Wolfgang Zink

Local Anesthetic Myotoxicity

Skeletal muscle toxicity is a rare and uncommon side effect of local anesthetic drugs. Intramuscular injections of these agents regularly result in reversible myonecrosis. The extent of muscle damage is dose dependent and worsens with serial or continuous administration. All local anesthetic agents that have been examined are myotoxic, whereby procaine produces the least and bupivacaine the most severe muscle injury. The histologic pattern and the time course of skeletal muscle injury appear rather uniform: hypercontracted myofibrils become evident directly after injection, followed by lytic degeneration of striated muscle sarcoplasmic reticulum, and by myocyte edema and necrosis over the next 1 to 2 days. Myoblasts, basal laminae, and connective tissue elements remain intact in most cases, which permits muscular regeneration within 3 to 4 weeks. Subcellular pathomechanisms of local anesthetic myotoxicity are still not understood in detail. Increased intracellular Ca2+ levels appear to be the most important element in myocyte injury; since denervation, inhibition of sarcolemmal Na+ channels, and direct toxic effects on myofibrils have been excluded as sites of action. In this respect, the quantitative impact of further mitochondria-mediated pathways—at least in bupivacaine toxicity—is still to be established. Although experimental myotoxic effects are impressively intense and reproducible, only a few case reports of myotoxic complications in patients after local anesthetic administrations have been published. In particular, the occurence of clinically relevant myopathy and myonecrosis has been described after continuous peripheral blocks, infiltration of wound margins, trigger point injections, and peri- and retrobulbar blocks.

The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades.

Compared with bupivacaine, acute myotoxicity of ropivacaine is less severe. Thus, in this study we compared the long term myotoxic effects of both drugs in a clinically relevant setting. Femoral nerve catheters were inserted in anesthetized pigs, and either 20 mL of bupivacaine (5 mg/mL) or ropivacaine (7.5 mg/mL) was injected. Subsequently, bupivacaine (2.5 mg/mL) and ropivacaine (3.75 mg/mL) were continuously infused (8 mL/h) over 6 h. Control animals were treated with corresponding volumes of normal saline. After 7 and 28 days, respectively, muscle samples were dissected at the former injection sites, and histological patterns of muscle damage were blindly scored (0 = no damage to 3 = marked lesions/myonecrosis) and compared. No morphological tissue changes were detected in control animals. In the observed period, both local anesthetics induced morphologically identical patterns of calcific myonecrosis, formation of scar tissue, and a marked rate of fiber regeneration. However, bupivacaine’s effects were constantly more pronounced than those of ropivacaine. These data show that both drugs induce irreversible skeletal muscle damage in a clinically relevant model, and confirm the exceeding rate of myotoxicity of bupivacaine. However, the clinical impact of these long term myotoxic effects still has to be assessed.

The toxicity of local anesthetics: the place of ropivacaine and levobupivacaine.

Purpose of review Ropivacaine and levobupivacaine were developed after evidence of bupivacaine-related severe toxicity. Despite a comparable analgesic profile, quantitative differences become evident with regard to their specific rate of systemic toxicity. The present article provides a concise review of the toxic potencies of levobupivacaine and ropivacaine. Recent findings As lipophilicity is known to be a major determinant in local anesthetic toxicity, the clinical safety profile of ropivacaine seems to be more favorable than that of levobupivacaine. Experimental studies and case reports confirm this hypothesis, showing that ropivacaine is characterized by fewer (cardio) toxic effects and, most probably, a greater margin of safety. Both agents also may dose dependently damage neurons and skeletal muscle tissue at the injection site. Although their specific rate of neurotoxicity appears to be rather low, levobupivacaine is characterized by an outstanding myotoxic potential. Summary Compared with bupivacaine, both agents may be considered as ‘more well tolerated’ but not as ‘totally well tolerated’, as they are still capable of inducing systemic and local toxicity. However, ropivacaine seems to have the greatest margin of safety of all long-acting local anesthetics at present.

