Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class.

Evidence accumulated over the past decade suggests that p21-activated kinase 1 (PAK1) is a critical cardiac-protective signalling molecule. The present article provides an updated review of recent findings regarding the role of PAK1 in maintaining normal cardiac electrophysiological function through its regulation of membrane and Ca2+ clocks. We first overviewed the PAK1 activation mechanism. We then discussed recent updated results showing the action mechanisms of PAK1 signalling on Cav1.2/Cav1.3 (ICaL)-mediated Ca2+ entry, ryanodine receptor type 2-mediated sarcoplasmic reticulum (SR) Ca2+ release, transcriptional regulation of SR Ca2+-ATPase 2a, Na+/Ca2+ exchangers, and Ca2+/calmodulin-dependent protein kinase II. Finally, we proposed a new and exciting route for developing a PAK1-based therapeutic strategy for cardiac arrhythmias. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

[The effect of emotional stressors on postoperative skin conductance indices: a prospective cohort pilot study]. / Efeito dos estressores emocionais nos índices de condutância cutânea no pós­operatório: estudo piloto de coorte prospectivo.

BACKGROUND: Skin conductance response reflects the activity of the sympathetic nervous system and is used to measure acute pain. This pilot study examines correlations of skin conductance response with emotional stressors postoperatively. METHODS: The correlation of skin conductance response with pain, anxiety, nausea and intellectual task performance was analyzed in postoperative patients. RESULTS: Significant correlations were observed between anxiety and pain during physical activity on both postoperative day 1 and 2. No significant correlations were found between skin conductance response versus mild pain, nausea, anxiety or intellectual task performance. CONCLUSION: This pilot study suggests that when the pain is well-controlled in the early postoperative period, skin conductance response monitoring may not be influenced by other emotional stressors.

The effect of emotional stressors on postoperative skin conductance indices: a prospective cohort pilot study / Efeito dos estressores emocionais nos índices de condutância cutânea no pós-operatório: estudo piloto de coorte prospectivo

Abstract Background: Skin conductance response reflects the activity of the sympathetic nervous system and is used to measure acute pain. This pilot study examines correlations of skin conductance response with emotional stressors postoperatively. Methods: The correlation of skin conductance response with pain, anxiety, nausea and intellectual task performance was analyzed in postoperative patients. Results: Significant correlations were observed between anxiety and pain during physical activity on both postoperative day 1 and 2. No significant correlations were found between skin conductance response versus mild pain, nausea, anxiety or intellectual task performance. Conclusion: This pilot study suggests that when the pain is well-controlled in the early postoperative period, skin conductance response monitoring may not be influenced by other emotional stressors.

Resumo Justificativa: A variação da condutância da pele reflete a atividade do sistema nervoso simpático e é usada para avaliar dor aguda. Este estudo piloto examinou as correlações entre a variação da condutância da pele e estressores emocionais no pós-operatório. Método: A correlação entre a variação da condutância da pele e dor, ansiedade, náusea e desempenho de tarefa intelectual foi analisada em pacientes no pós-operatório. Resultados: Correlações significantes foram observadas entre ansiedade e dor durante atividade física nos dias 1 e 2 pós-operatórios. Não foram encontradas correlações significantes entre a variação da condutância da pele e dor leve, náusea, ansiedade ou desempenho de tarefa intelectual. Conclusão: Este estudo piloto sugere que, quando a dor é bem controlada no pós-operatório inicial, o monitoramento empregando a variação da condutância da pele pode não ser influenciado por outros estressores emocionais.

A comparison of two different concentrations and infusion rates of ropivacaine in perineural infusion administered at the same total dose for analgesia after foot and ankle surgery: a randomized, double blinded, controlled study.

