadministered with 0.625%, 1.25%, 2.5%, or 5% CaCl2 (n = 8-10 per group). We assessed the complete-block time and complete-recovery time of proprioception, motor function, and nocifensive reaction. To elucidate the mechanism of nerve block, we performed electrophysiology experiments in cultured rat GH3 cells. Sciatic nerves were harvested at day 7 and stained with hemotoxylin/eosin.

Results: The addition of CaCl2 overall prolonged the duration of blockade by lidocaine or bupivacaine. Adding 10 mM CaCl2 to 300 microM lidocaine caused a right shift of the steady-state Na+-channel inactivation curve, indicating that the CaCl2 reduced the potency of lidocaine. Rat sciatic nerves treated with 1% lidocaine coadministered with 5% CaCl2 showed microscopic signs of neurotoxicity.

Conclusions: The mechanism of prolonged nerve block of CaCl2 coadministered with LAs seems to be a raised threshold for nerve excitation. Major histopathologic changes at higher concentrations of CaCl2 are evident, and therefore, clinical application as an adjuvant to LAs seems unlikely.
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http://dx.doi.org/10.1097/AAP.0b013e3181ac7f49DOI Listing
October 2009

Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.

Anesthesiology 2009 Jul;111(1):127-37

Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Background: Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314-mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia.

Methods: Lidocaine (0.5% [17.5 mM], 1% [35 mM], and 2% [70 mM]) alone, QX-314 (0.2% [5.8 mM]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block.

Results: Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block.

Conclusions: Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior.
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http://dx.doi.org/10.1097/ALN.0b013e3181a915e7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761747PMC
July 2009

An absorbable local anesthetic matrix provides several days of functional sciatic nerve blockade.

Anesth Analg 2009 Mar;108(3):1027-33

Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Functional blockade of peripheral nerves is the primary objective of local anesthesia, and it is often desirable to have a persistent blockade, sustained throughout and beyond a surgical procedure. Current local anesthetics give effective analgesia for <8-12 h after a single bolus injection. We report on an implantable, controlled-release drug delivery system intended for use in bone and consisting of a Food and Drug Administration-approved matrix containing lidocaine that is capable of local delivery for several days.

Methods: Xybrex, an absorbable, controlled-release delivery system containing 16% (w/w) lidocaine, was implanted next to the sciatic nerve of male rats (300-350 gm), at lidocaine doses of 5.3, 10.6, 16, and 32 mg lidocaine per rat. For comparison, a lidocaine HCl solution (0.2 mL, 2% = 4 mg) was injected in close proximity to the sciatic nerve. Rats were assessed behaviorally for analgesia by a forceps pinch of the lateral digits, and for motor block by quantifying the extensor postural thrust. Potential neurotoxicity of sciatic nerves was evaluated histologically at 24 h, 4 days, and 4 wk after implantation. The kinetics of lidocaine's release from the matrix was measured in vitro by ultraviolet detection of lidocaine in samples collected at 2.5, 6.5, 20, and 24.25 h.

Results: Xybrex at the highest doses (300 and 600 mg/kg, containing 16 and 32 mg of lidocaine free base, respectively) provided complete analgesia to an intense pinch for 7.0 +/- 2.0 h, 6.9 +/- 1.7 h and partial analgesia for 60.0 +/- 5.4 h, 58.8 +/- 4.2 h, respectively, compared to 0.61 +/- 0.03 h of complete analgesia and 0.96 +/- 0.03 h of partial analgesia by sciatic block from the 2% lidocaine solution (containing 4 mg lidocaine). These same high doses of Xybrex produced complete motor block for 17.0 +/- 3.3 h, 17.6 +/- 3.3 h with full recovery in 352.0 +/- 55.7 h (14.7 +/- 2.3 days), 579.0 +/- 36.1 h (24.1 +/- 1.5 days) respectively. Data are reported as mean +/- SE. P < 0.001 for all Xybrex groups compared to the 2% lidocaine group. Minor local tissue inflammation/pathology, primarily in the connective tissue and muscle 0.1 mm adjacent to the nerve, was observed equally in animals treated with Xybrex and 2% lidocaine solution. There were no behavioral signs of systemic toxicity. The in vitro release followed exponential kinetics and its comparison to the time-course of functional nociceptive deficit implied that the duration of nociception represented the local, immediate interaction of lidocaine between the nerve and the matrix and not a cumulative effect of previously released drug.