Differential effects of bupivacaine on intracellular Ca2+: Regulation potential mechanisms of its myotoxicity

BACKGROUND Bupivacaine produces skeletal muscle damage in clinical concentrations. It has been suggested that this may be caused by an increased intracellular level of [Ca2+]. Therefore, the aim of this study was to investigate direct intracellular effects of bupivacaine on Ca2+ release from the sarcoplasmic reticulum (SR), on Ca2+ uptake into the SR, and on Ca2+ sensitivity of the contractile proteins. METHODS Saponin skinned muscle fibers from the extensor digitorum longus muscle of BALB/c mice were examined according to a standardized procedure described previously. For the assessment of effects on Ca2+ uptake and release from the SR, bupivacaine was added to the loading solution and the release solution, respectively. Force transients and force decays were monitored, and the position of the curve relating relative isometric force free [Ca2+] was evaluated in the presence or absence of bupivacaine. RESULTS Bupivacaine induces Ca2+ release from the SR. In addition, the Ca2+ loading procedure is suppressed, resulting in smaller caffeine-induced force transients after loading in the presence of bupivacaine. The decay of caffeine-induced force transients is reduced by bupivacaine, and it also shifts [Ca2+]-force relation toward lower [Ca2+]. CONCLUSIONS These data reveal that bupivacaine does not only induce Ca2+ release from the SR, but also inhibits Ca2+ uptake by the SR, which is mainly regulated by SR Ca2+ adenosine triphosphatase activity. It also has a Ca2+ -sensitizing effect on the contractile proteins. These mechanisms result in increased intracellular [Ca2+] concentrations and may thus contribute to its pronounced skeletal muscle toxicity.

Lipid emulsion improves recovery from bupivacaine-induced cardiac arrest, but not from ropivacaine- or mepivacaine-induced cardiac arrest.

BACKGROUND: Cardiac toxicity significantly correlates with the lipophilicity of local anesthetics (LAs). Recently, the infusion of lipid emulsions has been shown to be a promising approach to treat LA-induced cardiac arrest. As the postulated mechanism of action, the so-called “lipid sink” effect may depend on the lipophilicity of LAs. In this study, we investigated whether lipid effects differ with regard to the administered LAs. METHODS: In the isolated rat heart, cardiac arrest was induced by administration of equipotent doses of bupivacaine, ropivacaine, and mepivacaine, respectively, followed by cardiac perfusion with or without lipid emulsion (0.25 mL · kg−1 · min−1). Subsequently, the times from the start of perfusion to return of first heart activity and to recovery of heart rate and rate-pressure product (to 90% of baseline values) were assessed. RESULTS: In all groups, lipid infusion had no effects on the time to the return of any cardiac activity. However, recovery times of heart rate and rate-pressure product (to 90% of baseline values) were significantly shorter with the administration of lipids in bupivacaine-induced cardiac toxicity, but not in ropivacaine- or mepivacaine-induced cardiac toxicity. CONCLUSIONS: These data show that the effects of lipid infusion on LA-induced cardiac arrest are strongly dependent on the administered LAs itself. We conclude that lipophilicity of LAs has a marked impact on the efficacy of lipid infusions to treat cardiac arrest induced by these drugs.

The cytotoxicity of bupivacaine, ropivacaine, and mepivacaine on human chondrocytes and cartilage.

BACKGROUND: Intraarticular injections of local anesthetics are frequently used as part of multimodal pain regimens. However, recent data suggest that local anesthetics affect chondrocyte viability. In this study, we assessed the chondrotoxic effects of mepivacaine, ropivacaine, and bupivacaine. We hypothesized that specific cytotoxic potencies directly correlate with analgesic potencies, and that cytotoxic effects in intact cartilage are different than in osteoarthritic tissue. METHODS: Human articular chondrocytes were exposed to equal and equipotent concentrations of bupivacaine, ropivacaine, and mepivacaine for 1 hour. Cell viability, apoptosis, and necrosis were determined at predefined time points using flow cytometry, live–dead staining, and caspase detection. Intact and osteoarthritic human cartilage explants were treated with equipotent concentrations of named drugs to determine cell viability applying fluorescence microscopy. RESULTS: Chondrotoxic effects increased from ropivacaine to mepivacaine to bupivacaine in a time-dependent and concentration-dependent manner. Compared with control, bupivacaine 0.5% decreased chondrocyte viability to 78% ± 9% (P = 0.0183) 1 hour and 16% ± 10% (P < 0.0001) 24 hours later, as determined by live–dead staining in monolayer cultures. Viability rates were reduced to 80% ± 7% (P = 0.0475) 1 hour and 80% ± 10% (P = 0.0095) 24 hours after treatment with ropivacaine 0.75%. After exposure to mepivacaine 2%, viable cells were scored 36% ± 6% (P < 0.0001) after 1 hour and 30% ± 11% (P < 0.0001) after 24 hours. Ropivacaine treatment was less chondrotoxic than bupivacaine (P = 0.0006) and mepivacaine exposure (P = 0.0059). Exposure to concentrations up to 0.25% of bupivacaine, 0.5% of ropivacaine, and 0.5% of mepivacaine did not reveal significant chondrotoxicity in flow cytometry. However, chondrotoxicity did not correlate with potency of local anesthetics. Immediate cell death was mainly due to necrosis followed by apoptosis. Cellular death rates were clearly higher in osteoarthritic compared with intact cartilage after bupivacaine, mepivacaine, and ropivacaine treatment in a decreasing order. CONCLUSION: Bupivacaine, ropivacaine, and mepivacaine are chondrotoxic in a time-dependent, concentration-dependent, and drug-dependent manner. Chondrotoxic and analgesic potencies do not directly correlate. Cellular death rates were higher in osteoarthritic compared with intact cartilage after local anesthetic treatment.