BACKGROUND: Continuous popliteal nerve block is utilized for postoperative analgesia after foot and ankle surgery. Whether only the total dose of local anesthetic or the combination of concentration and volume determine the characteristics of a continuous popliteal nerve infusion remains currently unknown. We hypothesized a reduction of the incidence of insensate extremity in patients given ropivacaine 0.4% at 4 mL/h compared to patients given ropivacaine 0.2% at 8 mL/h. METHODS: Sixty-four patients scheduled for major foot and ankle surgery requiring a continuous popliteal catheter infusion for postoperative analgesia were studied. Thirty-three patients were randomized to receive a continuous popliteal nerve block with 0.2% (basal 8 mL/h) and thirty-one with 0.4% (basal 4 mL/h) ropivacaine, reaching the same total dose (16 mg/h). The primary outcome was the incidence of persistent sensory block in the distal sciatic nerve distributions in the postoperative period. Secondary outcomes were the incidence of motor block, NRS pain scores at rest in the postoperative period up to 48 hours after surgery, opioid use and related side effects, patients' satisfaction. RESULTS: The incidence of persistent sensory block was similar in patients given 0.2% and in patients receiving 0.4% ropivacaine. The incidence of motor block, postoperative pain scores at rest, use of oral opioids, side effects and patients' satisfaction with the quality of recovery were also similar in both groups. CONCLUSIONS: Our results suggest that local anesthetic total dose is the primary determinant of continuous popliteal perineural infusion effects.

Changes in the Skin Conductance Monitor as an End Point for Sympathetic Nerve Blocks.

OBJECTIVE: There is a lack of objective methods for determining the achievement of sympathetic block. This study validates the skin conductance monitor (SCM) as an end point indicator of successful sympathetic blockade as compared with traditional monitors. METHODS: This interventional study included 13 patients undergoing 25 lumbar sympathetic blocks to compare time to indication of successful blockade between the SCM indices and traditional measures, clinically visible hyperemia, clinically visible engorgement of veins, subjective skin temperature difference, unilateral thermometry monitoring, bilateral comparative thermometry monitoring, and change in waveform amplitude in pulse oximetry plethysmography, within a 30-minute observation period. Differences in the SCM indices were studied pre- and postblock to validate the SCM. RESULTS: SCM showed substantially greater odds of indicating achievement of sympathetic block in the next moment (i.e., hazard rate) compared with all traditional measures (clinically visible hyperemia, clinically visible engorgement of veins, subjective temperature difference, unilateral thermometry monitoring, bilateral comparative thermometry monitoring, and change in waveform amplitude in pulse oximetry plethysmography; P ≤ 0.011). SCM indicated successful block for all (100%) procedures, while the traditional measures failed to indicate successful blocks in 16-84% of procedures. The SCM indices were significantly higher in preblock compared with postblock measurements (P < 0.005). CONCLUSIONS: This preliminary study suggests that SCM is a more reliable and rapid response indicator of a successful sympathetic blockade when compared with traditional monitors.

Effect of sphingosine-1-phosphate on L-type calcium current and Ca(2+) transient in rat ventricular myocytes.

Modulation of Ca(2+) homoeostasis in cardiac myocytes plays a major role in beat-to-beat regulation of heart function. Previous studies suggest that sphingosine-1-phosphate (S1P), a biologically active sphingomyelin metabolite, regulates Ca(2+) handling in cardiac myocytes, but the underlying mechanism is unclear. In the present study, we tested the hypothesis that S1P-induced functional alteration of intracellular Ca(2+) handling includes the L-type calcium channel current (ICa,L) via a signalling pathway involving P21-activated kinase 1 (Pak1). Our results show that, in rat ventricular myocytes, S1P (100 nM) does not affect the basal activity of ICa,L but is able to partially reverse the effect of the ß-adrenergic agonist Isoproterenol (ISO, 100 nM) on ICa,L. S1P (25 nM) also significantly prevents ISO (5 nM)-induced Ca(2+) waves and diastolic Ca(2+) release in these cells. Our further molecular characterisation demonstrates that Pak1 activity is increased in myocytes treated with S1P (25 nM) compared with those myocytes without treatment of S1P. By immunoprecipitation we demonstrate that Pak1 and protein phosphatase 2A (PP2A) are associated in ventricular tissue indicating their functional interaction. Thus the results indicate that S1P attenuates ß-adrenergic stress-induced alteration of intracellular Ca(2+) release and L-type Ca(2+) channel current at least in part via Pak1-PP2A-mediated signalling.

