Mantilla, Carlos B.

The diaphragm muscle (DIAm) is critically responsible for sustaining ventilation. Previously we showed in a commonly used model of spinal cord injury, unilateral spinal cord hemisection at C 2 (SH), that there are minimal changes to muscle fiber cross-sectional area (CSA) and fiber type distribution following 14 days of SH-induced ipsilateral DIAm inactivity. In the present study, effects of long-term SH-induced inactivity on DIAm fiber size and force were examined. We hypothesized that prolonged inactivity would not result in substantial DIAm atrophy or force loss. Adult rats were randomized to control or SH groups ( n = 34 total). Chronic bilateral DIAm electromyographic (EMG) activity was monitored during resting breathing. Minimal levels of spontaneous recovery of ipsilateral DIAm EMG activity were evident in 42% of SH rats (<25% of preinjury root mean square amplitude). Following 42 days of SH, DIAm specific force was reduced 39%. There was no difference in CSA for type I or IIa DIAm fibers in SH rats compared with age, weight-matched controls (classification based on myosin heavy chain isoform expression). Type IIx and/or IIb DIAm fibers displayed a modest 20% reduction in CSA ( P < 0.05). Overall, there were no differences in the distribution of fiber types or the contribution of each fiber type to the total DIAm CSA. These data indicate that reduced specific force following prolonged inactivity of the DIAm is associated with modest, fiber type selective adaptations in muscle fiber size and fiber type distribution.

Background Perioperative nerve injury (PNI) is a recognized complication of total hip arthroplasty (THA). Regional anesthesia (RA) techniques may increase the risk of neurologic injury. Using a retrospective cohort study, the authors tested the hypothesis that use of RA increases the risk for PNI after elective THA. Methods All adult patients who underwent elective THA at Mayo Clinic during a 20-yr period were included. The primary outcome was the presence of a new PNI within 3 months of surgery. Multivariable logistic regression was used to evaluate patient, surgical, and anesthetic risk factors for PNI. Results Of 12,998 patients undergoing THA, 93 experienced PNI (incidence = 0.72%; 95% CI 0.58-0.88%). PNI was not associated with type of anesthesia (OR = 0.72 for neuraxial-combined vs. general; 95% CI 0.46-1.14) or peripheral nerve blockade (OR = 0.65; 95% CI 0.34-1.21). The risk for PNI was associated with younger age (OR = 0.79 per 10-yr increase; 95% CI 0.69-0.90), female gender (OR = 1.72; 95% CI 1.12-2.64), longer operations (OR = 1.10 per 30-min increase; 95% CI 1.03-1.18) or posterior surgical approach (OR = 1.91 vs. anterior approach; 95% CI 1.22-2.99). Neurologic recovery was not influenced by the use of RA techniques in patients with PNI. Conclusions The risk for PNI after THA was not increased with the use of neuraxial anesthesia or peripheral nerve blockade. Neurologic recovery in patients who experienced PNI was not affected by the use of RA. These results support the use of RA techniques in patients undergoing elective THA given their known functional and clinical benefits.

Abstract—Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10−9to 10−5mol/L) and Ca2+ionophore (10−9to 10−6mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10−10to 10−5mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O2−) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn–superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10−5mol/L), reduced O2−production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [14C]l-Citrulline assay showed a decrease of Ca2+-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O2−and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O2−and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.

Background Perioperative nerve injury (PNI) is one of the most debilitating complications after total knee arthroplasty (TKA). Although regional anesthesia (RA) techniques reduce pain and improve functional outcomes after TKA, they may also contribute to PNI. The objective of this study was to test the hypothesis that PNI risk differs among patients according to RA use during TKA. Methods All patients aged at least 18 yr who underwent elective TKA from January 1988 to July 2007 were retrospectively identified. The primary outcome variable was the presence of a new PNI documented within 3 months of the procedural date. Age, sex, body mass index, type of procedure, tourniquet time, type of anesthesia, and use of peripheral nerve blockade were evaluated as potential risk factors for PNI using multivariable logistic regression. Results Ninety-seven cases of PNI were identified among 12,329 patients. Overall incidence of PNI was 0.79% (95% CI, 0.64-0.96%). PNI was not associated with peripheral nerve blockade (odds ratio [OR], 0.97) or type of anesthesia (OR, 1.10 [neuraxial vs. general]; OR, 1.82 [combined vs. general]). Risk for PNI decreased with age (OR, 0.68 [per decade]; P < 0.001) but increased with tourniquet time (OR, 1.28 [per 30-min increase]; P = 0.003) and bilateral procedures (OR, 2.51; P < 0.001). Patients with PNI who underwent peripheral nerve blockade were less likely to have complete neurologic recovery (OR, 0.37; P = 0.03). Conclusions Risk for PNI after TKA was unchanged by the use of RA techniques. This finding supports the notion that the known benefits of RA for patients undergoing TKA can be achieved without increasing risk of neurologic injury. However, in rare situations when PNI occurs, complete recovery may be less likely if it develops after peripheral nerve blockade.