Benefit-Risk Assessment of Ropivacaine in the Management of Postoperative Pain

Ropivacaine is a long-acting amide-type local anaesthetic, released for clinical use in 1996. In comparison with bupivacaine, ropivacaine is equally effective for subcutaneous infiltration, epidural and peripheral nerve block for surgery, obstetric procedures and postoperative analgesia. Nevertheless, ropivacaine differs from bupivacaine in several aspects: firstly, it is marketed as a pure S(−)-enantiomer and not as a racemate, and secondly, its lipid solubility is markedly lower. These features have been suggested to significantly improve the safety profile of ropivacaine, and indeed, numerous studies have shown that ropivacaine has less cardiovascular and CNS toxicity than racemic bupivacaine in healthy volunteers.Extensive clinical data have demonstrated that epidural 0.2% ropivacaine is nearly identical to 0.2% bupivacaine with regard to onset, quality and duration of sensory blockade for initiation and maintenance of labour analgesia. Ropivacaine also provides effective pain relief after abdominal or orthopaedic surgery, especially when given in conjunction with opioids or other adjuvants. Nevertheless, epidurally administered ropivacaine causes significantly less motor blockade at low concentrations. Whether the greater degree of blockade of nerve fibres involved in pain transmission (Aδ− and C-fibres) than of those controlling motor function (Aα− and Aβ-fibres) is due to a lower relative potency compared with bupivacaine or whether other physicochemical properties or stereoselectivity are involved, is still a matter of intense debate.Recommended epidural doses for postoperative or labour pain are 20–40mg as bolus with 20–30mg as top-up dose, with an interval of ≥30 minutes. Alternatively, 0.2% ropivacaine can be given as continuous epidural infusion at a rate of 6–14 mL/h (lumbar route) or 4–10 mL/h (thoracic route).Preoperative or postoperative subcutaneous wound infiltration, during cholecystectomy or inguinal hernia repair, with ropivacaine 100–175mg has been shown to be more effective than placebo and as effective as bupivacaine in reducing wound pain, whereby the vasoconstrictive potency of ropivacaine may be involved. Similar results were found in peripheral blockades on upper and lower limbs. Ropivacaine shows an identical efficacy and potency to that of bupivacaine, with similar analgesic duration over hours using single shot or continuous catheter techniques.In summary, ropivacaine, a newer long-acting local anaesthetic, has an efficacy generally similar to that of the same dose of bupivacaine with regard to postoperative pain relief, but causes less motor blockade and stronger vasoconstriction at low concentrations. Despite a significantly better safety profile of the pure S(−)-isomer of ropivacaine, the increased cost of ropivacaine may presently limit its clinical utility in postoperative pain therapy.