Risk Assessment for Chronic Pain and Patient Satisfaction After Total Knee Arthroplasty.

The estimated prevalence of patients who report minor or no improvement of their symptoms and pain after total knee arthroplasty (TKA) remains high, ranging from 5% to 40%. The authors sought to determine whether chronic pain and functional health are related to specific variations in demographic data, surgical techniques, or radiographic pre- and postoperative findings. They also sought to identify independent risk factors for persistent moderate-to-severe chronic pain after TKA. A total of 273 patients who underwent primary TKA from October 2007 to March 2010 with a minimum follow-up of 1 year were identified from electronic medical records. A questionnaire to identify persistent postoperative pain (36-item Short Form Health Survey [SF-36]) was mailed to these patients. Linear regression and logistic regression were used to identify predictors for SF-36 and chronic pain, respectively. Thirty-nine percent of patients reported persistent pain after TKA, with a median average pain score of 3 out of 10 and worst pain score of 5 out of 10. Independent risk factors for persistent pain are the length of the operative procedure (odds ratio [OR]=1.013), medical history of diabetes mellitus (OR=0.430), presence of preoperative flexion contracture (OR=1.089), and patellofemoral joint overstuffing (OR=0.915). Persistent postoperative pain is a common finding after TKA. Nonmodifiable risk factors could be used for risk stratification, whereas modifiable risk factors could be used as a clinical guidance for modification of some aspects of existing surgical techniques.

Lower-Dose Mepivacaine Plus Fentanyl May Improve Spinal Anesthesia for Knee Arthroscopy.

BACKGROUND: Previous work indicates that 30 mg isobaric mepivacaine 1.5% plus 10 µg fentanyl produces reliable anesthesia for knee arthroscopy with a more rapid recovery profile than 45 mg mepivacaine. QUESTIONS/PURPOSES: This randomized controlled trial compared plain mepivacaine to three reduced doses of mepivacaine with 10 µg fentanyl for spinal anesthesia. METHODS: Following written informed consent, subjects undergoing outpatient knee arthroscopy were prospectively randomized into one of four groups: mepivacaine 37.5 mg (M37.5); mepivacaine 30 mg plus fentanyl 10 µg (M30/F10); mepivacaine 27 mg plus fentanyl 10 µg (M27/F10); and mepivacaine 24 mg plus fentanyl 10 µg (M24/F10). The spinal was evaluated by the blinded anesthetist and surgeon. In the post-anesthesia care unit, sensory and motor block resolution was assessed. Subjects rated their satisfaction with the overall experience. RESULTS: Group M30/F10 (n = 6) had two "fair" anesthetics, and group M27/F10 (n = 10) had one "fair" and one "inadequate" anesthetic. Both groups were eliminated from further enrollment per study protocol. The recovery profiles showed little difference between groups M37.5 and M30/F10, except for motor block resolution (median (25th percentile, 75th percentile): 171 (135, 195) and 128 (120, 135), respectively). Groups M27/F10 and M24/F10 demonstrated recovery profiles that were faster than group M37.5. Patient satisfaction was 10/10 for all groups. CONCLUSIONS: Adding fentanyl 10 µg to a lower dose of mepivacaine 1.5% can lead to quicker recovery profiles. However, this advantage of a quicker recovery must be weighed against the likelihood of an incomplete anesthetic.

Association of obesity with inflammation and pain after total hip arthroplasty.