Unilateral denervation (DNV) of rat diaphragm muscle increases protein synthesis at 3 days after DNV (DNV-3D) and degradation at DNV-5D, such that net protein breakdown is evident by DNV-5D. On the basis of existing models of protein balance, we examined DNV-induced changes in Akt, AMP-activated protein kinase (AMPK), and ERK½ activation, which can lead to increased protein synthesis via mammalian target of rapamycin (mTOR)/p70S6 kinase (p70S6K), glycogen synthase kinase-3β (GSK3β), or eukaryotic initiation factor 4E (eIF4E), and increased protein degradation via forkhead box protein O (FoxO). Protein phosphorylation was measured using Western analyses through DNV-5D. Akt phosphorylation decreased at 1 h and 6 h after DNV compared with sham despite decreased AMPK phosphorylation. Both Akt and AMPK phosphorylation returned to sham levels by DNV-1D. Phosphorylation of their downstream effector mTOR (Ser2481) did not change at any time point after DNV, and phosphorylated p70S6K and eIF4E-binding protein 1 (4EBP1) increased only by DNV-5D. In contrast, ERK½ phosphorylation and its downstream effector eIF4E increased 1.7-fold at DNV-1D and phosphorylated GSK3β increased 1.5-fold at DNV-3D ( P < 0.05 for both comparisons). Thus, following DNV there are differential effects on protein synthetic pathways with preferential activation of GSK3β and eIF4E over p70S6K. FoxO1 nuclear translocation occurred by DNV-1D, consistent with its role in increasing expression of atrogenes necessary for subsequent ubiquitin-proteasome activation evident by DNV-5D. On the basis of our results, increased protein synthesis following DNV is associated with changes in ERK½-dependent pathways, but protein degradation results from downregulation of Akt and nuclear translocation of FoxO1. No single trigger is responsible for protein balance following DNV. Protein balance in skeletal muscle depends on multiple synthetic/degradation pathways that should be studied in concert.

Cigarette smoke, which serves as a nicotine delivery vehicle in humans, produces profound changes in physiology. Experimental studies suggest that nicotine has analgesic properties. However, epidemiologic evidence shows that smoking is a risk factor for chronic pain. The complex relationship between smoking and pain not only is of scientific interest, but also has clinical relevance in the practice of anesthesiology and pain medicine. This review will examine current knowledge regarding how acute and chronic exposure to nicotine and cigarette smoke affects acute and chronic painful conditions. It will cover the relevant pharmacology of nicotine and other ligands at the nicotinic acetylcholine receptor as related to pain, explore the association of cigarette smoking with chronic painful conditions and potential mechanisms to explain this association, and examine clinical implications for the care of smokers with pain.

Cardiopulmonary bypass (CPB) is associated with significant postoperative morbidity, but its effects on the neuromuscular system are unclear. Recent studies indicate that even relatively short periods of mechanical ventilation result in significant neuromuscular effects. Carbon monoxide (CO) has gained recent attention as therapy to reduce the deleterious effects of CPB. We hypothesized that 1) CPB results in impaired neuromuscular transmission and reduced diaphragm force generation; and 2) CO treatment during CPB will mitigate these effects. In adult male Sprague-Dawley rats, diaphragm muscle-specific force and neuromuscular transmission properties were measured 90 min after weaning from normothermic CPB (1 h). During CPB, either low-dose inhaled CO (250 ppm) or air was administered. The short period of mechanical ventilation used in the present study (∼3 h) did not adversely affect diaphragm muscle contractile properties or neuromuscular transmission. CPB elicited a significant decrease in isometric diaphragm muscle-specific force compared with time-matched, mechanically ventilated rats (∼25% decline in both twitch and tetanic force). Diaphragm muscle fatigability to 40-Hz repetitive stimulation did not change significantly. Neuromuscular transmission failure during repetitive activation was 60 ± 2% in CPB animals compared with 76 ± 4% in mechanically ventilated rats ( P < 0.05). CO treatment during CPB abrogated the neuromuscular effects of CPB, such that diaphragm isometric twitch force and neuromuscular transmission were no longer significantly different from mechanically ventilated rats. Thus, CPB has important detrimental effects on diaphragm muscle contractility and neuromuscular transmission that are largely mitigated by CO treatment. Further studies are needed to ascertain the underlying mechanisms of CPB-induced neuromuscular dysfunction and to establish the potential role of CO therapy.