Extracorporeal Circulatory Systems as a Bridge to Lung Transplantation at Remote Transplant Centers

BACKGROUND Worsening of lung function in patients awaiting lung transplantation can lead to ventilation-refractory hypoxemia or hypercapnia and respiratory acidosis. This report describes the successful use of different extracorporeal circulatory systems as a bridge to transplantation at remote centers. METHODS Between January 2003 and December 2009, we had 10 requests for implantation of extracorporeal circulatory systems (pumpless extracorporeal lung assist [PECLA] or extracorporeal membrane oxygenation [ECMO]) in patients decompensating on the waiting list to bridge to transplantation at three different transplant centers between 150 km and 570 km apart. Cannulas were inserted percutaneously with Seldingers technique. RESULTS The median patient age was 36 years (range, 24 to 53). Three patients were supported with PECLA and 7 with ECMO. The median duration of support was 23 days (range, 5 to 73). Two patients were initially provided with ECMO and then changed to PECLA after hemodynamic stabilization in the face of persisting pulmonary failure. Two patients died of multiorgan failure on ECMO while on the waiting list. One PECLA patient was successfully weaned and waiting for LTx. Before transplantation, 5 patients (4 PECLA and 1 ECMO) were successfully weaned from mechanical ventilation, and 3 PECLA patients were successfully weaned from the system. Seven patients were successfully bridged and transplanted. Five of 7 patients were discharged from the transplant centers. CONCLUSIONS This report suggests that implantation of extracorporeal circulatory systems is a safe method to bridge patients decompensating on the waiting list for transplantation. Support intervals of several weeks are possible.

Differential Effects of Bupivacaine and Ropivacaine Enantiomers on Intracellular Ca2+Regulation in Murine Skeletal Muscle Fibers

Background: Increased intracellular Ca2+ concentrations are considered to be a major pathomechanism in local anesthetic myotoxicity. Racemic bupivacaine and S-ropivacaine cause Ca2+ release from the sarcoplasmic reticulum of skeletal muscle fibers and simultaneously inhibit Ca2+ reuptake. Examining the optical isomers of both agents, the authors investigated stereoselective effects on muscular Ca2+ regulation to get a closer insight in subcellular mechanisms of local anesthetic myotoxicity. Methods: R- and S-enantiomers as well as racemic mixtures of both agents were tested in concentrations of 1, 5, 10, and 15 mm. Saponin-skinned muscle fibers from the extensor digitorum longus muscle of BALB/c mice were examined according to a standardized procedure. For the assessment of effects on Ca2+ uptake and release from the sarcoplasmic reticulum, agents were added to the loading solution and the release solution, respectively, and force and Ca2+ transients were monitored. Results: The effects of S-enantiomers on both Ca2+ release and reuptake were significantly more pronounced than those of racemic mixtures and R-enantiomers, respectively. In addition, the effects of racemates were markedly stronger than those of R-enantiomers. With regard to Ca2+ release, the effects of bupivacaine isomers were more pronounced than the isomers of ropivacaine. Conclusions: These data show that stereoselectivity is involved in alterations of intracellular Ca2+ regulation by bupivacaine and ropivacaine. S-enantiomers seem to be more potent than R-enantiomers, with intermediate effects of racemic mixtures. In addition, lipophilicity also seems to determine the extent of Ca2+ release by local anesthetics.

Late reoperations after repaired acute type A aortic dissection

OBJECTIVE Late complications can develop in patients after surgery for aortic type A dissection, mandating redo surgery on the ascending aorta and arch. METHODS From 2006 to 2010, 23 patients (aged 41-69 years) who had late complications related to previous aortic surgery for acute type A dissection underwent redo surgery. Initial surgery included ascending aorta replacement in all cases. RESULTS The main indications for reoperation were progressive enlargement of the false lumen of the aortic arch or descending aorta and suture line dehiscence in 10 patients each. All patients with progressive aneurysm formation in nonresected aortic segments had persistent dissection within the aortic arch since initial surgery. Suture line dehiscence led to a localized hematoma in most cases. Three patients presented with graft infection and extensive perigraft hematoma. The average time interval from the initial repair to the redo procedure was 71±56 months. Exchange of the formerly implanted Dacron graft in the ascending aorta was the most frequently used surgical procedure. Implantation of a valved conduit was deemed necessary in 4 cases, and isolated aortic valve replacement was necessary in 2 cases. A hybrid stent graft was used in 6 patients. All patients survived surgery, and 1 patient died of postoperative low output cardiac failure in hospital. Only 1 major stroke was noted. CONCLUSIONS Complex reoperations for repaired acute type A dissection can be performed safely. The concern for the reoperative risk should not dictate the operative strategy during the initial procedure in acute type A dissection.