BACKGROUND: The prevalence of obesity is increasing, and obesity often leads to degenerative joint disease requiring total hip arthroplasty (THA). Obesity is a proinflammatory state associated with an increase in chronic, low-grade inflammatory response. As such, it may augment the postoperative inflammatory response, which has been associated with postoperative pain and complications. QUESTIONS/PURPOSES: We determined whether severity of obesity was associated with (1) severity of inflammatory response, as measured by the in vivo circulating levels of cytokines and ex vivo functional reactivity of mononuclear blood cells, and (2) severity of pain, as measured by verbal pain scores and analgesic consumption, in the first 24 hours after THA. METHODS: We studied 60 patients (20 normal weight, 20 overweight, 20 obese) undergoing elective primary unilateral THA in this prospective cross-sectional study. Blood samples were collected for C-reactive protein and cytokine levels, including IL-1ß, IL-2, IL-6, IL-8, and tumor necrosis factor α (TNF-α), from patients before and 24 hours after surgery. Cytokine response of whole blood was evaluated ex vivo with or without two standard activators, phorbol-12-myristate-13-acetate and lipopolysaccharide, using standardized blood sample from patients at 24 hours. These standard immune activators are implicated in the inflammatory response to gram-negative infection, translocation of microbial products, pathophysiology of septic shock syndrome in human, and tumor promotion. Pain response was gauged using verbal pain scores (on a 0- to 10-point scale, where 0 = no pain and 10 = worst pain) at rest and with activity at 24 hours after surgery and analgesic consumption of volume of epidural analgesic solution for the first 24 hours after surgery. RESULTS: No correlation was found between BMI and postoperative spontaneous circulating cytokine levels. However, after activation of blood leukocytes with lipopolysaccharide, there was a significant positive correlation between the BMI and IL-1ß, IL-6, and TNF-α levels (r = 0.26-0.32; p = 0.03, p = 0.03, and p = 0.01, respectively), suggesting priming of the innate immune system in obesity and potential for excessive postoperative inflammatory response. Obesity was not associated with increased pain or analgesic consumption in the first 24 hours after surgery. CONCLUSIONS: Obesity is associated with a proinflammatory state after THA as demonstrated by enhanced cytokine reactivity. Larger studies exploring the specific impact of obesity and inflammation on surgical outcomes, including pain, are warranted. LEVEL OF EVIDENCE: Level II, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

The Impact of Hypotensive Epidural Anesthesia on Distal and Proximal Tissue Perfusion in Patients Undergoing Total Hip Arthroplasty.

Little data exists to detail the effect of hypotensive epidural anesthesia on differential tissue oxygenation changes above and below the level of neuraxial blockade. This study was designed to investigate tissue oxygenation in a clinical setting, using non-invasive near-infrared spectroscopy. METHODS: Patients aged 18 to 85 years scheduled to undergo primary total hip arthroplasty were enrolled. Muscle oxygenation saturation was measured above and below the level of neuraxial blockade (deltoid and vastus lateralis muscles). Other continuously recorded parameters included cardiac output, stroke volume, heart rate, invasive mean arterial blood pressure and arterial oxygen saturation. Recordings of muscle oxygenation were compared over time separately for upper and lower extremity. RESULTS: 10 patients were enrolled. We found an intermittent and significant unadjusted decline of mean muscle oxygenation saturation in the vastus lateralis muscle during first part of the surgery (nadir 2nd quintile: 71.0% vs. 63.3%, p<0.0001). This decline was followed by a return to baseline towards the end of the surgery (71.0% vs. 69.1%, p=0.3429). Mean muscle oxygenation saturation did not change for the same period of time in the deltoid muscle. When adjusting for covariates, the changes in muscle tissue oxygenation remained significant. CONCLUSION: These results indicate that muscle oxygenation saturation, a surrogate parameter for tissue perfusion, is decreased by hypotensive epidural anesthesia, but only within the functional limits of the neuraxial blockade. The etiology of these findings remains to be elucidated.

Predictors for moderate to severe acute postoperative pain after total hip and knee replacement.