Conclusions: Xybrex is an absorbable, controlled-release drug delivery system that provides several days of analgesia for rat peripheral nerves without apparent significant local neurotoxicity or systemic toxicity.
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http://dx.doi.org/10.1213/ane.0b013e318193596aDOI Listing
March 2009

Capsaicin combined with local anesthetics preferentially prolongs sensory/nociceptive block in rat sciatic nerve.

Anesthesiology 2008 Nov;109(5):872-8

Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Background: Transient receptor potential vanilloid 1 channels integrate nociceptive stimuli and are predominantly expressed by unmyelinated C-fiber nociceptors, but not low-threshold mechanoreceptive sensory or motor fibers. A recent report showed that the transient receptor potential vanilloid 1 channel agonist capsaicin allows a hydrophilic quaternary ammonium derivative of lidocaine, QX-314, to selectively block C fibers without motor block. The authors tested whether a similar differential block would be produced using amphipathic N-methyl amitriptyline, amitriptyline, bupivacaine, or lidocaine, either alone or together with 0.05% capsaicin, in a rat sciatic nerve block model.

Methods: Rats (n = 8/group) were anesthetized with sevoflurane, and 0.2 ml of drug was injected either alone or with capsaicin (simultaneously or 10 min later) next to the sciatic nerve in the sciatic notch. Motor function was assessed by the extensor postural thrust. Nociception was evaluated by the nocifensive withdrawal reflex and vocalization evoked by pinch of a skin fold over the lateral metatarsus (cutaneous pain) with a serrated forceps.

Results: N-Methyl amitriptyline, amitriptyline, bupivacaine, or lidocaine, followed by injection of capsaicin 10 min later, each elicited a predominantly nociceptive-specific blockade. In comparison, simultaneous application of each local anesthetic with capsaicin did not elicit a clinically significant differential block, with the exception of N-methyl amitriptyline.

Conclusions: Both tertiary amine local anesthetics and their quaternary ammonium derivatives can elicit a predominantly sensory/nociceptor selective block when followed by injection of capsaicin. The combined application of transient receptor potential vanilloid 1 channel agonists and various local anesthetics or their quaternary ammonium derivatives is an appealing strategy to achieve a long-lasting differential block in regional analgesia.
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http://dx.doi.org/10.1097/ALN.0b013e31818958f7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635105PMC
November 2008

Low-dose systemic bupivacaine prevents the development of allodynia after thoracotomy in rats.

Anesth Analg 2008 Nov;107(5):1587-91

Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.

Background: Chronic pain after thoracotomy has been recently reproduced in a rat model that allows investigation of the effect of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that intrathecal or systemic morphine, clonidine, neostigmine, and gabapentin reduce the incidence of allodynia in the rat postthoracotomy pain model. Our purpose was to test whether intercostal and systemic injection of bupivacaine prevented the development of allodynia in an animal model of chronic intercostal neuropathic pain.

Methods: Male Sprague-Dawley rats were anesthetized and the right 4th and 5th ribs surgically exposed. The pleura were opened and the ribs were retracted for 1 h. Intercostal or systemic bupivacaine 1 mg (0.2 mL at 0.5%) was injected before and after surgery, or before surgery; a control group underwent rib retraction and did not receive any drug. Rats were tested for mechanical allodynia at a predetermined area around the incision site during the 3 wk after surgery.

Results: Allodynia developed in 43% of the animals that did not receive bupivacaine (control group); in contrast, allodynia developed in only 6%, 12%, and 12% of those animals that received intercostal bupivacaine before surgery, after surgery, or systemically before surgery, respectively.

Discussion: Previous studies suggest that allodynia after rib retraction can be prevented by opioids, alpha2-adrenergic agonists, neostigmine, and gabapentin. The current results suggest that bupivacaine is effective in preventing mechanical allodynia, whether given by intercostal injection before or after surgery, or systemically before surgery.
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November 2008

Use of bulleyaconitine A as an adjuvant for prolonged cutaneous analgesia in the rat.

Anesth Analg 2008 Oct;107(4):1397-405

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.

Background: Bulleyaconitine A (BLA) is an analgesic and antiinflammatory drug isolated from Aconitum plants. BLA has several potential targets, including voltage-gated Na+ channels. We tested whether BLA elicited long-lasting cutaneous analgesia, when co-injected with lidocaine and epinephrine, as a model for prolonged infiltration anesthesia.