Background Ca2+ influx is a key component of neuronal intracellular Ca2+ ([Ca2+]i) regulation. The authors hypothesized that volatile anesthetic inhibition of neuronal activity is mediated by inhibition of Ca2+ influx via two major mechanisms: plasma membrane Na+-Ca2+ exchange (NCX) and the novel mechanism of Ca2+ influx triggered by endoplasmic reticulum Ca2+ depletion (store-operated Ca2+ channels [SOCCs]). Methods Differentiated rat pheochromocytoma cells loaded with the Ca2+ indicator fura-2 were Na+-loaded with 0 Ca2+, 145 mm Na+ Tyrode's and 5 microm cyclopiazonic acid plus 10 microm ryanodine (functionally isolating plasma membrane). Influx-mode NCX was rapidly reactivated by 0 Na+ and 2.5 mm Ca2+. The protocol was repeated in the presence of volatile anesthetics (0.5-1.5 minimum alveolar concentration [MAC] halothane, isoflurane, or sevoflurane) or other drugs to characterize NCX. To examine SOCCs, endoplasmic reticulum Ca2+ was depleted by cyclopiazonic acid in 0 extracellular Ca2+, and Ca2+ influx was triggered by rapid reintroduction of extracellular Ca2+. The protocol was repeated in the presence of anesthetics or other drugs to characterize SOCCs. Results Influx via NCX was not inhibited by voltage-gated Ca2+ channel blockers but was sensitive to NCX inhibitors. Halothane and isoflurane (0.5-1.5 MAC) significantly inhibited NCX (P < 0.05; paired comparisons), whereas sevoflurane at less than 1.5 MAC did not inhibit NCX. SOCC-mediated Ca2+ influx was insensitive to a variety of Ca2+ channel blockers but was inhibited by Ni2+. Such influx was sensitive only to halothane at greater than 1 MAC but not isoflurane or sevoflurane. Conclusions These data indicate that volatile anesthetics, especially halothane and isoflurane, interfere with neuronal [Ca2+]i regulation by inhibiting NCX but not SOCC-mediated Ca2+ influx (except high concentrations of halothane).

Background Prevention of thromboembolic complications after elective lower extremity arthroplasty has increasingly relied on routine thromboprophylaxis in all patients. Not all patients are at equal risk, however, and prophylaxis is not devoid of complications. The aim of this study was to examine the risk factors for clinically relevant pulmonary embolism and deep venous thrombosis after elective primary hip or knee arthroplasty in a large patient population. Methods During the 10-yr study period, 116 of 9,791 patients undergoing primary hip or knee arthroplasty at the authors' institution who experienced pulmonary embolism or deep venous thrombosis within 30 days of surgery were matched at a 1:1 ratio with patients undergoing the same surgery with the same surgeon who did not experience an adverse event. Medical records were reviewed, with data abstracted using a standardized data collection form. Results Increased body mass index (P = 0.031; odds ratio = 1.5 for each 5-kg/m2 increase) and American Society of Anesthesiologists physical status classification of 3 or greater (P = 0.005; odds ratio = 2.6) were found to independently increase the likelihood of pulmonary embolism or deep venous thrombosis. In addition, use of antithrombotic prophylaxis was found to decrease the likelihood of these thromboembolic events (P = 0.050; odds ratio = 0.2 for aspirin or subcutaneous heparin, and odds ratio = 0.4 for warfarin or low-molecular-weight heparin). Conclusions In patients undergoing primary elective lower extremity arthroplasty, obesity, poor American Society of Anesthesiologists physical status classification, and lack of thromboprophylaxis are independent risk factors for clinically relevant thromboembolic events.

Background There is limited information about the frequency of perioperative complications after elective primary orthopedic total hip and knee arthroplasty in contemporary practice. The purpose of this study was to determine the frequency of clinically relevant myocardial infarction, pulmonary embolism, deep venous thrombosis, and death within 30 days after elective primary hip or knee arthroplasty treated according to contemporary perioperative management. Methods The authors examined the medical records of consecutive patients undergoing hip or knee arthroplasty at their institution in a 10-yr period. Prospectively collected databases were used to identify patients with the diagnosis of myocardial infarction, pulmonary embolism, deep venous thrombosis, or death using strict validation criteria and diagnostic-certainty categories. Results A total of 10,244 patients underwent primary total hip or knee arthroplasty in the period of study. Of these, 224 patients had one or more adverse events (overall event rate: 2.2%; myocardial infarction: 0.4%; pulmonary embolism: 0.7%; deep venous thrombosis: 1.5%; death: 0.5%). Most adverse events (myocardial infarction, pulmonary embolism, and death) increased in frequency with older age, particularly for patients aged 70 yr or older. Myocardial infarction occurred more frequently in male patients. There were no differences in the overall event frequency between types of procedure. However, pulmonary embolism was highest in patients undergoing bilateral knee operations. Conclusions The overall frequency of serious complications within 30 days after primary total hip or knee arthroplasty with contemporary practice was 2.2%. Accurate knowledge of the perioperative risks associated with widely performed elective operations can be used to implement management strategies that may further improve patient outcomes and decrease cost.