PURPOSE: The ability to identify and focus care to patients at higher risk of moderate to severe postoperative pain should improve analgesia and patient satisfaction, and may affect reimbursement. We undertook this multi-centre cross-sectional study to identify preoperative risk factors for moderate to severe pain after total hip (THR) and knee (TKR) replacement. METHODS: A total of 897 patients were identified from electronic medical records. Preoperative information and anaesthetic technique was gained by retrospective chart review. The primary outcomes were moderate to severe pain (pain score ≥ 4/10) at rest and with activity on postoperative day one. Logistic regression was performed to identify predictors for moderate to severe pain. RESULTS: Moderate to severe pain was reported by 20 % at rest and 33 % with activity. Predictors for pain at rest were female gender (OR 1.10 with 95 % CI 1.01-1.20), younger age (0.96, 0.94-0.99), increased BMI (1.02, 1.01-1.03), TKR vs. THR (3.21, 2.73-3.78), increased severity of preoperative pain at the surgical site (1.15, 1.03-1.30), preoperative use of opioids (1.63, 1.32-2.01), and general anaesthesia (8.51, 2.13-33.98). Predictors for pain with activity were TKR vs. THR (1.42, 1.28-1.57), increased severity of preoperative pain at the surgical site (1.11, 1.04-1.19), general anaesthesia (9.02, 3.68-22.07), preoperative use of anti-convulsants (1.78, 1.32-2.40) and anti-depressants (1.50, 1.08-2.80), and prior surgery at the surgical site (1.28, 1.05-1.57). CONCLUSIONS: Our findings provide clinical guidance for preoperative stratification of patients for more intensive management potentially including education, nursing staffing, and referral to specialised pain management.

A cross-sectional survey on prevalence and risk factors for persistent postsurgical pain 1 year after total hip and knee replacement.

BACKGROUND AND OBJECTIVES: There is a paucity of large multi-institutional surveys to determine the prevalence of and risk factors for persistent pain after total hip (THR) and knee (TKR) replacements. We surveyed a variety of practices and patients and also correlated persistent pain with health-related quality-of-life outcomes. METHODS: From October 10, 2007, to March 15, 2010, patients who had undergone primary THR or TKR with a minimum follow-up of 1 year were identified. A previously published questionnaire to identify persistent postsurgical pain that included a 36-item Short Form Health Survey was mailed to this group. Independent risk factors for persistent pain were identified with logistic regression. RESULTS: Responses from 1030 patients who underwent surgery at some point in time between June 13, 2006, and June 24, 2009, were analyzed (32% response rate). Forty-six percent of patients reported persistent pain (38% after THR and 53% after TKR) with a median average pain score of 3 of 10 and worst pain score of 5. Independent risk factors for persistent pain were female sex (odds ratio [OR], 1.23), younger age (OR, 0.97), prior surgery on hip or knee (OR, 1.39), knee versus hip replacement (OR, 1.65), lower-quality postsurgical pain control (OR, 0.9), and presence of pain in other areas of the body (OR, 2.09). All scores in the 36-item Short Form Health Survey were worse (8%-28% decrease) in patients with persistent postsurgical pain (P < 0.001). CONCLUSIONS: Persistent postsurgical pain is common after THR and TKR and is associated with reduced health-related quality of life, although our survey may be biased by the low response rate and retrospective recall bias. Nonmodifiable risk factors may lead to risk stratification. Severity of acute postoperative pain may be a modifiable risk factor.

Association of perioperative use of nonsteroidal anti-inflammatory drugs with postoperative myocardial infarction after total joint replacement.

BACKGROUND AND OBJECTIVES: Use of nonsteroidal anti-inflammatory drug (NSAIDs) analgesics is controversial because of cardiovascular risk, but perioperative use may be advantageous for total joint replacement. Thus, we performed this single-center observational cohort study to determine any association between NSAID use and postoperative myocardial infarction (POMI). METHODS: All patient admissions undergoing total hip or knee replacement between March 3, 2009, and September 1, 2010, were identified. Nonsteroidal anti-inflammatory drug use was identified. Postoperative myocardial infarction was defined as troponin I level greater than 0.1 ng/mL. Propensity scores were calculated to adjust for bias of receiving NSAIDs and troponin measurements. Propensity scores and other covariates were used in logistic regression to determine the independent association of NSAID use with POMI. RESULTS: Of the 10,873 arthroplasty admissions, 1518 (14%) had serial troponins measured, and 97 had a POMI (0.9%). Incidence of POMI was 0.8% for the 9,831 who received NSAIDs and 1.8% for the 1,042 (10%) admitted patients who did not receive NSAIDs with a risk difference of -1% with 95% confidence interval (CI) of -0.2% to -1.9%. The adjusted odds ratio (0.95; 95% CI, 0.5-1.8) and relative risk (0.95; 95% CI, 0.5-1.8) indicated that NSAIDs were not significantly associated with the risk of POMI. Mean duration of NSAID use was 3 days. Length of stay (98 versus 115 hours) was significantly reduced in the NSAID group. CONCLUSIONS: Brief perioperative use of NSAIDs was not associated with increased risk for myocardial infarction after total hip and knee replacement; it may provide benefit in length of stay.