Methods: The local anesthetic properties of BLA were assessed by the patch-clamp technique in HEK293t cells expressing Nav1.7 and Nav1.8 neuronal Na+ channels, both crucial for nociception. Drug solutions (0.6 mL) were injected subcutaneously via rat shaved dorsal skin. Inhibition of the cutaneous trunci muscle reflex was evaluated by pinpricks. Skin cross-sections were stained with hematoxylin and eosin or with antibodies against PGP9.5.

Results: BLA at 10 microM interacted minimally with resting or inactivated Nav1.7 and Nav1.8 Na+ channels when infrequently stimulated to +50 mV for 3 ms. However, when stimulated at 2 Hz for 1000 pulses, their peak Na+ currents were >90% reduced by BLA. This use-dependent inhibition was not significantly reversed after 15-min washing. Complete nociceptive blockade after injection of lidocaine (0.5%)/epinephrine (1:200,000) lasted for approximately 1 h in rats; full recovery occurred after approximately 6 h. Co-injection of 0.125 mM BLA with lidocaine/epinephrine increased the duration of complete nociceptive blockade to 24 h. Full recovery occurred after approximately 6 days. Skin histology including peripheral nerve fibers appeared unaffected by BLA.

Conclusions: BLA inhibits Nav1.7 and Nav1.8 Na+ currents in a use-dependent manner. Co-injection of BLA at
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http://dx.doi.org/10.1213/ane.0b013e318182401bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712758PMC
October 2008

Postthoracotomy pain management problems.

Authors:
Peter Gerner

Anesthesiol Clin 2008 Jun;26(2):355-67, vii

Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

Pain after thoracotomy is very severe, probably the most severe pain experienced after surgery. Thoracic epidural analgesia has greatly improved the pain experience and its consequences and has been considered the standard for pain management after thoracotomy. This view has been challenged recently by the use of paravertebral nerve blocks. Nevertheless, severe ipsilateral shoulder pain and the prevention of the postthoracotomy pain syndrome remain the most important challenges for management of postthoracotomy pain.
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http://dx.doi.org/10.1016/j.anclin.2008.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453516PMC
June 2008

In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity.

Anesth Analg 2008 May;106(5):1456-64, table of contents

Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstr. 35, 6020 Innsbruck, Austria.

Background: Animal models show us that specific activation of the p38 mitogen-activated protein kinase (MAPK) may be a pivotal step in lidocaine neurotoxicity, but this has not been investigated in the case of two very widely used local anesthetics, bupivacaine and ropivacaine. We investigated the hypotheses that these drugs (A) are less neurotoxic than the prototype local anesthetic, lidocaine (B) are selectively toxic for subcategories of dorsal root ganglion neurons and (C) induce activation of either p38 MAPK or related enzymes, such as the c-jun terminal N-kinase (JNK) and extracellular signal-regulated kinase (ERK).

Methods: We incubated primary sensory neuron cultures with doses of lidocaine, bupivacaine, and ropivacaine equipotent at blocking sodium currents. Next, we sought to determine potential selectivity of bupivacaine and ropivacaine toxicity on neuron categories defined by immunohistochemical staining, or size. Subsequently, the involvement of p38 MAPK, JNK, and ERK was tested using enzyme-linked immunosorbent assays. Finally, the relevance of MAPK pathways in bupivacaine- and ropivacaine-induced neurotoxicity was determined by selectively inhibiting activity of p38 MAPK, JNK, and ERK.

Results: We found that the neurotoxic potency of bupivacaine and ropivacaine is dose-dependent and similar in vitro, but is not selective for any of the investigated subgroups of neurons. Neurotoxicity of bupivacaine and ropivacaine was mediated, at least in part, by MAPKs. Specifically, we demonstrated the relevance of both p38 MAPK and JNK pathways for the neurotoxicity of bupivacaine and characterized the involvement of the p38 MAPK pathway in the neurotoxicity of ropivacaine.

Conclusions: Given equipotent doses, the neurotoxic potential of lidocaine does not appear to be significantly different from that of bupivacaine and ropivacaine in vitro. Moreover, bupivacaine and ropivacaine do not exert their neurotoxicity differently on specific subsets of dorsal root ganglion neurons. Their neurotoxic effects are brought about through the activation of specific MAPKs; the specific pharmacologic inhibition of these kinases attenuates toxicity in vitro.
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http://dx.doi.org/10.1213/ane.0b013e318168514bDOI Listing
May 2008

Impact of analgesia on bone fracture healing.

Anesthesiology 2008 Mar;108(3):349-50

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http://dx.doi.org/10.1097/ALN.0b013e318164938cDOI Listing
March 2008