A prospective survey of patient-controlled epidural analgesia with bupivacaine and clonidine after total hip replacement: a pre- and postchange comparison with bupivacaine and hydromorphone in 1,000 patients.

BACKGROUND AND OBJECTIVES: Patient-controlled epidural analgesia (PCEA) with bupivacaine and hydromorphone provides high quality analgesia after orthopedic surgery but is associated with a frequent incidence of opioid-related side effects (15%-30%). Epidural clonidine has a different side effect profile, but there are no large surveys documenting its use. We performed this prospective survey to evaluate analgesia and the side effect profile in total hip replacement patients before and after a systematic change from PCEA with bupivacaine/hydromorphone to bupivacaine/clonidine. METHODS: Five hundred consecutive patients received PCEA with 0.06% bupivacaine and hydromorphone (10 mcg/mL) as a previously described prechange control group. The standard analgesic regimen was then systematically changed to 0.06% bupivacaine and clonidine (1 mcg/mL) without changing the PCEA settings or other aspects of perioperative care, and 500 consecutive patients were included as a postchange group. All data were prospectively entered and then abstracted from the electronic medical record. Data collection included daily verbal pain scores (VPS), pruritus, nausea, hypotension, need for IV fluid boluses, sedation, and respiratory depression. An online survey to measure staff satisfaction with the changeover was sent to all participating surgeons, anesthesiologists, physical therapists, and physician's assistants. RESULTS: Patient characteristics were similar between groups. Most patients received central neuraxial anesthesia (99%). The clonidine group had lower VPS at rest (2.3 vs 3.7, P<0.001 with 95% confidence interval [CI] of difference of 1.4 [1.1, 1.7]) on POD0. The incidence of nausea was 10%-11% for clonidine and 13%-15% for hydromorphone. The incidence of pruritus was less with clonidine (1 vs 10%, P<0.01 with 95% CI of difference of 9% [6, 12]). However, the incidence of hypotension (20 vs 11%, P<0.001 with 95% CI of differences 9% [5, 14]) and IV fluid boluses was more frequent with clonidine (36 vs 19%, P<0.001 with 95% CI of differences of 16 [11, 12]). Sixty-five percent of staff completed the online survey, and 70% considered clonidine worse than hydromorphone. CONCLUSION: The systematic changeover from epidural hydromorphone to clonidine produced mixed results without obvious superiority. The VPS at rest was reduced only on postoperative day 0; pruritus was reduced, but hypotension was increased. On the basis of medical staff preference, we discontinued the systematic change and returned to our previous standard solution of bupivacaine and hydromorphone for PCEA after total hip replacement.

Increased transforming growth factor-ß1 modulates glutamate receptor expression in the hippocampus.

Transforming growth factor-beta 1 (TGF-ß1) is an inflammation-related cytokine. Its expression in the brain increases under conditions of neurodegenerative diseases and injuries. Previous studies have shown that genomic alterations of TGF-ß1 expression in the brain cause neurodegenerative changes in aged mice. The present study revealed that increased production of TGF-ß1 in transgenic mice resulted in gliosis at young ages. In addition, the increased TGF-ß1 augmented the expression of some key subunits of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the hippocampus. Treatment of cultured hippocampal neurons with TGF-ß1 facilitated neurite outgrowth and enhanced glutamate-evoked currents. Together, these data suggest that increased TGF-ß1 alters ionotropic glutamate receptor expression and function in the hippocampus.